Everything

IL-2

-Secreted by all T cells -Stimulates growth of helper, cytotoxic, and regulatory T cells, and NK cells.

Lupus glomerulonephritis

-Subepithelial deposits = under podocyte -Subendothelial deposit = wire loop -Deposits in the mesangial matrix -BM remodels around deposits - can see caps of ECM and spikes because lupus is around for a while

If graft rejection occurs, several agents can be used to control the rejection process, including: Corticosteroids: These drugs, such as prednisone and methylprednisolone, are commonly used to treat acute rejection. They work by suppressing the immune system and reducing inflammation, thereby preventing further damage to the transplanted organ. Calcineurin inhibitors: Examples include cyclosporine and tacrolimus. These drugs block the activity of calcineurin, a protein that is involved in the activation of T cells. By inhibiting T cell activation and proliferation, calcineurin inhibitors can prevent rejection. Antimetabolites: Azathioprine and mycophenolate mofetil are examples of antimetabolites that are used to suppress the immune system. They work by interfering with DNA synthesis in rapidly dividing cells, including immune cells, thereby inhibiting their proliferation and activity. Anti-lymphocyte antibodies: These are antibodies that target and destroy specific immune cells, such as T cells, B cells, or natural killer cells. Examples include anti-thymocyte globulin (ATG) and anti-CD3 antibodies. These agents can be used to treat acute rejection or to prevent rejection in high-risk patients. mTOR inhibitors: Sirolimus and everolimus are examples of mTOR inhibitors that are used to suppress the immune system. They work by blocking the activity of mTOR, a protein that regulates cell growth and proliferation. By inhibiting T cell activation and proliferation, mTOR inhibitors can prevent rejection.

If graft rejection occurs, which agents can be used to control this rejection? What is their mechanism of action?

Recombination activating genes (RAG)

two genes that are essential for the rearrangement of immunoglobulin and T-cell receptor genes in B cells and T cells, respectively. They encode the proteins RAG-1 and RAG-2, which form a protein complex that catalyzes the recombination process.

ITIMs

Immunoreceptor tyrosine based inactivating motifs. Intracellular proteins associated with Fc receptors that do not recruit activating signal transduction pathways and that are sometimes inhibitory.

CGD (Chronic Granulomatous Disease) is a rare genetic disorder characterized by defective synthesis of oxygen radicals in phagocytic cells, including granulocytes and monocytes. The absence or dysfunction of the NADPH oxidase enzyme complex, which is responsible for generating reactive oxygen species (ROS) necessary for intracellular killing of bacteria, makes these cells ineffective in destroying certain types of bacteria. As a result of this impaired immune response, CGD patients are prone to recurrent and severe bacterial and fungal infections that can lead to the formation of granulomas. Granulomas are compact aggregates of immune cells, such as macrophages, that are activated in response to persistent infection or inflammation. They typically form in tissues that are unable to effectively clear pathogens, leading to a chronic inflammatory response. In CGD patients, the inability of immune cells to properly clear bacterial infections can lead to the formation of granulomas in various tissues, including the lungs, liver, lymph nodes, and skin. These granulomas are composed of activated macrophages and other immune cells that attempt to contain the infection and prevent its spread, but are unable to fully eliminate the pathogens due to the defective synthesis of oxygen radicals.

In CGD patients, the intracellular killing of bacteria is impaired by defective synthesis of oxygen radicals. Explain the reason that this disease is clinically characterized by 'granulomas'.

Anergy is a state in which T cells are unable to respond to antigen stimulation due to a lack of signaling or a failure to generate an adequate response. Anergy can be induced by several different mechanisms, including a lack of co-stimulatory signals, the presence of inhibitory signals, or a lack of persistence of the antigenic stimulus. Anergic T cells are characterized by a lack of proliferation, cytokine production, and effector function. Anergy is an important mechanism for preventing autoimmune reactions and controlling self-reactivity. By inhibiting the response of self-reactive T cells, anergy helps to prevent autoimmune disease and maintain self-tolerance.

In addition to the ITIM-mediated inhibitory receptors, there is another molecular mechanism leading to termination of T cells response. Which mechanism?

HLA matching

In kidney transplants: substantial benefit if all the polymorphic HLA alleles are matched (both inherited alleles of HLA-A, -B, and DR) - Not done for transplants of liver, heart, and lungs

Mechanisms involved in both TCR and BCR diversity: Gene rearrangement, Random combination of gene segments, Nucleotide addition Mechanisms involved in TCR diversity but not BCR diversity: somatic mutation Mechanisms involved in BCR diversity but not TCR diversity: switch recombination

In theme 4, you mastered a number of molecular mechanisms that play a role in the creation of the diversity of the T cell repertoire. Which of them are also involved in the diversity of B cell receptors, and which are not?

In antigen presenting cells: B-cells, macrophages, and dendritic cells

In which cells are MHC Class II presented?

Between the pro-B cell and pre-B cell stages, there is a higher rate of cell loss compared to the transition from pre-B cell to immature B cell. This is because the gene rearrangement process that generates the immunoglobulin heavy chain gene is still ongoing during this phase, and the formation of a functional heavy chain gene is a critical checkpoint for the development of the B cell. If the rearrangement is not successful and results in a non-functional heavy chain gene, the B cell undergoes apoptosis (programmed cell death) to eliminate cells with non-functional antigen receptors. This mechanism ensures that only B cells with functional antigen receptors are allowed to mature and participate in the adaptive immune response. In contrast, during the transition from pre-B cell to immature B cell, the B cell has already formed a functional heavy chain gene and the pre-BCR, a temporary but crucial checkpoint in B cell development, has signaled to the cell to promote cell survival, growth, and differentiation. At this stage, the rate of cell loss is lower because the cell has already passed the critical checkpoint of gene rearrangement and is on its way to becoming a mature, antigen-specific B cell.

In which phases do successful (= productive) gene rearrangements occur during the development of B cells (fig. 8-13)? Explain why many more B cells are lost in the phase between pro-B cell and pre- B cell, then in the transition phase from pre-B cell to 'immature B cell'.

T cells can cause autoimmune diseases in several ways, including: Direct attack on self-tissue: T cells can recognize and attack self-tissues, leading to damage and inflammation. This is the case in diseases such as multiple sclerosis, where T cells attack the myelin sheath that surrounds nerve fibers in the central nervous system. Activation of other immune cells: T cells can activate other immune cells, such as B cells and macrophages, which can then attack self-tissues. This is the case in diseases such as rheumatoid arthritis, where T cells activate B cells to produce autoantibodies that attack the joints. Cross-reactivity with microbial antigens: T cells can sometimes mistakenly recognize self-tissue as foreign due to similarities between self-antigens and microbial antigens. This is called molecular mimicry and is thought to be involved in diseases such as Guillain-Barre syndrome, where T cells attack nerve cells due to cross-reactivity with a bacterial antigen. Failure of self-tolerance mechanisms: T cells undergo a process of education in the thymus to ensure that they do not attack self-tissues. However, in some cases, this process may fail, leading to the development of autoimmunity. This is thought to be the case in diseases such as type 1 diabetes, where T cells attack the insulin-producing cells in the pancreas.

In which ways can T cells cause autoimmune diseases?

subunit vaccines

use antigenic fragments to stimulate an immune response

Molecular mimicry: Microbial antigens can be structurally similar to self-antigens, leading to cross-reactivity between the microbial antigen and self-antigen. This can result in the activation of autoreactive immune cells and the development of autoimmune disease. Epitope spreading: In response to an initial infection, immune cells may recognize and attack self-antigens that are unrelated to the microbial antigen. This can lead to the activation of autoreactive immune cells and the development of autoimmune disease. Bystander activation: Inflammatory responses to microbial infections can cause damage to nearby tissues, releasing self-antigens and activating autoreactive immune cells. Superantigens: Some microbial toxins, such as those produced by Staphylococcus aureus, can activate a large number of T cells by binding to the T cell receptor and the major histocompatibility complex (MHC) class II molecules, leading to the activation of autoreactive T cells.

Indicate in which ways microorganisms can induce autoimmunity.

Similarities: Both viral infections and tumors can be recognized by the immune system as foreign or abnormal and can elicit an immune response. In both cases, the immune response involves the activation of effector cells, such as cytotoxic T cells, natural killer (NK) cells, and macrophages, that can target and eliminate infected or abnormal cells. The immune response against both viral infections and tumor cells can involve the production of cytokines, such as interferons, which can inhibit viral replication and promote immune cell activation. Both viral infections and tumors can evolve mechanisms to evade or suppress the immune response, leading to chronic infections or tumor growth. Differences: Viral infections are caused by infectious agents (viruses) that enter the body, whereas tumors arise from the patient's own cells that have undergone genetic mutations. The immune response against viral infections is typically driven by T cells specific to viral antigens presented by infected cells, while the immune response against tumor cells can involve both T cell and B cell responses. Tumor cells may have unique immunosuppressive properties that can limit immune cell activation and promote immune evasion, while viral infections may trigger more generalized immune activation. Viral infections can be prevented through vaccination or treated with antiviral drugs, whereas tumors are typically treated with surgery, radiation, chemotherapy, or immunotherapy.

Indicate the main similarities and differences between the immune response against viral infections and tumor cells

Gene duplication, Gene conversion, Recombination, Balancing selection

Indicate which genetic processes are supposed to contribute to MHC polymorphism.

DNA/RNA vaccines

uses DNA or RNA molecules to teach the immune system to target key viral proteins

CTLA-4 and PD-1

Inhibitory receptors Terminate responses of activated T cells Evolved to prevent immune responses against self antigens Involved in inhibitory responses to some tumors, chronic viral infections

MBL is a PAMP receptor, it is part of the complement system

Is MBL a PAMP receptor (PAMP-R)?

females, mostly in the child bearing age

Is autoimmunity more prevalent in males or females?

In X-linked hyper-IgM syndrome (HIGM-1), affected individuals have a genetic defect in the CD40L gene, which encodes for CD40 ligand, a protein that is expressed on activated T cells and is important for the interaction between T cells and B cells during the humoral immune response. In the absence of CD40L, B cells are unable to undergo isotype switching, and therefore, affected individuals with HIGM-1 are unable to produce antibodies of any class other than IgM. As a result, affected individuals with HIGM-1 produce large amounts of IgM but very little or no IgG, IgA or IgE. IgM is the first antibody produced during an immune response and has low affinity to the antigen. It cannot cross the placenta or enter tissues, but it can effectively neutralize pathogens in the blood and lymphatic system.

Isotype switching and the subsequent affinity maturation are important for the humoral adaptive response and for the generation of memory cells. In X-linked hyper-IgM syndrome (HIGM-1), large amounts of IgM are produced, while hardly any IgG is produced. How is this possible?

a. In LFA-1 deficiency, the expression of LFA-1 on granulocytes is impaired, which can have several consequences for the functioning of these cells. Granulocytes may be unable to properly migrate to sites of infection or inflammation, which can impair their ability to clear pathogens and contribute to chronic infections. The impaired interaction with other cells can also lead to decreased phagocytic activity, reduced production of antimicrobial substances, and impaired activation of other immune cells, all of which can further compromise the immune response. b. Yes, infected tissues in LFA-1 deficiency can contain pus. c. In LFA-1 deficiency, the number of granulocytes in the blood is typically normal or slightly elevated. This is because LFA-1 deficiency does not directly affect the production or release of granulocytes from the bone marrow, which is the organ responsible for the production of blood cells. Instead, LFA-1 deficiency affects the ability of granulocytes to function properly, including their ability to migrate to sites of infection and interact with other cells in the immune system.

LFA-1 deficiency is a rare, hereditary disorder, in which the expression of integrins on granulocytes is impaired. a. What is the consequence for the functioning of granulocytes? b. Will infected tissues contain pus? c. Will the number of granulocytes in the blood be increased or decreased?

In LFA-1 deficiency, the expression of LFA-1 on T cells is impaired, which can lead to several consequences for the functioning of these cells. T cells may be unable to properly migrate to sites of infection or inflammation, which can impair their ability to clear viral infections. In addition, the impaired interaction with APCs can lead to decreased activation of T cells and impaired production of cytokines, which are important signaling molecules that are necessary for effective antiviral immune responses. Furthermore, LFA-1 deficiency can lead to an increased susceptibility to bacterial infections, which can further impair the immune response to viral infections by activating immune suppressive pathways that can negatively affect T cell function.

LFA-1 is also found on T cells. It is involved in their migration and in their interaction with APCs. Thus, in LFA-1 deficiency the T cell immunity is also (slightly) distorted. With this in mind, can you explain why some patients with LFA-1 deficiency die from viral infections?

An antibody molecule, also known as an immunoglobulin (Ig), consists of four protein chains: two identical heavy (H) chains and two identical light (L) chains. Each chain has distinct functional domains that contribute to the overall structure and function of the antibody molecule. The functional elements of an antibody molecule include: Antigen-binding sites: these are located at the tips of the Y-shaped antibody molecule and contain unique amino acid sequences that allow the antibody to recognize and bind to specific antigens. Constant regions: these are found in the stem and lower regions of the antibody molecule and determine the antibody's isotype (e.g., IgG, IgA, IgM)

List the different protein chains and the functional elements of an antibody molecule.

Antibody-mediated diseases are caused by antibodies that directly target and damage specific cells or tissues, while immune complex-mediated diseases are caused by immune complexes that deposit in tissues and trigger inflammation and tissue damage. Antibody-mediated diseases typically involve a single antigen or a limited number of antigens, while immune complex-mediated diseases can involve a wide range of antigens and affect multiple organs and tissues. Antibody-mediated diseases are often associated with a humoral immune response, involving B cells and antibody production, while immune complex-mediated diseases can involve both humoral and cellular immune responses. Antibody-mediated diseases are typically treated with therapies that target antibody production or activity, such as immunosuppressants or monoclonal antibodies, while immune complex-mediated diseases are typically treated with therapies that reduce inflammation and immune activation, such as corticosteroids or immunosuppressants

List the main differences between antibody-mediated diseases and immune complex-mediated diseases.

Live attenuated vaccines

Live pathogen, but weakened. May cause minor illness in rare cases.

Effector memory T cells

Long-lived effector T cells that circulate in peripheral tissues and can respond rapidly to antigen encountered in tissues. They are already differentiated to a particular T-cell subtype, so they can respond immediately.

Autoimmunity

Loss of tolerance for self antigens

MHC class I molecules have a groove that can bind peptides that are usually 8-10 amino acids long. The groove is closed at both ends, which limits the length of peptides that can bind to it. In contrast, MHC class II molecules have a groove that is open at both ends, allowing longer peptides, typically 13-25 amino acids long, to bind. The open structure of the MHC class II groove allows for more flexibility in the size and shape of the peptide it can accommodate. In addition, the amino acid residues that line the groove of MHC class II molecules have a greater variety of chemical properties than those in MHC class I molecules. This increased chemical diversity in MHC class II molecules allows them to bind a wider range of peptide sequences, including longer peptides that may have more complex three-dimensional structures.

MHC II molecules can bind longer peptides than MHC I molecules due to their three-dimensional structure. Explain this.

IgM and IgD

Mature B cells express both _____ and ____.

Extracellular bacteria: Capsule production to avoid phagocytosis and complement-mediated lysis; Production of enzymes that degrade antibodies and complement factors; Modulation of surface proteins to avoid recognition by the immune system; Triggering of host cell apoptosis to evade immune cells Intracellular bacteria: Inhibition of phagosome-lysosome fusion to prevent bacterial degradation; Escape from the phagosome into the cytoplasm to avoid recognition by immune cell; Modification of phagosome contents to avoid degradation and recognition by immune cells; Production of proteins that interfere with antigen processing and presentation Viruses: Down regulation of MHC class I expression to evade recognition by cytotoxic T cells; Inhibition of apoptosis to prevent destruction of infected cells by immune cells; Modulation of cytokine production to avoid an effective immune response; Antigenic variation through mutation or recombination to avoid recognition by antibodies; Immune cell apoptosis to evade the immune response

Microorganisms have developed several mechanisms to escape from the immune response, this is called immune evasion. Summarize the mechanisms that are used by extracellular bacteria, intracellular bacteria and viruses

PAMPs

Molecules associated with groups of pathogens that are recognized by cells of the innate immune system.

They rely on cloning of B cells that make only 1 antibody. So you get a very specific antibody proliferation to target a part of the immune response for eg inflammation.

Monoclonal antibodies provide a fourth category of immunomodulating agents. Their mode of action is roughly based on two different mechanisms, which are they?

Similarities: Non-MHC restricted: All three cell types can recognize antigens without the need for presentation by major histocompatibility complex (MHC) molecules, although they may also respond to antigens presented by MHC molecules. Cytotoxicity: All three cell types can lyse target cells directly and have the ability to kill infected or abnormal cells. Immune regulation: All three cell types can participate in immune regulation and can modulate the activity of other immune cells. Differences: Development: NKT cells, NK cells, and T cells develop from different precursors and follow distinct developmental pathways. NKT cells are a hybrid of T cells and NK cells, while NK cells develop from a different line of precursors than T cells. T cell receptor (TCR) diversity: T cells have a highly diverse TCR repertoire, which allows them to recognize a wide range of antigens. NKT cells have a restricted TCR repertoire, which allows them to recognize specific antigens, while NK cells do not have TCRs. Activation signals: T cells are activated by antigens presented by MHC molecules, while NKT cells can be activated by both antigens presented by MHC molecules and by lipids presented by CD1d molecules. NK cells are activated by a variety of signals, including cytokines and signals from stress-induced ligands on target cells. Function: T cells are involved in the adaptive immune response, while NKT cells have a unique role in bridging the adaptive and innate immune responses. NK cells are a key component of the innate immune response.

NKT cells combine features from NK cells and T cells, but are also different. Explain the similarities and differences of NKT cells with NK cells and T cells, respectively.

1. Neutralization - antibodies can bind to pathogens or toxins, preventing them from interacting with host cells or tissues and neutralizing their activity. 2. Opsonization - antibodies can bind to pathogens, marking them for phagocytosis by cells of the innate immune system, such as macrophages and neutrophils. 3. Complement activation - antibodies can bind to antigens on the surface of pathogens and activate the complement system, which leads to the recruitment of inflammatory cells, lysis of pathogens, and phagocytosis. 4. Antibody-dependent cell-mediated cytotoxicity (ADCC) - antibodies can bind to infected or cancerous cells and recruit natural killer (NK) cells or other immune cells to lyse these cells, either by direct contact or by the release of cytotoxic granules.

Name 4 effector mechanisms of antibodies

The innate immune system protects the host during the time between microbe exposure and initial adaptive responses. The innate immune system recognizes microbes directly through pattern recognition receptors (PRRs), which are receptors specific for molecular components of micro-organisms that are not made by the host.

Name the main functions of the innate immune system

1. Dendritic cells (DCs) are specialized APCs that are highly efficient at capturing, processing, and presenting antigens to T cells. DCs can be found in many tissues throughout the body and play a critical role in initiating and regulating immune responses. 2. Macrophages are phagocytic cells that can engulf and digest foreign particles, including pathogens. After phagocytosis, macrophages can present antigen peptides to T cells via MHC class II molecules, thereby activating the T cell response. 3. B cells are best known for their role in antibody production, but they can also function as APCs to activate T cells. After encountering an antigen, B cells can internalize and process it before presenting antigen peptides on MHC class II molecules to T cells. This co-stimulation of T cells by B cells is important for the initiation of humoral immune responses.

Name three cell types that can function as APCs to activate naive CD4-positive T cells?

1. Surface markers: Immature dendritic cells express high levels of certain surface markers such as CD11c, CD80, and CD86, but low levels of other markers such as major histocompatibility complex (MHC) class II and CD40. In contrast, mature dendritic cells express high levels of MHC class II and CD40, as well as co-stimulatory molecules such as CD80 and CD86, which are required for optimal activation of T cells. 2. Antigen uptake and processing: Immature dendritic cells have a high capacity for antigen uptake through phagocytosis, macropinocytosis, and receptor-mediated endocytosis. They can capture antigens from the extracellular environment and transport them to the endosomal/lysosomal compartment for processing and presentation to T cells. Mature dendritic cells, on the other hand, have reduced capacity for antigen uptake but are more efficient in processing and presenting antigens to T cells. 3. Immune response modulation: Immature dendritic cells have the ability to induce peripheral tolerance and inhibit immune responses through various mechanisms, including the production of anti-inflammatory cytokines and the induction of regulatory T cells. In contrast, mature dendritic cells are potent inducers of immune responses and promote the activation and proliferation of T cells, leading to the generation of effector T cells that can eliminate the pathogen.

Name three differences between immature and mature dendritic cells.

Prevents, controls or eliminates invading microbes. Elimination of damaged cells and initiation of the process of tissue repair. Activation of the adaptive immune system

what are the functions of the innate immune system?

Local inflammation: ensures adhesion molecules are present and increased permeability in the vessel wall. Systemic: when it is present in the brain a fever occurs, when it is present in the liver is makes acute phase proteins, and when it is in the bone marrow it leads to leukocyte production

what are the local and systemic action of cytokines in inflammation?

Acute rejection

Occurs within first few months after transplantation with signs of organ failure; may occur months or years after immunosuppression has been terminated T lymphocytes respond to antigens in the graft tissue

CTLA-4. CTLA-4 binds B7 (CD80 or CD86) more avidly than does CD28 and delivers inhibitory signals to activated T-cells. This gives a contraction to the immune response

Once a T-cell is activated what is expressed on the surface?

IL-6 promotes systemic effects ("acute phase response" ofliver, including C-reactive protein- CRP; clinically used asan indication of inflammation)

what is the role of IL-6?

Inactivated vaccines

Pathogen has been completely killed. Frequently requires boosters.

polysaccharide encapsulated bacteria

Polysaccharide encapsulated bacteria are bacteria that produce a thick polysaccharide capsule surrounding their cell wall. This capsule acts as a protective layer that helps the bacteria evade the host immune system and resist phagocytosis.

In positive selection, the MHC complex brings a foreign antigen to the TCR. If it recognises it, it lives. In negative selection, the MHC brings a self antigen to the TCR, if it has high affinity with it it dies.

Positive and negative selection is caused by interactions between the same molecules (peptide- MHC complexes and TCRs of T cells). Explain the difference between positive and negative selection.

Severe Combined Immunodeficiency (SCID) is a genetic disorder characterized by a profound deficiency in both the cellular and humoral arms of the immune system. As a result, affected individuals are unable to mount effective immune responses against infectious agents. One of the reasons why SCID babies usually present with severe opportunistic infections, such as with cytomegalovirus (CMV), is that these infections can be caused by viruses that have evolved mechanisms to evade or suppress the host immune response. In the case of CMV, for example, the virus can interfere with the function of immune cells, particularly T cells, which are critical for controlling viral infections.

SCID babies usually present with severe opportunistic infections, such as with the cytomegalovirus (CMV). They rarely present with pneumococcal infections (for which the specific humoral immunity is important, see also question 7). Why is that?

TCRaB

which has a higher junctional diversity, Ig or TCRaB?

Nucleic acid-based vaccines

Segments of naked nucleic acid either DNA or RNA from an infectious agent

Despite the process of negative selection in the thymus, some self-reactive T cells can escape elimination and are released into circulation. These self-reactive T cells are prevented from causing autoimmune responses in the body by several mechanisms, including peripheral tolerance mechanisms such as anergy, suppression, and deletion. Self-reactive T cells that are not eliminated in the thymus can become functionally inactivated, a process known as anergy. In the absence of co-stimulatory signals, anergic T cells are unable to mount an immune response against self-antigens, and are rendered harmless. Regulatory T cells (Tregs) are a specialized subset of T cells that can suppress the activation of self-reactive T cells. Tregs act by releasing suppressive cytokines or by direct cell-to-cell contact with self-reactive T cells, leading to their functional inactivation. Self-reactive T cells that enter peripheral tissues can be eliminated by clonal deletion, a process that involves activation-induced cell death triggered by the recognition of self-antigens.

Some self-reactive T cells are not deleted in the thymus by negative selection. What happens with these cells?

NKT cells develop in the bone marrow. NKT cells express an invariant αβ TCR and share specific markers (CD56) with NK cells. The NKT cell TCR recognize lipids that are bound to CD1 (aM HC-like molecule)

State some characteristics of NKT cells.

γδ T cells are not MHC-restricted. γδ T cells constitute 5-10% of all T cells. γδ TCR recognize lipids and phosphorylated proteins. γδ T cells are present in epithelial layers

State some characteristics of γδ cells.

Transplantation patients are more prone to develop cancer, Immunodeficiencies (AIDS, aging) can lead to cancer development, Antibodies against cancer can be found in the blood, Infiltration of tumors by lymphocytes / macrophages, Spontaneous remissions

State some evidence of Cancer immunosurveillance

Type I-III are mediated by antibodies, while Type IV are mediated by cells. Type I is mediated by IgE, Type II and III is mediated by IgG. Type I is allergy since the reactivity is developed against foreign antigens which are normally not recognised by the immune system. Type II is different from Type III because the antigen is fixed, either on the cell surface or on an extracellular matrix. This antibody leads to the activation of complement of Fc receptors, phagocytosis of cell which is the removal of target antigens. If you have an antibody against the cell-surface receptor, this can lead to an altered cellular function. Type III is caused by the binding of an IgG antibody to a soluble antigen, that means it can circulate in the body. Therefore, there is much more systemic manifestation of this form of auto immunity. These antibody can activate Fc receptors on complement cells can activate complement and inflammation. Type IV is mediated by T-cells. These T-cells can either induce inflammation by producing cytokines or directly killing of the cells. An example of this is Type I diabetes.

State the differences in all the types of auto-immune diseases.

You have different gene segments, many encoding for the V, J, and G of the heavy and light chain. These are then bought together by RAG enzymes, which cut out any genes in the middle. Then random nucleotides are deleted or inserted to create lots of variation. This is also high risk that you get out of frame proteins or stop codons, which causes the cell to die.

Summarize Ig heavy and light chain recombination and expression

Adoptive cellular therapy

T lymphocytes are isolated from blood or tumor infiltrates of a patient, expanded by culture, and injected back to the same patient

Chronic rejection

T-cell, antibody mediated vascular damage. Months to years after. Irreversible.

Cellular Immunity: The cellular component of the immune system (e.g. NK cells, cytotoxic T cells) is capable to eliminate other cells of the body. Cells that will be eliminated include cells that are infected with a virus or bacterium and tumour cells. These affected cells are normally not very mobile. Therefore, they can be 'captured' easily by immune cells of the cellular component. Humoral Immunity: Smaller particles that move freely in body fluids, such as bacteria or viruses in the blood, can be eliminated more efficiently by soluble (humoral) components, such as antibodies, which are small and which can diffuse very easily to all parts of the body. After binding pathogens, the antibodies can get help from other cells that bind to the Fc-regions of the antibodies.

The adaptive immunity can be subdivided into the cellular ('cell - mediated') and the humoral immunity. Briefly describe the division of tasks between the cellular and humoral immunity.

Clonal deletion refers to a process in which developing T or B cells that have self-reactive or auto-reactive immune receptors are eliminated during the development process. This helps to prevent the development of potentially harmful immune responses against the body's own tissues and ensures the integrity and stability of the immune system.

The binding of self-antigens to immature B cells in the bone marrow leads to clonal deletion. What does the term 'deletion' mean in this case?

humoral response

The branch of acquired immunity that involves the activation of B cells and that leads to the production of antibodies, which defend against bacteria and viruses in body fluids.

The lectin pathway ends with lysis and the classic pathway ends with inflammation.

The classical pathway and lectin pathway use the same complement proteins (in chronological order: C4, C2 and C3). What is the functional difference between these two pathways?

Vaccines containing dead or inactivated viruses can induce a humoral immune response by stimulating B cells to produce virus-specific antibodies. These antibodies can neutralize the virus before it has a chance to enter and infect host cells, and can also facilitate the clearance of virus-infected cells by recruiting other immune cells such as phagocytes. Furthermore, vaccines containing dead viruses can also induce a cellular immune response, including the activation of virus-specific CD4+ T cells, which can help B cells to produce antibodies and CD8+ T cells, which can recognize and kill virus-infected cells.

The defense against intracellular infections requires an effective cellular immunity. However, we can induce humoral immunity that protects against the virus by vaccinating with dead (!) viruses. How is this possible?

Germinal center reaction

The development of B cells producing high-affinity isotype-switched antibodies and memory B cells.

junctional diversity

The heterogeneity that results from either the removal or addition of bases at the junction of DNA segments V, D, J

Cancer immunosurveillance

The immune system eradicates cancer cells throughout our life

affinity maturation

The increase in affinity for their specific antigen of the antibodies produced as an adaptive immune response progresses. This phenomenon is particularly prominent in secondary and subsequent immunizations.

After the T and B lymphocytes have matured in the thymus and bone marrow, they then travel to the lymph nodes and spleen where they remain until the immune system is activated. B cells are primarily clustered in structures called lymphoid follicles, whereas T cells are found mainly in the paracortex. The spleen is composed of white pulp and red pulp. The white pulp consists of T and B lymphocytes, which reside in the T-cell zone and the B-cell zone, respectively, rather than mixing together Parafollicular cortex (T-cell zone) Primary lymphoid follicle (B cell zone)

The lymph node consists of different compartments, concerning the localization of T cells and B cells. What is meant by this? Is this also true for the spleen?

Follicular B cells

The majority population of long-lived recirculating conventional B cells found in the blood, the spleen, and the lymph nodes. Also known as B-2 B cells.

The third signal in T cell activation is typically provided by cytokines, which are soluble proteins secreted by various cells of the immune system. Cytokines can bind to specific receptors on the surface of T cells, triggering intracellular signaling pathways that influence T cell proliferation, differentiation, and effector function. The nature of the cytokine signals received by a T cell can strongly influence the fate of the cell, determining whether it becomes an effector cell capable of mounting an immune response, or a regulatory cell that helps to dampen or resolve an immune response.

The membrane-bound co-stimulation molecules are largely responsible for signal 2 in T cell activation. What is the 3rd signal that is involved in the activation and differentiation of T cells?

herd immunity

The resistance of a group to an attack by a disease to which a large proportion of the members of the group are immune

adaptive immune response

The response of antigen-specific B and T lymphocytes to antigen, including the development of immunological memory.

bivalent interaction

There are 2 antigens bound (both arms are bound). This means there is a low affinity (it won't bind more antigen) and a high avidity

conjugate vaccines

These vaccines work by linking or conjugating a piece of the bacterial capsule polysaccharide to a carrier protein, such as diphtheria toxoid or tetanus toxoid. The conjugation of the polysaccharide to the protein enhances the immune response to the polysaccharide, making it more effective in inducing a protective immune response against the encapsulated bacteria.

First, anti-inflammatory IDS which target the innate and adaptive immune response, dampening both. Anti-metabolite ISD target proliferation of all cells. Inhibitors of T cells target the different activation signals of T cells

Three major classes of immunosuppressants are used in organ transplantation to prevent rejection: corticosteroids, cytotoxic drugs (such as mycophenolate and azathioprine, which is not mentioned in Abbas) and other agents, such as cyclosporin and rapamycin. At which level do these three types of immunosuppressive agents exert their effects (cell proliferation, cell communication or intracellular signal transduction)?

Anti-GBM glomerulonephritis

Type II Hypersensitivity (Antigen Mediated AND Complement Dependent) Formation of antibodies against the glomerular basement membrane Attraction of Neutrophils and a release of Phagocytic cells; these can't do the job so they release enzymes Enzymes destroy the basement membrane (GBM), epithelial cells, and podocytes Final result is vasculitis

Live attenuated vaccines

Weakened pathogens [mimic the natural behavior]; modify the pathogen so it is unable to cause disease

ITAMs and ITIMs are molecular signaling motifs found on certain proteins in the immune system that play important roles in regulating immune cell activation.ITAM stands for "Immunoreceptor Tyrosine-based Activation Motif", while ITIM stands for "Immunoreceptor Tyrosine-based Inhibitory Motif". Both motifs are short stretches of amino acid residues in the cytoplasmic tail of certain receptor proteins on immune cells, such as B cells, T cells, and natural killer cells.ITAMs and ITIMs are important regulatory motifs that help to balance the activation and inhibition of immune cells, ensuring that immune responses are appropriately targeted and controlled.

What are ITAMs and ITIMs?

Follicular helper T (Tfh) cells are specialized providers of T cell help to B cells, and are essential for germinal center formation, affinity maturation, and the development of most high affinity antibodies and memory B cells. Follicular dendritic cells (FDCs) are a specialized type of antigen-presenting dendritic cells that are largely restricted to lymphoid follicles. They form dense three-dimensional meshwork patterns within benign follicles, which maintain the follicular architecture.

What are TFH cells and what is their function? And FDCs?

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. TLR recognition of microbial ligands results in the activation of several signaling pathways and ultimately transcription factors, which induce the expression of genes whose products are important for inflammatory and antiviral responses.

What are Toll-like receptors, i.e. what is their function?

Acute phase proteins (APPs) are a group of proteins that are produced by the liver in response to inflammation or infection. They are part of the acute phase response, which is a rapid and non-specific reaction of the body to tissue injury, infection, or other types of stress.

What are acute phase proteins?

PAMPs :Shared by a large group of pathogens (general patterns & non-specific). Conserved and not subject to antigenic Variability. Pathogens cannot change them because they are Essential for survival or pathogenicity. Distinct from self-antigens

What are important characteristics of PAMPs

It produces IgA protease. It cuts part of the IgA and makes sure the IgA is bound to the bacteria. However, it is not able to be recognised by the immune system. It can also produce pilling with variable V and G region on exterior. Decoy membrane blobs, so the immune system is not focused on the bacterium but the blobs.

What are some examples of bacteria tricking the immune system?

Phagocytes (neutrophils, macrophages and dendritic cells) and Natural Killer cells

What are some examples of patrolling cells?

HLA matching: match the HLA molecules between donor and recipient; Screening for anti HLA-antibodies: Anti-HLA antibodies are antibodies that target human leukocyte antigens (HLA) and are commonly tested in transplant recipients to assess the risk of rejection; cross-match: This involves testing the patient's serum against the donor's HLA antigens to see if there is a strong antibody response. If the crossmatch is positive, the donor organ may not be suitable for transplantation; immunosuppression

What are some examples to prevent rejection?

Mutations in DNA, Uncontrolled proliferation, Environment, Nutrition, Viruses, Immunosuppression

What are the causes of cancer?

Innate: cellular -> macrophages and granulocytes; humoral -> complement and cytokines Adaptive: cellular -> T lymphocytes and B lymphocytes; humoral -> antibodies and cytokines

What are the cellular and humeral components for both the innate and adaptive immune system?

Two types: class I and class II. Different genes in each class (class I =HLA-A/B/C and class II = DR/DQ/DP). Extremely polymorphic in the population

What are the characteristics of MHC?

Shared by a large group of pathogens (general patterns & non-specific). Conserved and not subject to antigenic variability. Pathogens cannot change them because they are essential for the survival or pathogenicity. Distinct from self-antigens

What are the characteristics of PAMPs?

Small MW proteins. De-novo synthesized during the inflammatory response. Effect through specific receptors. Redundant (two or more genes perform the same biochemical function). Pleiotropic (one gene producing more than one effect). Cytokines broad activation; chemokines migration. Dinstinction: pro - and anti-inflammatory cytokines. Dinstinction: Inflammatory and homeostatic chemokine

What are the characteristics of cytokines?

Immune evasion: Prevents fusion phagosome/lysosome and Chronic T-cell and macrophage activation (granulomas). Latent infections: Weak immune system: reactivation

What are the consequences of Mycobacterium tuberculosis?

Additional mechanisms to generate BCR receptor diversity. Selection processes differ for B/T cells. Antigen recognition is different for BCR and TCR. Life span in peripheral organs is different for B/T cells. Signal 2 for full activation is different for B/T cells

What are the differences between B and T cells?

There are organ specific autoimmunity that are localised in specific organs and there are systemic auto-immunity which are due to the organ being wide distributed.

What are the different types of auto-immunity?

life long therapy, increased risk of opportunistic infection, increased risk of malignancies

What are the disadvantages of immunosuppression?

1. Th1 and CTLs: CXCR3, CCR5 → sites of innate immune reaction 2. Th2: CCR3, CCR4, CCR8 → sites of helminth infection or allergic reactions 3. Th17: CCR6 → sites of bacterial and fungal infection

What are the distinct homing phenotypes of Th1, Th2, and Th17?

1) Phagocyte adheres to pathogens or debris. 2) Phagocyte forms pseudopods that eventually engulf the particles forming a phagosome. 3) Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. 4) Lysosomal enzymes digest the particles, leaving a residual body. 5) Exocytosis of the vesicle removes indigestible and residual material.

What are the events of phagocytosis?

1st is a non-specific external barrier such as our skin and mucous membranes. 2nd is the innate immune system which is non-specific patrols that consist of different types of cells and proteins

What are the first and second lines of defence in our body?

release perforin protein, insert into membrane of target cell, forms pore allowing fluid to flow in & out of cell, cell ruptures (lysis), apoptosis

What are the function of natural killer cells?

Stimulate innate response via cytokine production (IFN-gamma /macrophages, IL-17/neutrophils). Stimulate antibody production by B-cells via cytokine production (extracellular). Kill infected cells (intracellular). Control autoimmune responses

What are the functions of the T-cells?

While the innate immune response is immediate, the adaptive immune response is not. However, the effect of the adaptive immune response is long-lasting, highly specific, and is sustained long-term by memory T cells.

What are the main differences between the innate immunity and the adaptive immunity?

Clonal deletion by apoptosis: if the cell is removed it will not be activated wrong. Functional deletion by anergy: the cell still exists but becomes blind. Suppression by regulatory T cells: suppress auto reactive diseases. Receptor editing (B cells): if you have a B cell receptor that is auto reactive the light chain of the receptor has the possibility to get more arrangements and become non-self. Sequestration of auto-antigens: there are certain boxes in out body that can't be reached, but if these boxes are open then it can be

What are the mechanisms for generation of self-tolerance?

Antigenic variation: Influenza (Constant mutations), HIV Inhibit class I MHC presentation: Blocking pathways antigen presentation Production inhibitory molecules: IL-10 (Epstein Barr Virus) + Competitive antagonists for cytokines Latent infections: Virus not active and not detected (Herpes simplex)

What are the mechanisms immune evasion viruses

hemodialysis and peritoneal dialysis and renal transplantation

What are the renal replacement therapies?

1. Presentation of the antigen to T cells 2. Selective activation of antigen-specific T cells 3. Avoidance of T cell activation in harmless conditions 4. Activation of the correct type of effector cell 5. Generation of sufficient numbers of effector cells 6. Homing of effector cells to the site of infection 7. Contraction of the T cell response 8. Generation of memory

What are the requirements for an adequate T cell response?

Both precursor stem cells for B and T cells originate from the bone marrow (but T cells finally develop in the Thymus). Generation of BCR/TCR diversity via combinatorial and junctional diversity. The majority of developing B/T cells go into apoptosis. Both B/T cells undergo selection processes. For full activation both B and T cells require 2 signals

What are the similarities between B and T cells?

Patrolling cells, innate immune receptors, proteins

What are the three components of the innate immune system?

CDR1, CDR2, CDR3 (located both in the heavy and light chain)

What are the three regions within the variable region?

recognition phase, induction phase, effector phase

What are the three stages of immune response?

Anti-inflammatory drugs (e.g. prednison), Anti-metabolites (e.g. Azathioprine/MMF), Inhibitors of T-cell signaling (cyclosporin / rapamycin)

What are the three types of immunosuppressive drugs?

induction of intracellular signalling and adhesion of one cell to another cell, or to the extracellular matrix

What are the two major functions of cell surface receptors?

The help between the T-cell and the macrophage goes through two pathways. One is done with membrane molecules on both cells, and the second way is through soluble molecules.

What are the two pathways that T-cell and macrophages interact?

HLA can be presented by donor cells which are present in the graft and leave the graft to enter the circulation of the recipient. These have foreign HLA molecules directly on the surface. Or HLA antigen can be picked up by recipient antigen presenting cells and be presented in the groove of the MHC molecules (indirect presentation)

What are the two ways foreign antigens can present?

immunosuppressive drugs, "biologicals (immunomodulatory drugs)"

What are the two ways to induce farmacotherapy?

complement factors and toll-like receptors

What are two examples of signals that can help to enhance B-cell activation?

dendritic cells

What cell activates the innate to the adaptive immune system?

It depends on which signal arrives first. If the are to develop into a γδ T cell, then it will shut off the B-chain gene rearrangement and commit to the γδ lineage and vice versa. If it commits to γδ, then that cell will mature and migrate to various epithelial sites in periphery. While if it commits to αβ, then rearrangement of the TCRa locus deletes the entire δ locus and creates mature αβ TCR.

What determines whether the cell will becoming a γδ (gamma-delta) T cell or αβ T cell?

Cell surface TLRs recognise bacterial cell wall structures. Intracellular TLRs recognise pathogen nucleic acids. Location likely aids discrimination of viral vs. host nucleic acids.

What do intra and extra cellular TLRs recognise?

Leaky to fluid (influx of plasma; containing antibodies, complement components, etc.). Sticky for leukocytes, leading to influx of first neutrophils, later monocytes, lymphocytes

What do the TNF and Il-1 signal do to endothelial cells?

NK cells, T-cells, IFN-gamma

What do we need to clear bacteria that profligate intracellular?

phagocytes, complement, antibodies, b-cells, CD4 T-cells

What do we need to clear bacteria that proliferate in the extracellular environment?

Phagocytes, Th17 (Th1) cells

What do we need to clear fungal infections?

cell-mediates immunity, Th2 cells, IgE, eosinophils

What do we need to clear infections with parasites?

Type 1 interferons, NK cells, T-cells, antibodies

What do we need to clear viral infections?

A Fab fragment is a portion of an antibody molecule that contains one complete antigen-binding site. Fab fragments retain the ability to specifically bind to antigens, but they lack the effector functions associated with the constant regions of the intact antibody molecule.

What is a Fab fragment?

Antigen recognition: γδ T cells recognize antigens differently from αβ T cells. γδ T cells can recognize antigens directly without the need for presentation by major histocompatibility complex (MHC) molecules, while αβ T cells recognize antigens presented by MHC molecules. Tissue distribution: γδ T cells are found primarily in tissues, such as the skin, mucosal membranes, and epithelium, while αβ T cells are more abundant in peripheral blood and lymphoid organs. Function: γδ T cells have a distinct role in immune surveillance, particularly in the detection and response to intracellular pathogens and cancer cells. αβ T cells, on the other hand, have a broader role in immune defense and are involved in the response to extracellular pathogens Development: γδ T cells develop in a different manner compared to αβ T cells. γδ T cells differentiate from a distinct pool of T cell progenitors, while αβ T cells differentiate from a common T cell progenitor.

What is a γδ (gamma-delta) T cell and how does it differ from conventional αβ T cells

Alloreactivity refers to the immune response that occurs when immune cells recognize and respond to antigens that are from a genetically different individual of the same species. This response is mediated by the recognition of the major histocompatibility complex (MHC) molecules, which are highly polymorphic and vary between individuals. The magnitude of alloreactivity can be explained by several factors, including the degree of genetic mismatch between the donor and recipient, the type of transplant (e.g., solid organ, bone marrow), the immunosuppressive regimen used, and the overall health of the recipient. The greater the genetic disparity between the donor and recipient, the stronger the alloreactive response is likely to be.

What is alloreactivity and how can its magnitude be explained?

An adjuvant is a substance that is added to a vaccine to enhance the body's immune response to the vaccine. Adjuvants work by stimulating the immune system in a way that enhances the body's ability to recognize and respond to the antigens present in the vaccine. This can result in a stronger and longer-lasting immune response, leading to better protection against the targeted disease.

What is an adjuvant

Isotype switching, also known as class switching, is a process that occurs in activated B cells during the maturation of the immune response. During this process, the B cells change the type of antibody isotype they produce from IgM to another isotype, such as IgG, IgA, or IgE. The process of isotype switching involves a rearrangement of the DNA segments that encode the constant regions of the antibody heavy chain genes. This rearrangement allows the B cell to produce an antibody with a different constant region while keeping the same variable region, which determines the specificity of the antibody.

What is isotype switching? How does this affect the specificity of the antibody that is produced?

Hormonal factors, Genetic factors, Environmental factors, Infections

What is loss of tolerance and auto-immunity are associated with?

Activation-induced T cell apoptosis, also known as activation-induced cell death (AICD), is a process of programmed cell death that occurs in T cells following activation. This process is triggered when T cells receive a strong or prolonged activation signal through their T cell receptors (TCRs). During AICD, T cells undergo a series of biochemical and morphological changes that lead to their death. The process is mediated by the upregulation of pro-apoptotic proteins, such as Fas ligand (FasL) and tumor necrosis factor (TNF), and the downregulation of anti-apoptotic proteins, such as Bcl-2.

What is meant by 'activation-induced' T cell apoptosis ?

alternative macrophage activation represents a complex and dynamic process that can have both beneficial and detrimental effects depending on the context

What is meant by 'alternative macrophage activation'?

Lymphocyte repertoires may be defined as sets of clones or phenotypic subsets. Lymphocytes generate the immune repertoire by recombining the genes encoding immunoglobulins and T cell receptors through V(D)J recombination. Although there are only a few of these genes, all their possible combinations can result in a wide variety of immune repertoire proteins.

What is meant by 'lymphocyte repertoire'? How is this repertoire created?

A set of circulating and cell surface proteins that act in a cascade to 1) opsonize microbes 2) promote recruitment of phagocytes 3) to attack and kill extracellular pathogens

What is the complement system?

When a T cell recognizes an antigen without co-stimulation, it will not be fully activated and may become unresponsive or even undergo cell death

What is the consequence of antigen recognition by a T cell in the absence of co-stimulation?

When in the secondary lymph nodes, with B-cells the antigen is fully intact so instead of the T-cell where you have processed antigens. Therefore, B-cells recognise antigens by whole structures.

What is the difference between antigen interaction between T and B cells in the lymph node?

Central tolerance induction occurs during T cell development in the thymus gland. In the thymus, T cells undergo a process of selection where they are tested for reactivity against self-antigens. T cells that recognize self-antigens too strongly are eliminated, a process known as negative selection. This ensures that only T cells that are capable of recognizing foreign antigens are released into circulation. Peripheral tolerance induction, on the other hand, occurs in peripheral tissues outside of the thymus after T cells have matured and left the thymus. This mechanism is responsible for eliminating or suppressing self-reactive T cells that have escaped central tolerance. It can occur through several mechanisms, such as clonal deletion, anergy, or suppression by regulatory T cells.

What is the difference between central and peripheral T cell tolerance induction?

Live-attenuated vaccines contain a weakened form of the virus that can still replicate but is less virulent, meaning it causes less severe disease. When the vaccine is administered, the weakened virus replicates in the body and triggers an immune response, which leads to the production of specific antibodies that provide long-lasting protection against the virus. Because the vaccine contains a live virus, it can produce a stronger and longer-lasting immune response than an inactivated vaccine. Inactivated vaccines, on the other hand, are made from viruses that have been killed or inactivated so they cannot replicate in the body. The virus is chemically treated or heated to destroy its ability to cause disease, but it still contains antigens that can stimulate an immune response. When the vaccine is administered, the immune system recognizes these antigens and produces antibodies to protect against future infection with the live virus. Inactivated vaccines tend to produce a weaker immune response than live-attenuated vaccines and may require booster doses to maintain protection over time.

What is the difference in the response to vaccination with a live-attenuated (= weakened) virus and that of vaccination with an inactivated (= killed) virus?

The binding of IFN-γ to its receptor on macrophages can enhance the ability of these cells to fight off infections, by increasing their phagocytic and killing activity, promoting antigen presentation, and stimulating the production of antimicrobial molecules and pro-inflammatory cytokines.

What is the effect of binding of IFN-γ ('Interferon-gamma') to the IFN-γreceptor on macrophages?

the final result of the activation of B cells is the production of antibodies that are specific for the antigen that initially activated the B cell, providing a targeted and specific immune response against invading pathogens.

What is the final result of the activation of B cells?

When T cells are activated, they undergo a series of changes that allow them to become fully functional immune cells. Activated T cells divide rapidly, produce cytokines, and express different surface markers, such as CD25 and CD69. They also undergo a process known as clonal expansion, in which the activated T cells produce many daughter cells that are specific for the same antigen. Once activated, T cells can perform different functions, depending on the type of T cell and the nature of the antigen. For example, CD4+ T cells can help activate and coordinate other immune cells, such as B cells and macrophages, to help clear the infection. CD8+ T cells can directly kill infected cells.

What is the final result of the activation of T cells?

The first intracellular step in the initiation of signal transduction, after a B cell has been activated by the binding of an antigen to its B cell receptor (BCR), is the phosphorylation of the tyrosine residues in the immunoreceptor tyrosine-based activation motifs (ITAMs) located on the CD79a and CD79b chains of the BCR.

What is the first intracellular step in the initiation of signal transduction, after the B cell has been activated?

Fc receptors (FcR) on B cells are membrane-bound receptors that bind to the Fc region of antibodies. The function of Fc receptors on B cells is to capture and internalize immune complexes formed by antibodies bound to their cognate antigen. Binding of the ligand (i.e., immune complex) to the Fc receptor on B cells leads to the internalization of the antigen-antibody complex into the B cell, which then presents the processed antigenic peptides on its surface in association with major histocompatibility complex (MHC) molecules to interact with T helper cells. This presentation of antigenic peptides to T helper cells is a critical step in initiating the humoral immune response, as it leads to T cell activation, proliferation, and differentiation into helper T cells that can provide help to B cells to produce high-affinity antibodies.

What is the function of Fc receptors on B cells? What happens after binding of the ligand to this receptor?

Natural Killer (NK) cells are a type of lymphocyte that play an important role in the immune system's defense against cancer and viral infections. NK cells are able to recognize and kill abnormal cells, including tumor cells and virally-infected cells, without the need for prior activation or recognition of specific antigens.

What is the function of NK cells?

suppress or active innate and adaptive immune responses

What is the function of NKT cells?

TLR recognition of microbial ligands results in the activation of several signaling pathways and ultimately transcription factors, which induce the expression of genes whose products are import for inflammatory and antiviral responses

What is the function of TLR?

to recognise and destroy transformed cells before they grow into tumours, to kill tumours after they are formed

What is the function of cancer immunosurveillance?

Clonal selection is used during negative selection to destroy lymphocytes that may be able to bind with self antigens. Clonal selection is the theory that specific antigen receptors exist on lymphocytes before they are presented with an antigen due to random mutations during initial maturation and proliferation. Clonal selection is thought to cause mutations of antigen-binding affinity in memory cells during clonal expansion so that memory cells have greatly increased antigen-binding affinity than the effector cells during the first response.

What is the function of clonal selection for the antigen-specific immune response?

helper and cytotoxic functions (innate immunity)

What is the function of γT lymphocytes cells?

The hallmark of the induction of anergy in T cells is the functional inactivation of the T cell response to its target antigen, even in the presence of co-stimulatory signals. There are several mechanisms of T cell anergy that have been described, including: Lack of co-stimulation: T cell activation requires both antigen recognition and co-stimulation through the engagement of co-stimulatory molecules such as CD28. If a T cell recognizes its target antigen in the absence of co-stimulation, it can become anergized. Inhibition of signaling pathways: Anergy can also result from inhibition of signaling pathways downstream of the T cell receptor (TCR). For example, the activation of the phosphatase calcineurin can inhibit the signaling pathways necessary for T cell activation, leading to anergy. TCR desensitization: Prolonged or repeated exposure to antigen can lead to TCR desensitization, which can result in T cell anergy. Regulatory T cell suppression: Regulatory T cells (Tregs) can suppress the activation of self-reactive T cells and induce anergy through the release of suppressive cytokines or through direct cell-to-cell contact. Cytokine-mediated anergy: Certain cytokines, such as interleukin-10 (IL-10), can induce T cell anergy through the inhibition of T cell activation signaling pathways. T cell exhaustion: Prolonged antigen exposure can also result in T cell exhaustion, which is characterized by decreased cytokine production and reduced cytotoxic activity.

What is the hallmark of the induction of anergy in T cells? What are the mechanisms of T cell anergy?

The immunological synapse is the specialized structure that forms between antigen-presenting cells (APCs) and T cells during the process of T cell activation. The immunological synapse is composed of two main regions: the central supramolecular activation cluster (cSMAC) and the peripheral supramolecular activation cluster (pSMAC). The cSMAC is a highly organized region in the center of the synapse where T cell receptor (TCR) complexes and other signaling molecules are concentrated. This region is characterized by the clustering of TCR complexes, CD3 molecules, and the co-receptor CD4 or CD8. The cSMAC provides the platform for T cell signaling and activation. The pSMAC is a more diffuse region that surrounds the cSMAC and is composed of other cell surface molecules, including adhesion molecules, cytokine receptors, and other signaling molecules. The pSMAC plays a role in maintaining contact between the APC and T cell, allowing for continued signaling and activation.

What is the immunological synapse between APCs and T cells? Which molecules are present and interacting?

Production : bone marrow, Education: thymus, Contact with antigen: lymphe node, Perform function: lymphe node and tissues

What is the life cycle of the T-cell?

Receptor editing is a process that occurs in mature B cells to rescue them from apoptosis (programmed cell death). It involves the rearrangement and modification of the B cell receptor (BCR), which is a protein on the surface of the B cell that recognizes and binds to antigens. Under normal circumstances, when a B cell first encounters an antigen, its BCR is activated and signals the cell to divide and differentiate into a plasma cell, which produces and secretes antibodies. However, if the BCR is not properly functional or recognizes self-antigens, the B cell can undergo apoptosis.

What is the meaning of 'receptor editing' for rescuing B cells from apoptosis? Under which circumstances does this process occur?

First, it acts as a checkpoint to ensure that the gene rearrangement process that generates the immunoglobulin heavy chain gene has been successful and that the B cell has a functional antigen receptor. Second, the pre-BCR signals to the developing B cell, promoting cell survival and growth, as well as initiating further differentiation and gene rearrangement processes. Third, the pre-BCR plays a role in ensuring the allelic exclusion of the immunoglobulin heavy chain gene, meaning that only one functional allele is expressed in each B cell.

What is the meaning of the temporary pre-B cell receptor (and pre-T cell receptor, see theme 4) for the development of lymphocytes?

Need a pre T cell receptor because it's a checkpoint for future development. The pre T cell has a CD3 that is a transmembrane protein. It needs it there to check if the TCR is binding properly to antigens and assembles properly. If the TCR is not properly formed, then the pre T cell will not develop. Upon recognition of a foreign antigen by the TCR, the TCR and CD3 complex undergoes a conformational change that allows it to activate a series of intracellular signaling pathways. These signaling pathways lead to the activation and differentiation of T cells, allowing them to become fully functional immune cells capable of recognizing and responding to invading pathogens.

What is the meaning of the temporary pre-T cell receptor for the development of T cells

binding to specific receptors on immune cells or antibodies. An epitope, also known as an antigenic determinant, is the specific part of an antigen that is recognized and bound by an antibody or T-cell receptor. Antigens can have one or more epitopes that are recognized by different parts of the immune system.

What is the relation between an antigen and an epitope

Activation-induced cytidine deaminase (AID) is an enzyme that plays a critical role in isotype switching, a process that enables B-cells to change the type of immunoglobulin (antibody) they produce without changing their antigen specificity. During SHM, the variable (V) region of the immunoglobulin gene undergoes random point mutations, which leads to the production of B-cells with varying affinities for the antigen. This process is essential for the development of high-affinity antibodies that can more effectively neutralize the pathogen. The role of AID in SHM is to deaminate cytosine residues in the V region of the immunoglobulin gene, converting them to uracil. The uracil residues are then recognized by DNA repair enzymes, which introduce random mutations at the site of deamination.

What is the role of AID in isotype switching and affinity maturation?

Regulatory T cells (Tregs) are a specialized subset of T cells that play a critical role in maintaining immune homeostasis and preventing autoimmune reactions. Tregs express high levels of the transcription factor FOXP3, which is required for their development and function. In the context of autoimmune reactions, Tregs play a critical role in preventing the activation and expansion of self-reactive T cells that could otherwise attack healthy tissues. Tregs can recognize and suppress self-reactive T cells in a tissue-specific manner, allowing them to maintain tolerance to self-antigens without compromising the immune response to foreign pathogens.

What is the role of regulatory T cells in preventing autoimmune reactions?

When a B cell turns into a plasma cell, the B cell receptor turns into an antibody as a soluble form. There are two light chains and two heavy chains. There are also constant regions and variable regions. The constant region is known as the Fc region which differs between different isotopes. Variable regions are present in both the heavy and light chain, which are involved in antigen binding.

What is the structure of a B cell receptor?

Manthoux test in skin: Delayed Type hypersensitivity and Quantiferon: M. tuberculosis specific T cells: IFNγ

What is the test conducted for Mycobacterium tuberculosis?

sustaining proliferative signalling, evading growth suppressors, activation innovation and metastasis, enabling replicative immortality, inducing angiogenesis, resisting cell death

What makes a cell a cancer cell?

inhibition of H chain recombination (allelic exclusion); proliferation of pre-B cells; stimulation of light chain recombination; shut off of surrogate light chain transcription

What occurs at the Pre-B cell stage?

Firstly, recognition occurs through TLR receptors. The alternative pathway then can label the bacteria and make phagocytosis easier. Phagocytosis takes place as well which causes cytokines to release and cause inflammation.

What role does in the innate immunity play to extracellular bacteria?

Th2 cells

What subset of CD4 T cells is responsible for mast cell and eosinophil precursor proliferation?

bone marrow

Where are t-cells produced?

They are formed in bone marrow and they develop in the thymus. IL7 cytokine. If weak recognition by MHC1 then mature CD8 cell. If weak recognition by MHC2 then mature CD4 cell. If no recognition of MHC then apoptosis. If strong recognition of MHC1 or 2 then apoptosis (because MHC presents self-antigen)

Where are the T cells formed and where do they develop? Which cytokine contributes to the proliferation of immature 'progenitor cells'? Describe the processes that cause selection of early T cells.

Central tolerance of T-cells is in the thymus, while for the B-cells it is in the bone marrow. Peripheral tolerance occurs in various organs or in secondary lymphoid tissues.

Where are the sites of tolerance induction?

a)Bone marrow b) apoptosis

Where do B cells arise? What happens when a B cell comes into contact with a self-antigen?

B-cells develop in the bone marrow and then migrate to secondary lymphoid tissues

Where do B-cells develop and then migrate to?

Positive selection takes place at the phase of the cortical epithelial cells and negative selection takes place by dendritic cells and macrophages expressing self antigens.

Where does positive and negative selection in the thymus?

In the lymphoid tissues (lymph nodes)

Where does the activation from naive T cells to effector T cells take place?

Dendritic cells pick up antigens and travel to the secondary lymph nodes to activate T-cells.

Where does the activation of T-cells normally occur?

b. opsonorization

Which antibody functions are important in the clearance of extracellular bacteria? a. complement activation b. opsonorization c. neutralisation d. induction of antibody dependent cellular cytotoxicity

central lymphoid organs: the thymus and the bursa or bone marrow. peripheral lymphoid organs: lymph nodes, spleen, tonsils, and mucosal-associated lymphoid tissues in which immune responses are induced.

Which are the central lymphoid organs (also called 'generative' lymphoid organs)? And which are the peripheral lymphoid organs? List more than one organ.

Current immunosupressors are expensive and have side effects that could hinder patients from taking them long term.

Which are the disadvantages of the current immunosuppressants?

The main functional differences between an antibody and a Fab fragment are related to their effector functions. While intact antibodies can activate complement and bind to Fc receptors on immune cells, Fab fragments lack these abilities. However, Fab fragments can be used in various research and clinical applications where specific antigen binding is required without the potential for effector functions, such as in diagnostic assays or targeted drug delivery.

Which are the functional differences between an antibody and a Fab fragment?

Cytotoxic T lymphocytes (CTLs) are a type of T cell that play a critical role in the immune response against viral and bacterial infections, as well as in the control of tumor growth. CTLs contain specialized granules in their cytoplasm that are packed with cytotoxic molecules, including perforin and granzymes, which are the main components of the granules.

Which are the main components of the granules of cytotoxic T lymphocytes?

At the basic level the broad functions of the complement system can be split into three areas: (1) the activation of inflammation; (2) the opsonization (labeling) of pathogens and cells for clearance/destruction; (3) the direct killing of target cells/microbes by lysis.

Which are the three main functions of complement activation?

B cells produce immunoglobulins (B cell receptors for antigens), which can recognize intact proteins or carbohydrates. The portions of the protein that they recognize ('epitope') can lie in a linear structure ('linear epitope'), but also in a conformational structure ('discontinuous epitope'). Initially, a mature B cell produces IgM antibodies. When a B cell becomes fully activated (helped by a T helper cell), class switching occurs (not shown in the animation). The B cell will switch to the production of IgG, IgA or IgE.

Which cells and soluble products arise from B cells after their activation by antigens?

The process of negative selection, which eliminates self-reactive T cells during T cell development in the thymus, is primarily mediated by thymic epithelial cells (TECs) and dendritic cells (DCs). TECs play a critical role in negative selection by presenting self-antigens to developing T cells. The interaction between TECs and developing T cells expressing T cell receptors (TCRs) that recognize self-antigens too strongly leads to the elimination of these self-reactive T cells through apoptosis. In the thymus, DCs can present self-antigens to developing T cells and promote negative selection by inducing apoptosis of self-reactive T cells.

Which cells are important for the induction of negative selection in the thymus?

Regulatory T cells (Tregs): Tregs are a type of immune cell that help to suppress immune responses and maintain immune tolerance. However, in the context of tumors, Tregs can inhibit the immune response against tumor cells, promoting immune evasion and tumor growth. Tumor-associated macrophages (TAMs): TAMs are a type of immune cell that can be recruited to the tumor microenvironment and promote tumor growth. They can produce factors that promote angiogenesis and tissue remodeling, which can help to create a favorable environment for tumor growth. Myeloid-derived suppressor cells (MDSCs): MDSCs are a type of immune cell that can suppress immune responses and promote immune tolerance. In the context of tumors, MDSCs can inhibit the activation and function of immune cells, promoting immune evasion and tumor growth. B cells: While B cells are typically associated with antibody production and immune surveillance, in some cases, they can promote tumor growth by producing factors that promote angiogenesis and tissue remodeling.

Which cells of the immune system can stimulate tumor growth and how do they achieve this?

d. NK cell

Which cells of your innate immune system are important in clearance of viruses? a. macrophage b. mast cell c. neutrophil d. NK cell

dendritic cells and mast cells

Which cells of your innate immune system are important in the clearance of parasites? a. macrophages b. neutrophils c. mast cells d. NK cells e. dendritic cells

The complement system is the humoral (soluble) component of the innate immune system. This system comprises a large number of serum proteins, of which some have proteolyticactivity. The binding of certain antibodies to the surface of a bacterium activates the complement system. The function of the complements system is 'complementary' to that of antibodies, hence its name. However, activation of complement also occurs prior to the adaptive response, if the complement factors come in contact with the surface of a bacterium ('alternative pathway'). Activation of complement triggers a cascade of proteolytic processes in which different cleavage products are released, which each have their own function

Which cells/soluble factors are important for the adaptive immune system? And which for the innate immune system? Describe the global functions of all the cells and factors you mentioned, without going into details.

In order to provide efficient help to T cells in response to protein antigens, B cells must undergo a process called class switching and differentiate into antibody-secreting plasma cells. Class switching is a process by which B cells change the class of antibody they produce, from IgM to IgG, IgA, or IgE. This process is triggered by cytokines produced by activated CD4+ T cells, such as interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-6 (IL-6). The specific cytokines produced depend on the type of antigen and the type of immune response that is required. In addition to class switching, B cells must also undergo affinity maturation, which is a process by which B cells with higher-affinity B cell receptors (BCRs) are selected for survival. Affinity maturation occurs in germinal centers within lymphoid tissues and requires interaction between B cells and T follicular helper (TFH) cells, which are specialized CD4+ T cells that provide help to B cells.

Which changes occur in B cells so that they can provide efficient help to T cells in case of antigens with protein components?

There are five major classes, or isotypes, of immunoglobulins (Igs) in humans: IgM, IgG, IgA, IgD, and IgE. IgM: This is the first antibody produced during an initial immune response to an antigen. It is primarily found in the bloodstream and lymph, and its large size and pentameric structure allow it to efficiently activate complement and neutralize pathogens. IgG: This is the most abundant antibody in the bloodstream and is the only isotype that can cross the placenta to provide passive immunity to a developing fetus. IgG can also activate complement and bind to Fc receptors on immune cells, making it important in both the early and late phases of an immune response. IgA: This is the predominant antibody found in mucosal secretions, such as saliva, tears, and breast milk. It helps prevent pathogen attachment to mucosal surfaces and can neutralize toxins and viruses. IgD: This is the least understood of the isotypes and is primarily found on the surface of mature B cells. Its function is not well-defined, but it may play a role in B-cell activation and differentiation. IgE: This is the isotype involved in allergic reactions and defense against parasites. It binds to Fc receptors on mast cells and basophils, triggering the release of histamine and other mediators that cause inflammation and tissue damage.

Which classes of immunoglobulins ('isotypes') do exist? What are the main functions of the different isotypes?

The beta chain gets rearranged first.

Which genes encoding one of the chains of the T cell receptor are subject to gene rearrangement first? What happens afterwards, before the gene rearrangements of the genes encoding the other chain begins?

adaptive immune response, therefore it is antigen specific

Which immune response does a vaccination induce?

IgM and IgD

Which isotypes of membrane-bound immunoglobulins are present on naive B cells?

T cell-independent (TI) antigens are those that can directly stimulate B cells without the need for T cell help. TI antigens can be divided into two categories: TI-1 and TI-2. Advantages of TI B cell activation include: Rapid response: TI B cell activation can occur quickly, without the need for T cell help, and can lead to the production of large amounts of low-affinity antibodies. Independence from T cell help: TI B cell activation is particularly important in neonates and in individuals with T cell deficiencies, as it allows for antibody production without the need for T cell help. Disadvantages of TI B cell activation include: Limited isotype switching: TI antigens are less effective at inducing class switching, so the antibodies produced in response to TI antigens are usually restricted to IgM. Limited affinity maturation: TI antigens do not stimulate germinal center reactions, which are necessary for affinity maturation. As a result, antibodies produced in response to TI antigens have lower affinity than those produced in response to T cell-dependent antigens. Limited memory formation: TI antigens do not induce long-lived memory B cells, so the immune response to subsequent exposure to the same antigen may be weaker or absent.

Which kind of antigens can induce T cell-independent B cell proliferation and antibody production? What are the advantage and disadvantage of this kind of B cell activation?

IgD or CD19; Allelic exclusion is an important mechanism that ensures that each B cell expresses a unique set of genes and contributes to the functional diversity of the immune system. By expressing only one functional allele of the immunoglobulin heavy chain gene, B cells are able to generate a diverse range of BCRs that can effectively recognize and respond to a wide range of antigens.

Which marker demonstrates that the B cell is mature and immunocompetent, i.e. which membrane molecule is expressed during the transition phase from immature B cell to mature B cell? 7. What does 'allelic exclusion' mean and how is it achieved

Central tolerance for T-cells include negative selection of T-cells. While in the peripheral tolerance for T-cells include anergy, regulatory T-cells, and sequestered auto-antigen. Central tolerance for B-cells include clonal deletion, receptor editing, and anergy. Peripheral tolerance for B-cells include anergy and require no T-cell help.

Which mechanisms are done in the central and peripheral tolerance for T cells? B cells?

the immunoglobulin molecules and accessory signaling molecules form the BCR complex, which allows B cells to recognize and respond to a wide range of antigens.

Which membrane molecules constitute the BCR?

The TCR is a complex of two transmembrane glycoprotein chains (α and β chains) and intracellular CD3 molecules that are responsible for recognizing antigens presented by MHC molecules and transmitting the signal for T cell activation. Alternative TCR chains, such as γ and δ chains, can also be expressed by some T cell subpopulations.

Which membrane molecules constitute the TCR?

T cells have dual specificity, so they recognize both self-major histocompatibility complex molecules (MHC I or MHC II) and peptide antigens displayed by those MHC molecules. A T cell, however, cannot recognize intact proteins. Their receptors recognize only linear fragments of proteins (peptides) that are presented in the context of MHC molecules.

Which molecules are involved in the recognition of an antigen by T cells?

CD19, CD21

Which molecules on B cells function as co-receptors?

In a patient with a pneumococcal infection, the production of IL-6, IL-10, and IFN-g is likely to be increased.In a worm infection, the production of IL-4, IL-5, and IL-13 is likely to be increased.

Which of the following cytokines will be produced mainly in a patient with a pneumococcal infection? And in a worm infection? IL-4 IL-5 IL-6 IL-10 IL-12 IFN-g

The TCR is made up of a alpha chain and a beta chain. Each chain has a C segment and VDJ segment. The VDJ part is most variable. No it's the V and C parts that binds the MHC.

Which part of the T cell receptor chain is the most variable? Do you think that this part of the receptor is involved in binding to the MHC-peptide complex?

The receptor-ligand interaction essential for the occurrence of isotype switching (or class switching) is the interaction between CD40, a receptor on the surface of B cells, and CD40L (also known as CD154), a ligand on the surface of activated T helper cells.

Which receptor-ligand interaction is essential for the occurrence of isotype switching (also known as 'class switching')?

Heavy chain: V, D, and J segment. Light chain: V and J segment

Which segments are present in the heavy and light change?

After an antigen binds to a B lymphocyte receptor, the essential step required to activate the B lymphocyte is the signal transduction that occurs through the B cell receptor (BCR) complex.

Which step after the binding of an antigen to a B lymphocyte receptor is essential to activate the B lymphocyte?

c. Th17 cells

Which t-helper cells are important in the clearance of fungal infections? a. Th1 cells b. Th2 cells c. Th17 cells

a. Th1 cells

Which t-helper cells are important in the clearance of intracellular bacteria? a. Th1 cells b. Th2 cells c. Th17 cells

1. Central memory T cells (Tcm) are characterized by their ability to home to secondary lymphoid organs such as lymph nodes and spleen. They can rapidly proliferate and differentiate into effector cells upon antigen re-exposure, and are important for maintaining long-term immunity. 2. Effector memory T cells (Tem) are characterized by their ability to rapidly migrate to peripheral tissues and mount a rapid response upon antigen re-exposure. They are important for providing immediate protection against pathogens in peripheral tissues. 3. Tissue-resident memory T cells (Trm) are characterized by their ability to reside in non-lymphoid tissues such as skin, lung, and gut. Trm cells are maintained independently of circulating T cells and provide long-lasting protection against pathogen re-infection in the tissues where they reside. They express tissue-specific integrins, chemokine receptors, and transcription factors that allow them to remain in the tissue and rapidly respond to pathogen re-exposure.

Which three subsets of memory T cells can be distinguished?

First an antigen needs to be present, while the second signal is can happen in two ways: 1. Through contact between a ligand on one cell and a receptor on the other cell. 2. By soluble cytokines that are produced by one cell that bind to a receptor on the other cell. APC refers to a group of cell types, (Dendritic cells, macrophages, and B cells).

Which two signals are needed to activate a lymphocyte? Does an antigen presenting cell (APC) refer to one cell type or to a group of cell types?

A graft biopsy from a patient with acute graft rejection is likely to show the presence of activated T cells, specifically CD4+ T helper cells and CD8+ cytotoxic T cells.

Which type of T cells is found in a graft biopsy from a patient with acute graft rejection?

T cell-dependent (TD) antigens are those that require the participation of T cells in the development of antibodies. TD antigens are typically protein antigens, such as those found on viruses, bacteria, or other pathogens. The stimulation of T cells in response to TD antigens requires the presentation of antigen peptides by MHC class II molecules on the surface of APCs. This process is tightly regulated and requires the engagement of co-stimulatory molecules, such as CD80/86 on the surface of APCs and CD28 on the surface of T cells.

Which type of antigen leads to participation of T cells in the development of antibodies? How are the T cells stimulated?

linear and discontinuous epitopes

Which types of epitopes can be recognised by B-cells?

Non-melanoma skin cancer, post-transplant lymphoproliferative disorder, Kaposi's sarcoma, Liver cancer

Which types of tumours are especially more frequent in transplant recipients?

Enhancing T cell activation: CD4 and CD8 can enhance T cell activation by providing additional signaling to the T cell receptor (TCR) complex and CD3 molecules when they bind to the MHC molecules on APCs. This results in stronger and more efficient activation of intracellular signaling pathways, which drive T cell activation, proliferation, and effector function.

Why are CD4 and CD8 molecules called co-receptors for T cells? In which two ways can they function as co-receptors?

T cells play a critical role in the rejection of transplants because they are a key component of the adaptive immune system, which is responsible for recognizing and responding to foreign antigens, including those expressed by transplanted tissues. This immune response can lead to rejection of the transplanted tissue, as T cells and other immune cells attack the transplanted cells and attempt to destroy them. Thus, understanding and managing the T cell response is a critical part of preventing transplant rejection, and immunosuppressive drugs are often used to dampen the immune response and prevent rejection.

Why are T cells important in the rejection of transplants?

Many T cell-mediated autoimmune diseases are organ-specific because the immune system is programmed to recognize and respond to antigens that are specific to particular organs. Each organ in the body has its own unique set of antigens that are expressed only in that organ. These antigens are often sequestered from the rest of the body, meaning that they are not normally exposed to the immune system.

Why are many T cell-mediated autoimmune diseases organ-specific?

Immunosuppressants are used in both graft rejection and controlling autoimmune diseases because in both cases it's the body attacking itself.

Why are the types of drugs that are used to prevent graft rejection, also used in controlling autoimmune diseases?

Immunosuppression is still necessary even in cases of transplantation between HLA-identical individuals, such as HLA-identical siblings, because even though the major histocompatibility complex (MHC) antigens are identical, there are still other genetic differences between individuals that can lead to immune responses. There are minor histocompatibility antigens (mHA) that differ between individuals and can still trigger an immune response, even in the case of HLA-identical transplantation. In addition, there are also non-HLA genes that can affect immune responses and the risk of rejection. Furthermore, even if the transplanted tissue is HLA-identical, the recipient may still have a pre-existing immune response to other antigens present in the transplanted tissue, such as viral or bacterial antigens.

Why is immunosuppression given after transplantation between HLA-identical persons, e.g. HLA- identical siblings?

Better quality of life, Higher clearance of waste products, Less demanding, Lower mortality, Cheaper (after first year)

Why is renal transplantation first choice?

Lymphocyte recirculation allows the lymphocytes to meet their cognate antigens and other leucocyte subsets to evoke an efficient immune response. Lymphocytes interact with the vessel wall in a multistep fashion, using several leukocyte surface molecules, which recognise their counter receptors on endothelial cells.

Why is the recirculation of lymphocytes important?

There are more cells involved in cell-mediated immunity (NK cells, macrophages). T cells coordinate the function of B cells (humoral immunity)

Why isn't the following phrase not true "Cell mediated immunity is the type of host defense that is mediated by T lymphocytes, and it serves as the defense mechanism against intracellular and phagocytosed microbes"

Xenotransplantation, which involves the transplantation of organs or tissues from one species to another, has been proposed as a possible solution to the shortage of donor organs. However, one major obstacle to xenotransplantation is the presence of natural antibodies in the recipient that can lead to very rapid rejection of the transplanted organ. These antibodies recognize carbohydrate antigens on the surface of pig cells, which are different from those on human cells, and can trigger an immune response that destroys the transplant within minutes to hours. To overcome this problem, several strategies have been developed to reduce the immunogenicity of the pig organ and/or to suppress the recipient's immune response.

Xenotransplantation might be a possible solution for the shortage of donor organs. Explain how the presence of natural antibodies can lead to very rapid rejection. How can this problem be solved?

C-reactive protein (CRP)

a blood test to measure the amount of C-reactive protein in the blood, which, when elevated, indicates inflammation in the body. It is sometimes used in assessing the risk of cardiovascular disease

serum sickness

a classic example of type III hypersensitivity that involves a drug allergy to antitoxin serum from horses

Immunoreceptor tyrosine activation motif (ITAM)

a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of certain cell surface proteins of the immune system

Secondary immunodeficiencies

acquired after birth and caused by natural or artificial agents

Corticosteroids

anti-inflammatory agents that treat skin inflammation

Patrolling cells

attack pathogens, but don'tremember for the next time

Loss of tolerance to self-antigens

autoimmune disease

molecular mimicry

body forms antibodies to an antigen as well as antibodies to body tissue mistaken for an antigen

Negative selection of B cells

causing apoptosis in cells that are self-reactive

Central tolerance of B cells

cells that bind to "self" cells are eliminated in bone marrow

Th1 cells

cells that secrete cytokines that enhance the activity of macrophages and other cells

Thymus-dependent antigens

contains protein component (conjugated H influenzae vaccine); class switching and immunologic memory occur as a result of direct contact of B cells with Th cells and release of IL4, IL5, and IL6

combinatorial diversity

created by somatic recombination of randomly-selected gene segments

DAMPs

damage associated molecular patterns

peritoneal dialysis

dialysis in which the lining of the peritoneal cavity acts as the filter to remove waste from the blood

Toll-like receptors

each recognize a specific "danger" molecule AND transmit a message to the cell's nucleus.

discontinuous epitope

epitope that does not have a linear sequence

HLA

human leukocyte antigen

Passive immunotherapy

immune molecules are given to patients who don't produce themon their own

Adjuvent

induction of an innate immune response through a slow release of antigens

Farmacotherapy

inhibition/activation/depletion of a (component of) the immune system to modulate the immune response.

Natural killer cells

innate lymphoid cells

CD8+ T-cells (Cytotoxic T-cells)

kill virus-infected cells directly

Thymus-independent antigens

lacks peptide component; cannot be presented by MHC to T cells; stimulates release of IgM antibodies only, no memory formation, no isotope switching

polyvalent interaction

more than one binding sites are occupied, making the strength of the binding strong

monovalent interaction

only one antigen binding site is occupies

Primary immunodeficiencies

present at birth (congenital), usually stemming from genetic errors, recessive

Th17 cells

produce IL-17 and contribute to inflammation

reverse vaccinology

promising technology screening pathogen genetic material to discover all antigens previously unknown-> develop antibodies in lab or VLP's, etc. By studying a pathogen and their interaction with an individual as well as their genome, you verify specifically target the enter way for example.

perforin

punctures cell membrane

Central memory T cells

recirculate through lymph nodes where they can mount secondary responses to captured antigens

Innate immune receptors

recognizes featurescommon to many pathogens

Receptor editing

replacement of L-chains can rescue some self- reactive B cells by changing their Ag specificity; if cell remains self-reactive it will undergo apoptosis

Peripheral Tolerance of B cells

self-reactive B cells escaping central tolerance receive constant low level stimulation via B cell surface receptor and render them anergic as long as this chronic stimulation is present (no T cell help, no inflamm signals)

Active immunotherapy

setting an immune response in patients to fight cancer

Downregulation of antigen presentation: Tumor cells may reduce the presentation of mutated intracellular proteins on their surface by downregulating the expression of major histocompatibility complex (MHC) molecules or by inhibiting the processing of antigens. This can prevent recognition of the tumor cells by T cells. Upregulation of immune checkpoint molecules: Tumor cells may upregulate immune checkpoint molecules such as PD-L1, which interact with inhibitory receptors on T cells (such as PD-1), leading to suppression of T cell function and evasion of immune surveillance. Recruitment of immunosuppressive cells: Tumor cells may recruit immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment. These cells can inhibit the function of effector T cells and promote immune evasion. Production of immunosuppressive factors: Tumor cells may produce factors such as TGF-β and IL-10, which can inhibit the function of T cells and promote immune evasion. Resistance to apoptosis: Tumor cells may develop resistance to apoptosis, a process by which cells undergo programmed cell death. This can prevent elimination of the tumor cells by the immune system, as apoptotic cells are more readily recognized and cleared by immune cells.

A certain tumor is characterized by the mutation of an intracellular protein at two places. Describe the steps in this process that tumor cells could use to prevent their elimination by the immune system (evasion).

B-1 cells

A class of atypical, self-renewing B cells (also known as CD5 B cells) found mainly in the peritoneal and pleural cavities in adults. They have a much less diverse antigen-receptor repertoire than conventional B cells.

Major Histocompatibility Complex

A group of genes coding for molecules that providethe context for the recognition of foreign antigensby T-lymphocytes

membrane attack complex (MAC)

A molecular complex consisting of a set of complement proteins that forms a pore in the membrane of bacterial and transplanted cells, causing the cells to die by lysis.

sphingosine 1-phosphate (S1P)

A phospholipid with chemotactic activity that controls the egress of T cells from lymph nodes.

cytokine storm

A potentially fatal immune reaction caused by highly elevated levels of various cytokines

innate immune response

A quick, general immune response that all living things are born with.

Hyper acute rejection

A rejection that occurs few hours after Tx. This is due to pre-existing antibodies against donor antigens which causes complement activation and intravascular coagulation. (Type II autoimmunity response)

hemodialysis

A technique in which an artificial kidney machine removes waste products from the blood

Marginal zone B cells

A unique population of B cells found in the spleen marginal zones; they do not circulate and are distinguished from conventional B cells by a distinct set of surface proteins.

CD4+ T helper cells

Activate B-cells and release cytokines that stimulate other immune cells

Isotope Switching

Also called class switching. A change in the predominant antibody isotype produced by a B cell.

Tolerance for self

An individual mounts receptors for selfepitopes which have to be removed fromthe repertoire to avoid self destruction

In healthy individuals, the immune response against Pneumocystis carinii involves activation of T cells, which then stimulate macrophages to phagocytose and kill the pathogen. Activated macrophages produce reactive oxygen species and reactive nitrogen intermediates, which are essential for killing the pathogen. In HIGM-1 patients, however, there is a defect in isotype switching, leading to a lack of IgG antibodies. Since antibodies are important for opsonization of pathogens and activation of complement, the lack of IgG antibodies in HIGM-1 patients results in impaired opsonization and phagocytosis of Pneumocystis carinii by macrophages. As a result, the pathogen can persist and cause severe infections in these patients.

Another feature of HIGM-1 is the occurrence of life-threatening infections with Pneumocystis carinii (now called Pneumocystis jiroveci). In healthy organisms, this microorganism is combated by activated macrophages. Explain why HIGM-1 patients are susceptible to infection with this pathogen.

IgD antibody

Antibody located on the surfaces of B lymphocytes. Information about its role is limited.

IL2

stimulates survival, proliferation, and differentiation of antigen-activated T-cells.

monoclonal antibody

Any of a preparation of antibodies that have been produced by a single clone of cultured cells and thus are all specific for the same epitope.

B cells are also subject to peripheral tolerance induction mechanisms, similar to T cells. Regulatory T cells (Tregs) can suppress the activation of autoreactive B cells, and cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) can also inhibit the activation and proliferation of B cells. Additionally, there are specialized subsets of B cells called regulatory B cells (Bregs) that can suppress immune responses and promote tolerance. The mechanisms of central and peripheral tolerance induction in B cells are similar to those in T cells. In the bone marrow, immature B cells undergo central tolerance induction, where self-reactive B cells are eliminated through clonal deletion or receptor editing. In the periphery, B cells are subject to peripheral tolerance induction mechanisms, which can include suppression by Tregs and cytokine-mediated inhibition. One key difference between central and peripheral tolerance induction in B cells and T cells is the location where they occur. B cell central tolerance induction occurs in the bone marrow, while T cell central tolerance induction occurs in the thymus. Additionally, the mechanisms of central tolerance induction can differ between B cells and T cells, as they have different mechanisms of antigen receptor generation and signaling. However, the overall goal of central and peripheral tolerance induction in both B cells and T cells is to prevent the development of autoreactive cells and maintain immune tolerance.

Are B cells also subject to central and peripheral tolerance induction? If so, what is the difference?

Similarities: Both B cells and T cells initially develop from hematopoietic stem cells in the bone marrow. The receptors on both B cells and T cells are generated by somatic recombination of gene segments during lymphocyte development. The antigen-specificity of both BCRs and TCRs is determined by the variable regions of the receptors, which contain unique combinations of gene segments. In both B cells and T cells, the process of negative selection eliminates cells that recognize self-antigens to prevent autoimmune responses. Differences: B cells undergo somatic recombination of their BCR genes in the bone marrow, while T cells undergo somatic recombination of their TCR genes in the thymus. BCRs are membrane-bound immunoglobulins (antibodies) that can recognize and bind to soluble or membrane-bound antigens, while TCRs recognize and bind to antigenic peptides presented by MHC molecules on the surface of other cells. B cells undergo a process of affinity maturation in the germinal centers of lymphoid organs, where they can undergo somatic hypermutation and class switch recombination to generate high-affinity and isotype-switched antibodies. T cells do not undergo these processes. B cells can differentiate into plasma cells that secrete antibodies, while T cells differentiate into various effector and memory T cell subsets, including cytotoxic T cells, helper T cells, and regulatory T cells.

Briefly describe the similarities and differences between the development of the B cell receptor and that of the T cell receptor.

Children younger than two years produce less antibodies after vaccination with only polysaccharides because their immune system is not yet fully developed. Polysaccharide antigens are complex sugars that can stimulate an immune response, but they are not as effective at inducing antibody production as protein-based antigens.

Children younger than two years produce hardly any antibodies after vaccination with only polysaccharides. Why is that?

Proteins

Complement, acute phase proteins andcytokines

T cells recognize foreign antigens when they are presented on the surface of APCs bound to MHC molecules. The T cell receptor (TCR) on the surface of T cells recognizes the foreign antigen-MHC complex and triggers the activation and proliferation of the T cell. T cell receptor diversity: T cells have a highly diverse T cell receptor (TCR) repertoire, which allows them to recognize a wide range of antigens. This diversity ensures that a sufficient number of T cells are present in peripheral lymphoid organs to respond to new antigens. Homeostatic cytokines: Naive T cells receive signals from homeostatic cytokines, such as interleukin-7 (IL-7) and interleukin-15 (IL-15), that promote their survival. These cytokines are produced by stromal cells in peripheral lymphoid organs and help to maintain the pool of naive T cells. Lower activation threshold: T cells have a lower activation threshold compared to B cells, which allows them to respond to low levels of antigens. This makes it possible for T cells to respond to new antigens even in the absence of direct activation signals, which helps to ensure their survival in peripheral lymphoid organs. On the other hand, B cells have a less diverse B cell receptor (BCR) repertoire, and they require more direct stimulation from antigens to be activated and proliferate. This, combined with the absence of homeostatic cytokines that promote B cell survival, means that B cells have a shorter lifespan in peripheral lymphoid organs compared to T cells.

Consider an individual mature T cell. Realize that T cells are subject to both positive and negative selection. What does a T cell recognize when it is activated by a foreign antigen? Why can naive T cells survive for a long time in peripheral lymphoid organs compared to B cells?

Naive T cells arrive in the lymph nodes via the blood and the lymphatic vessels. They enter the lymph node through specialized vessels called high endothelial venules (HEVs) located in the outer cortex of the lymph node. HEVs are specialized blood vessels. Once inside the lymph node, naive T cells migrate through the lymph node parenchyma and scan for the presence of antigens presented by specialized antigen-presenting cells (APCs) such as dendritic cells. The dendritic cells are located in the T cell zone of the lymph node, which is an area where T cells and APCs interact to initiate the adaptive immune response.

Describe (with molecular details) how naive T cells arrive at this location, and how they reach the antigens.

First, the innate immune system will recognize the transplanted organ as foreign and mount a non-specific response. This may include the activation of complement, recruitment of neutrophils and other inflammatory cells, and the release of cytokines. Within days to weeks, the adaptive immune system, specifically T cells, will recognize the transplanted organ as foreign and initiate an immune response. T cells recognize and respond to antigens presented on the surface of cells via the major histocompatibility complex (MHC) molecules. In the case of transplantation, the donor's MHC molecules will be recognized as foreign by the recipient's T cells, leading to activation and proliferation of T cells. The activated T cells will then migrate to the transplanted organ and infiltrate the tissue, where they will release cytokines and other mediators that can damage the tissue. B cells may also be activated and produce antibodies against the transplanted organ. These antibodies can contribute to tissue damage and can also activate complement, further exacerbating tissue damage. Over time, the continued immune response will lead to chronic inflammation and tissue damage, which can cause dysfunction and eventually failure of the transplanted organ. If the immune response is not controlled, the rejection process will ultimately lead to graft failure and loss of the transplanted organ.

Describe chronologically the immunological reactions that will occur if an organ is transplanted with out immunosuppression.

Antigen presentation: Macrophages phagocytose invading pathogens and present antigens from the pathogens on their cell surface using major histocompatibility complex (MHC) molecules. T cell activation: Th1 cells recognize the antigen-MHC complex on the macrophage surface through their T cell receptor (TCR), leading to their activation. Cytokine secretion: Upon activation, Th1 cells secrete cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), which bind to receptors on the surface of macrophages. Activation of macrophages: The binding of IFN-gamma and TNF-alpha to macrophage receptors triggers a cascade of events that activate macrophages. This includes the upregulation of MHC molecules, the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and the release of pro-inflammatory cytokines. Enhanced phagocytosis and killing: The activation of macrophages by Th1 cells leads to increased phagocytosis and killing of invading pathogens, as well as the activation of other immune cells such as T cells and natural killer cells.

Describe how macrophages can be activated by Th1 cells.

IgG: IgG is the most abundant antibody isotype in the blood and can cross the placenta to provide passive immunity to the fetus. It is involved in opsonization, neutralization, and complement activation. IgG can also bind to Fc receptors on immune cells, leading to ADCC and antibody-dependent cellular phagocytosis (ADCP). IgA: IgA is primarily found in mucosal secretions such as saliva, tears, breast milk, and intestinal fluid. It is involved in neutralization and agglutination of pathogens and prevents their attachment to mucosal surfaces. IgA can also interact with immune cells to mediate ADCC. IgM: IgM is the first antibody isotype produced during the primary immune response and is primarily found in the blood. It is involved in complement activation and agglutination of pathogens. IgM also serves as a B cell receptor and plays a crucial role in B cell activation and differentiation. IgE: IgE is primarily found in tissues that are in contact with the environment such as the skin, lungs, and intestines. It is involved in allergic reactions and defense against parasitic infections. IgE binds to Fc receptors on mast cells and basophils, leading to the release of inflammatory mediators such as histamine. IgD: IgD is primarily found on the surface of mature B cells and serves as a B cell receptor. It plays a crucial role in B cell activation and differentiation

Describe how the different isotypes of antibodies exert their effects in the different compartments of the body.

There are three pathways of complement activation: the classical pathway, which is triggered directly by pathogen or indirectly by antibody binding to the pathogen surface; the MB-lectin pathway: recognises mannose on microbe surface; and the alternative pathway, which recognises N-acetylglucosamine on bacterial cell wall

Describe the different pathways through which the complement system can be activated immediately after contact with an infectious microorganism

the Mantoux test is based on the principle of delayed-type hypersensitivity, which involves the activation of T cells in response to TB antigens in the PPD solution. The resulting DTH reaction produces a characteristic induration at the injection site, which is used to diagnose TB infection.

Describe the principle of the Mantoux (= PPD) test.

During the immune response, naive T cells interact with APCs to recognize and respond to foreign antigens. LFA-1 plays a crucial role in this interaction by mediating adhesion and signaling between these cells. First, LFA-1 on naive T cells binds to its ligand intercellular adhesion molecule-1 (ICAM-1) on the surface of APCs. This interaction facilitates the formation of a stable contact between the two cells, known as the immunological synapse. This contact allows for the exchange of information between the T cell and the APC. Once the immunological synapse is formed, LFA-1 is also involved in signaling events that promote T cell activation and differentiation. LFA-1 engagement leads to the recruitment of intracellular signaling molecules such as protein kinase C (PKC) and the activation of downstream pathways including the mitogen-activated protein kinase (MAPK) pathway.

Describe the role of LFA-1 (CD11a/CD18) in the interaction between naive T cells and APCs?

Recognition: The first step is for the lymphocyte to recognize the antigen as foreign. Lymphocytes have receptors on their surface that can recognize specific antigens. If the receptor on the lymphocyte matches the antigen, it binds to it, signaling that the antigen is foreign and should be eliminated. Activation: Once the lymphocyte recognizes the antigen, it becomes activated. This involves a series of biochemical events that stimulate the lymphocyte to divide and multiply rapidly, creating an army of identical cells that can target the same antigen. Activated lymphocytes can differentiate into different types of immune cells, such as B cells or T cells, depending on the type of antigen and where it is located. Response: The final step is for the activated lymphocytes to mount an immune response against the antigen. B cells produce antibodies that can bind to and neutralize the antigen, while T cells can directly attack infected cells or help activate other immune cells. The immune response is tailored to the specific antigen and is designed to eliminate it from the body.

Describe the three processes that can occur when a lymphocyte 'meets' an antigen

VDJ on the heavy chain and VJ on the light chain; Before the gene rearrangement of the genes encoding the other chain begins, the B cell must undergo a series of checks and differentiation steps to ensure that it is functional and non-self-reactive, and that it has a functional and non-self-reactive heavy chain gene.

During the production of antibodies, which genes encoding which chain are subject to gene rearrangement first? What happens before the gene rearrangement of the genes encoding the other chain will start?

1. Th1 cells: Th1 cells secrete interferon-gamma (IFN-γ), tumor necrosis factor (TNF), and interleukin-2 (IL-2), among other cytokines. Th1 cells express the transcription factor T-bet and the surface marker CD161. They play a critical role in cell-mediated immunity against intracellular pathogens, such as viruses and intracellular bacteria, by activating macrophages and inducing the production of antibodies. 2. Th2 cells: Th2 cells secrete cytokines such as IL-4, IL-5, and IL-13. Th2 cells express the transcription factor GATA-3 and the surface marker CRTh2. They play a critical role in the immune response against extracellular parasites, such as helminths, and in the development of allergic responses. 3. Th17 cells: Th17 cells secrete cytokines such as IL-17, IL-21, and IL-22. Th17 cells express the transcription factor RORγt and the surface marker CCR6. They play a critical role in the immune response against extracellular bacteria and fungi and in the pathogenesis of autoimmune diseases. 4. Treg cells: Treg cells, also known as regulatory T cells, secrete cytokines such as IL-10 and transforming growth factor-beta (TGF-β). Treg cells express the transcription factor FoxP3 and the surface marker CD25. They play a critical role in maintaining immune tolerance and preventing

Effector T lymphocytes can be divided into 4 subtypes/subsets. Give their names, explain how you can distinguish between these subsets and describe the main functions of the 4 different subsets.

Linear epitope

Epitope of a protein recognized by antibody that consists of a linear sequence of amino acids within the protein's primary structure.

Checkpoint antibody therapy is a type of cancer treatment that involves the use of antibodies to block certain proteins, known as checkpoint proteins, that prevent the immune system from attacking cancer cells. These proteins, such as PD-1 and CTLA-4, are found on the surface of immune cells, including T cells, and can inhibit their activity. Checkpoint antibody therapy works by blocking these checkpoint proteins, allowing the immune system to recognize and attack cancer cells. This approach has been successful in treating several types of cancer, including melanoma, lung cancer, and kidney cancer.

Explain Checkpoint antibody therapy

There is an antigen to which the antibody binds, which activates complement leading to the position of C3b on the surface. These are recognised by C3b receptors or Fc receptor on phagocytes leading to phagocytosis. Another way to produce inflammation is through the split products of C3a and C5a will recruit leukocytes to the site of inflammation which will cause inflammation of tissue injury. An antibody can recognise a cell surface receptor and stimulates receptor without ligand. This will leads to continuous production of that hormone. SUMMARY: auto-ag on cell surface/extra-cellular matrix, but if cell receptor cellular dysfunction

Explain Type II of auto immunity.

This is mainly due to formation of immune complex. If you have a soluble antigen within the circulation that the antibody binds, then you have aggregates (?) of antibodies and antigens and at a certain moment these aggregates don't dissolve anymore and deposit in the vessel wall. This leads to inflammation. Since is it in the vessel wall it causes vasculitis. It mainly occurs at sites where deposition is enhances such as the skin, joints, and the kidney. SUMMARY: soluble/circulating auto-ag due to depostion of immune complexes

Explain Type III of auto immunity.

Type IV is mediated by T-cells. These T-cells can either induce inflammation by producing cytokines or directly killing of the cells. An example of this is Type I diabetes. SUMMARY: Th1 -> macrophage activation; Th2 -> IgE production/mast cell activation; CTL -> cytotoxicity

Explain Type IV of auto immunity.

Direct and indirect Ag-presentation. Infiltration of T-cells and macrophages between tubule and in vessel wall. Anti-HLA antibodies -> complement activation + ADCC -> vasculitis (Type IV autoimmunity)

Explain acute rejection

Recognition of non-self. There is no negative selection for non-self MHC-peptide complexes in the thymus! T-cell receptor recognizes: Non-self MHC-peptide complexes and Self MHC with non-self (MHC)-peptide. In any donor-recipient combination, about 5-10% of all T cells (positively selected for self-MHC) will be alloreactive due to cross-reactivity

Explain alloreactivity

Indirect Ag-presentation, mainly antibody mediated, intimal smooth muscle cell proliferation, interstitial fibrosis and tubular atrophy

Explain chronic rejection

B cell binds bacterial polysaccharide epithet linked to tetanus taxied protein. Antigen is internalised and processed. Peptides from protein component are presented to the T-cell. Activated B cell produces antibody against polysaccharide antigen on the surface of the bacterium.

Explain conjugate vaccine

All nucleated cells have HLA Class I. Within the cell a cytosolic microbe is present which cuts all proteins into pieces including pathogens. They are transported to the endoplasmic reticulum, where the HLA Class I are present without peptides. The small peptides from the pathogens will bind into the groove if it fits. Then it will go to the surface of the cell and be presented.

Explain how HLA Class I allows pathogens to be presented.

HLA Class II are not present on all cells and they take up pathogens that are extracellular. Firstly, endocytosis occurs in which the cell takes up a pathogen from the outside. It ends up in the vesicle, which is broken down by lysosomes into small parts. Then the small parts are transported to a vesicle which a HLA Class II molecule is present without a peptide. The small peptides from the pathogens will bind into the groove if it fits. Then it will go to the surface of the cell and be presented.

Explain how HLA Class II allows pathogens to be presented.

the production of IgD is regulated by the rearrangement and expression of the immunoglobulin heavy chain gene in B cells and is dependent on the synthesis and assembly of the δ chain and light chain proteins.

Explain how IgD is produced.

Cytotoxic T cells (CD8+). These cells can kill cells that are infected with viruses or bacteria. MHC class I molecules present proteins that are produced in the cell and that are present in the cell's cytosol. In case of infections with viruses or intracellular bacteria, these proteins can also have a viral or bacterial origin. After digestion in the cytosol, these proteins come into the ER and are presented on MHC class I molecules to cytotoxic T cells (CTL; CD8+ T cells).

Explain how T cells contribute to the eradication of an infection with intracellular bacteria or viruses.

The first step in T cell homing is the expression of tissue-specific adhesion molecules on the activated T cell. These adhesion molecules, such as integrins, allow the T cell to bind to the endothelial cells that line the blood vessels in the target tissue. The second step is the interaction between chemokine receptors on the activated T cell and chemokines produced by the endothelial cells in the target tissue. Chemokines are a class of small signaling proteins that attract immune cells to sites of infection or inflammation. The chemokine receptors on the activated T cell, such as CXCR3 or CCR5, bind to the chemokines produced by the endothelial cells, allowing the T cell to roll along the vessel wall and eventually transmigrate into the tissue. Once the T cell has entered the tissue, it begins to carry out its effector functions, such as releasing cytokines or directly killing infected or abnormal cells. The T cell may also undergo further activati

Explain how a T cell reaches its destination after activation in the lymph node.

Dendritic cell vaccination is a type of cancer treatment that involves using a patient's own immune cells, called dendritic cells, to stimulate an immune response against cancer cells. In dendritic cell vaccination, dendritic cells are extracted from a patient's blood and then treated with a protein or antigen found on the surface of cancer cells. This treatment activates the dendritic cells, causing them to present the antigen to T cells, which are another type of immune cell. The activated T cells can then recognize and attack cancer cells that express the antigen. The treated dendritic cells are then injected back into the patient's body, where they can activate T cells and stimulate an immune response against cancer cells. This approach has shown promise in treating several types of cancer, including melanoma, prostate cancer, and leukemia.

Explain how dendritic cell vaccination works

You have a pathogen that has been treated in some way so it is not fully able to replicate and cause illness in an individual. However, it is still alive so it replicates at a very slow rate. The major advantage is that it injects target cells in the normal way and therefore antigen presentation as MHC class I. Therefore, the whole immune response is activated and natural response. The risk is that it may remutate and mount disease in patients. People who have immunedeficienies therefore don't receive these vaccines e.g. mumps

Explain how live attenuated vaccines work.

Phagocytes such as neutrophils are flowing through the blood stream. At the site of inflammation, cytokines are released and attach to the vessel wall. This triggers adhesion molecules in the inner lining of the wall to show. Neutrophils then attach to these adhesion molecules are slid along the membrane until they can travel through the vessel wall to the site of inflammation.

Explain how patrolling cells are brought to the site of inflammation.

The developed T cell with a TCR goes into thymus. If the cell can recognise the MHC then it stays alive. Useful for diversifying repertoire, preventing autoimmune disease, maintaining good immune system.

Explain how positive selection in the thymus is achieved. Which cells are involved? What is the 'usefulness' of positive selection?

The success of the gene rearrangement process determines whether the B cell will proceed down a productive or non-productive pathway. If the rearrangement results in a functional heavy chain gene, it is considered a "productive gene rearrangement" and the B cell continues to develop into a mature, antigen-specific B cell. If the rearrangement results in a non-functional heavy chain gene, the B cell undergoes apoptosis, or programmed cell death. This mechanism ensures that only B cells with functional antigen receptors are allowed to mature and participate in the adaptive immune response.

Explain how the development of B cells (and T cells, see theme 4) is controlled by whether a 'productive gene rearrangement' occurs?

The beta chain is considered to be the heavy chain as it has three gene segments encoding the variable region. While the light chain resembles the alpha chain as there are only two gene segments. The TCR gene goes through VDG recombination. The VDG segments are joined together in a random combination to form a functional TCR. This makes lots of diverse TCRs and if the made TCR isn't viable then apoptosis.

Explain how the development of T cells (as for B cells) is controlled by a 'productive gene rearrangement'.

In the innate immunity, the macrophages are recognised by neutrophils. These macrophages produce IL-12 and the NK cells will produce IFN-gamma to stimulate phagocytosis in the macrophages. In the adaptive immune system, the IFN-gamma will also stimulate phagocytosis to eradication the infection in macrophages. When the bacteria are in the phagolysosomes both IFN-gamma and CD4+ T cells are needed. If the bacteria goes into the cytosol the cytotoxic t-cells are important

Explain how the immunity reacts to intracellular bacteria.

The first thing produced is type 1 interferons, which stop viral replication in the cells. Then NK cells are activated. In the adaptive system, the cytotoxic t-cells are important. Antibodies can neutralise a virus and prohibit infection of another cell.

Explain how the immunity reacts to viruses

The typical granulomas in TB arise as a result of the immune system's response to M. tuberculosis infection. The granuloma consists of a central core of infected macrophages surrounded by a layer of immune cells, including T cells, and is enclosed by a fibrous capsule. The granuloma helps to contain the infection and prevent the bacteria from spreading throughout the body.

Explain how the typical granulomas arise in TB

Membrane-bound Ig (mIg) is found on the surface of B-cells and functions as a receptor for antigens. When an antigen binds to the mIg, it triggers a signal transduction cascade that activates the B-cell and initiates the process of antibody production. Soluble Ig (sIg), on the other hand, is secreted by plasma cells, which are differentiated B-cells. sIg circulates in the bloodstream and other body fluids and functions to neutralize pathogens and activate other cells of the immune system. It is important to note that B-cells can switch between producing mIg and sIg during the process of antibody production. Initially, B-cells produce mIg, which serves as a receptor for the antigen. Once the B-cell is activated, it can differentiate into plasma cells, which secrete large amounts of sIg.

Explain how there are both membrane-bound and soluble Ig

Downregulation of MHC molecules: MHC molecules are critical for presenting tumor antigens to T cells. Tumor cells can downregulate MHC molecules, making it more difficult for T cells to recognize and target them. Upregulation of immune checkpoint molecules: Immune checkpoint molecules, such as PD-1 and CTLA-4, help to regulate the immune response and prevent excessive inflammation. Tumor cells can upregulate these molecules, which can inhibit T cell activation and promote immune evasion. Production of immunosuppressive factors: Tumor cells can produce factors that inhibit the function of immune cells, such as TGF-beta and IL-10, or promote the recruitment of immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). These factors can inhibit the activation and function of T cells and other immune cells, promoting immune evasion. Alteration of the tumor microenvironment: Tumor cells can alter the tumor microenvironment to promote immune evasion. For example, they can recruit immunosuppressive cells or induce the expression of factors that inhibit immune cell function. They can also promote angiogenesis, which can help to create a physical barrier that limits the infiltration of immune cells into the tumor. Production of decoy antigens: Tumor cells can produce antigens that mimic self-antigens or produce decoy antigens that compete with tumor antigens for recognition by T cells. This can reduce the ability of the immune system to recognize and target tumor cells.

Explain how tumor cells can actively inhibit the immune system.

If you want to reduce side effects you only use parts of the virus or bacteria. You only take part of the pathogen that is recognised and that is what you vaccinate with.

Explain subunit vaccines

Cross-presentation is a process by which extracellular antigens, such as those from viruses, bacteria, or tumors, are presented by MHC class I molecules to CD8+ cytotoxic T cells. This process allows the immune system to detect and eliminate infected or abnormal cells that do not express MHC class I molecules on their surface, which is typically the case for extracellular antigens.

Explain the concept of cross-presentation

A defective β2M gene can have significant consequences for antigen presentation and immune responses. The loss or dysfunction of MHC class I molecules can impair the recognition and elimination of infected or transformed cells and may contribute to the development of autoimmune diseases.

Explain the consequences of a defective β2 -microglobulin gene for antigen presentation.

Transplanting an organ in the presence of a positive cross-match test can have serious consequences, as the recipient's pre-existing antibodies can rapidly recognize and attack the transplanted organ. This can lead to hyperacute rejection, which is a severe and rapid form of rejection that can occur within minutes to hours after transplantation. Hyperacute rejection is characterized by widespread thrombosis (clotting) of blood vessels within the transplanted organ, leading to ischemia (lack of blood flow) and irreversible damage. Hyperacute rejection is often refractory to treatment and usually results in graft loss.

Explain the consequences of transplanting an organ when the cross-match test between donor and recipient is positive.

PAMPs and DAMPs are structures presented on the outside of microbes. These PAMPs and DAMPs have receptors on the antigen presenting cells which senses that there is something wrong. When these receptors on antigen presenting cells, there is a signal to induce a higher expression of costimulator molecules on the APC. CD80 and CD86 are the most important costimulator example. During the travel from the periphery to the lymph node, the dendritic cells will up regulate the MHC molecule and up regulate expression of costimulator molecule. If only the first signal (antigen recognition) and not the second signal (costimulatory) then there is no T-cell response or tolerance. And if there is a secondary signal there is a full T-cell response of survival, proliferation, and differentiation.

Explain the danger signal in PAMPs and DAMPs

After the B-cell has recognised the antigen and had an interaction with a T-cell, it will migrate back into the B-cell area o the lymph node to create the germinal centre. In this area, they interact with a subset of T helper cells which are called follicular T-helper cells. This follicular T-helper cells further interact with the B-cell and leads to further activation of the B-cell, including somatic maturation, affinity maturation, and isotope switching.

Explain the germinal centre reaction.

When there are large amount of of IL12, then a naive T-cell when activated will differentiate to a Th1 subtype which will produce large amount of interfere on gamma. This is regulated by the activation of gene by transcription factors, so in the end interfere on gamma is true. This is a feedback loop. Additionally, Th1 helps with the complement binding and opsonising IgG antibodies (B-cells) for the humoral response.

Explain the induction of Th1 cell.

IL6, IL1 and TNF beta. TH17 cells are specialised in the activation of neutrophils and the process of inflammation. Additionally, stimulating epithelial cells for increased barrier function.

Explain the induction of Th17 cell.

IL4 will induce Th2 cells as well as IL4, IL5, and IL13. Th2 cells also activate macrophages, which are involved in tissue repair. IL4, IL5, and IL13 activate eosinophils to produce intestinal mucus secretion. Th2 cells also interact with the T follicular helper cells (helper of B-cell), which produces IL4. This will then stimulate plasma cells producing IgG. IgG works against allergic reactions.

Explain the induction of Th2 cell.

Antibodies bound by the Fc receptor on the surface will lead to blocking in B cell receptor signalling.

Explain the inhibition of B-cells by negative feedback.

T-cells are activated by dendritic cells and B-cells are activated by follicular dendritic cells. They both migrate from their areas in the lymph nodes to come together. B-cells can pick up an antigen because they bind to it with an antibody. It phagocytosis this protein and then will be presented on the surface of the B-cell as a Class II MHC-peptide complex. A T-cell will recognise this. This T-cell will start upregulating CD40 ligand and it will start producing cytokines. The receptor ligand signal and the cytokines will lead to a further activation of the B-cell.

Explain the initial interaction between T and C cells.

By treating a dead organism you don't have the risk that they will mutate and cause harm to the individual. Once you treat such a pathogen, it that the antigenic epitopes must stay intact.. e.g. influenza

Explain the killed microorganism vaccine

There are two different ways. The first way is the cell produced perforin/granzyme. Perforin creates a hole in the target cell and granzymes goes through the whole and initiates apotheosis in the cell. The second way is that there is an interaction between Fas on CTL with Fas on target cell which also leads to apoptosis of target cell.

Explain the mechanisms of CTL-mediated killing of target cells

First one of the three pathways is activated by different recognition on the microbe. This leads to activation of C3. C3 gets cleaved into C3a and C3b. C3a enhances inflammation and recruitment of other cells. C3b will bind to the surface of microbes, which allows the immune system to find the microbe better. C3b also leads to the cleavage of C5 to C5a and C5b. C5b is a important protein leads to the membrane attack complex which leads to lysis of the microbe.

Explain the pathway of the complement activation.

CTLA-4 is a normal T-cell suppressing force that is expressed when there are too many T cells. CTLA-4 works on initial stage of priming CTLA-4 competes with CD28 (Costimulating receptor) with higher affinity to CD86. Acts as an off switch when bound.

Explain the role of anti-CTLA-4

TCR complex and core receptors cluster within membrane lipid rats upon antigen recognition. Lck (tyrosine kinase) phosphorylates tyrosines in ITAMS. ZAP-70 binds to phosphotyrosines and phosphorylates adaptor proteins including LAT (linker for the activation of T-cells). Assembly of adaptor protein and enzyme scaffolds; multiple signalling pathways are activated such as the activation of PLCγ1 = phospholipaseC γ1. PLCγ1 is activated by Itk, and cleaves phosphatidylinostiol bisphosphate (PIP2) to yield diaclyglycerol (DAG) and inositol triphosphate (IP3). IP3 increases intracellular CA2+ concentration, activating a phosphatase, calcineurin. Calcineurin activates a transcription factor, NFAT (nuclear factor of activated T cells). The transcription factors act to induce specific gene transcription, leading to cell proliferation and differentiation

Explain the steps of the early events in T cell activation.

They both have a peptide binding roof. HLA I is a single molecule because it has three alpha chains and one beta complex to make it stable. HLA II is a two molecules as it has two alpha chains and two beta chains. This allows for longer structures to fit in the binding roof.

Explain the structure of HLA Class I + II.

The T cell receptor comprises two chains for antigen recognition (αβ).Additional chains function in signal transduction, CD3 (δ, ε, γ-chain) and ζ-chains. In the cytoplasmic tails ITAM motifs are present

Explain the structure of the TCR complex

Follicular dendritic cells (FDCs) play a key role in determining the localization and survival of B cells within lymphoid organs, particularly in the context of B cell follicles.

Explain which types of cells in the lymphoid organs determine where B cells prefer to settle. What unique feature do these cell types have?

1. stromal cells: Stromal cells are specialized cells that provide support and organization for the immune cells within the lymphoid organs. They express specific adhesion molecules and chemokines that attract T cells to specific regions within the lymphoid organs. 2. Antigen-presenting cells (APCs): APCs, such as dendritic cells and macrophages, are key players in the immune response. They play a role in determining where T cells prefer to settle by presenting antigens to T cells, which in turn activates and directs the T cells to specific regions of the lymphoid organs. 3. B cells: B cells are responsible for producing antibodies in response to foreign antigens. They also produce cytokines that influence the localization and activation of T cells. 4. Fibroblastic reticular cells (FRCs): FRCs are specialized stromal cells that are found in the T cell zones of lymphoid organs. They provide a physical scaffold for the organization of immune cells, and also produce chemokines that attract and retain T cells in specific regions of the lymphoid organs.

Explain which types of cells in the lymphoid organs determine where T cells prefer to settle. What unique feature do these cell types have?

X-linked agammaglobulinemia (XLA) is a rare genetic disorder that affects the immune system's ability to produce antibodies, leading to recurrent bacterial infections. In XLA patients, the B cells are unable to differentiate into mature antibody-producing plasma cells, resulting in very low levels of immunoglobulins (antibodies) in the blood. In XLA patients, the immune response to bacterial infections is impaired due to the lack of antibodies. Without sufficient antibody production, the immune system is unable to mount an effective response to the bacterial infection, resulting in frequent and recurrent infections. As a result, the lymph nodes in the neck may not become externally palpable, as the immune response is not strong enough to cause visible swelling or inflammation. Therefore, XLA patients may not exhibit the typical signs and symptoms of a bacterial throat infection, such as swollen and tender lymph nodes, even though they may be infected with bacteria. Instead, they may experience recurrent infections, such as pneumonia, sinusitis, or ear infections, due to the underlying immune deficiency.

Explain why XLA patients will rarely have externally palpable lymph nodes during a 'normal' bacterial throat infection.

The selective expression of MHC II on professional APCs is functional in the context of an adequate immune response because it allows for specialized antigen presentation and activation of CD4+ helper T cells, which play a critical role in coordinating and regulating immune responses. In contrast, the expression of MHC I on most nucleated cells allows for the detection and elimination of intracellular pathogens

Explain why a selective expression of MHC II is functional in the context of an adequate immune response. Compare this to the expression of MHC I.

Ig heavy chain class switching occurs rapidly after activation of mature naïve B cells, resulting in a switch from expressing IgM and IgD to expression of IgG, IgE, or IgA; this switch improves the ability of antibodies to remove the pathogen that induces the humoral immune response.

Explain why an IgM-producing B cell can switch to an IgE-producing cell, while the reverse is not possible

Antigen-presenting cells (APCs) play a central role in the defense against tumor cells because they are responsible for presenting tumor antigens to immune cells. APCs, such as dendritic cells, macrophages, and B cells, have the ability to take up and process tumor antigens and then present them on their surface in a form that can be recognized by T cells. Tumor cells often have mutations or abnormal proteins on their surface that can serve as tumor-specific antigens. When APCs present these tumor antigens to T cells, it can activate an immune response against the tumor cells. The activated T cells can then proliferate and differentiate into effector cells, which can directly attack the tumor cells or activate other immune cells to target the tumor.

Explain why antigen-presenting cells play a central role in the defense against tumor cells. Similarly, how can a tumor antigen be presented to the immune system in order to achieve a specific immune response?

In patients with an IFN-γ receptor defect, the immune system is unable to respond to IFN-γ, which can lead to a decreased ability to control TB infection. Specifically, the IFN-γ receptor is important for the activation of macrophages, which are the primary immune cells responsible for killing the TB bacteria. Without a functional IFN-γ receptor, macrophages are unable to become fully activated and are less effective at killing the TB bacteria.

Explain why tuberculosis is also more severe in patients with an IFN-γ receptor defect.

In patients with HIV/AIDS, the virus attacks and destroys CD4+ T cells, leading to a weakened immune system. As a result, HIV-positive individuals are at a higher risk of developing TB, and are more likely to have severe and widespread TB disease.When the CD4+ T cell count is low, as in HIV/AIDS, the immune response to TB is weakened. This can result in a decreased ability to control the TB bacteria, leading to more severe and widespread disease. Additionally, HIV-positive individuals are more likely to develop extrapulmonary TB (TB outside the lungs), which is associated with higher mortality rates.

Explain why tuberculosis is more severe in patients with a low CD4 count (as in AIDS).

the failure of the immune system to recognize and clear tumor cells can be due to a complex interplay of factors related to the tumor cells themselves, the immune system, and the tumor microenvironment. Understanding these factors is critical for developing effective strategies to enhance the immune response against tumors.

Explain why tumor cells are not always recognized by the immune system and /or why are they not always cleared?

Maternal antibodies provide temporary humoral protection to fetuses and newborns through the transfer of maternal IgG antibodies across the placenta and the ingestion of maternal IgA antibodies in breast milk. This protection is not permanent and gradually decreases as the infant's immune system matures and begins producing its own antibodies.

Fetuses and newborns receive humoral protection from their mother. Which two mechanisms are responsible for that protection? Is this permanent protection or only temporary? Explain your answer

IgM antibodies

First antibody produced in response to infection

CD4+ T cells can assist CD8+ T cell responses in several ways. One of the most important mechanisms is through the production of cytokines which can activate and promote the survival and proliferation of CD8+ T cells. CD4+ T cells can also help to promote the differentiation of CD8+ T cells into cytotoxic T lymphocytes (CTLs), which are the effector cells responsible for killing infected or cancerous cells. CD4+ T cells can provide signals to other immune cells, such as APCs, to enhance their antigen-presenting and co-stimulatory functions. This can result in increased activation and differentiation of CD8+ T cells

For strong activation of cytotoxic T cells, the assistance of CD4-positive T cells is often required. How do CD4+ cells assist in the activation of CD8+ cells?

Antibody-dependent cell-mediated cytotoxicity (ADCC) is the effector function of antibodies for which no other components are required. IgA, especially the secretory IgA (sIgA) is particularly suited for this effector function because it is the predominant antibody isotype found in mucosal secretions such as saliva, tears, breast milk, and intestinal fluid. sIgA has a unique structure that allows it to bind to pathogens or toxins and prevent their attachment to the mucosal surfaces. Additionally, sIgA can interact with immune cells such as neutrophils, macrophages, and natural killer (NK) cells to mediate ADCC without the involvement of complement or other effector molecules.

For which effector function of antibodies are no other components required? Why does especially IgA exert this effector function?

In the thymus, T cells undergo a process of negative selection that eliminates self-reactive T cells, preventing them from entering the periphery. In the periphery, regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and preventing autoimmune reactions. Tregs can suppress the activation and effector function of other immune cells, including self-reactive T cells, through a variety of mechanisms. However, the balance between T cell activation and tolerance can be disrupted in certain circumstances, such as when there is a breakdown in central or peripheral tolerance mechanisms, or when there is chronic exposure to self-antigens. This can lead to the activation of self-reactive T cells and the development of autoimmune diseases.

Give a summary of the balance between T cell activation and T cell tolerance

Some examples of autoimmune diseases with a known genetic predisposition include: Type 1 diabete, Rheumatoid arthritis, Systemic lupus erythematosus (SLE), Multiple sclerosis. The mechanisms by which these genetic variants increase the risk of autoimmune disease are not fully understood. However, it is thought that these variants may lead to defects in immune system regulation, resulting in the activation of autoreactive immune cells and the development of autoimmune disease. Additionally, environmental factors, such as viral infections or exposure to toxins, may interact with genetic predisposition to trigger autoimmune disease development.

Give examples of genetic predisposition to certain autoimmune diseases. Which mechanisms play a role?

CTLA-4

High-affinity inhibitory cell-surface receptor on T cells that interacts with B7 co-stimulatory molecules.

Correlates of protection

Host immune responses associated with disease prevention

B and T cells typically meet each other in secondary lymphoid organs, such as lymph nodes and spleen, where they interact with each other to mount an immune response to an antigen. TCR-MHC-peptide interaction: This interaction occurs between the T cell receptor (TCR) on the surface of CD4+ T cells and the antigen-MHC complex presented by APCs. Co-stimulatory molecule interactions: These interactions involve the engagement of co-stimulatory molecules on the surface of APCs and T cells. Examples of co-stimulatory molecules include CD28 on T cells and CD80/86 on APCs. Cytokine signaling: CD4+ T cells produce cytokines, such as interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-6 (IL-6), that provide help to B cells by promoting class switching, affinity maturation, and plasma cell differentiation. BCR-antigen interaction: This interaction occurs between the B cell receptor (BCR) on the surface of B cells and the antigen. The specific molecular interactions involved depend on the type of antigen and the type of immune response required.

How and where do the B-and T cells meet each other? Which interactions are important for their cooperation?

Self-antigens are expressed in the thymus by specialized cells known as thymic epithelial cells (TECs). TECs play a critical role in the development and maturation of T cells, and they are responsible for presenting self-antigens to developing T cells during the process of negative selection. The expression of self-antigens by TECs ensures that developing T cells encounter a diverse range of self-antigens and are able to recognize and become tolerant to these antigens.

How are 'self-antigens' expressed in the thymus?

Autoreactive B cells can be eliminated through a process called clonal deletion, which occurs during B cell development in the bone marrow. B cells that recognize self-antigens with high affinity are either deleted or undergo receptor editing, a process where the B cell receptor (BCR) is altered to reduce its affinity for self-antigens.

How can autoreactive B cells be eliminated?

Autoreactive T cells that have escaped central negative selection in the thymus can be rendered harmless in the periphery through a process known as peripheral tolerance. Peripheral tolerance is essential to prevent autoreactive T cells from causing autoimmune responses in the body.

How can autoreactive T cells that have escaped the central negative selection in the thymus be rendered harmless in the periphery?

Regulatory T cells (Tregs) can exert their function through several mechanisms, including: Suppression of effector T cells: Tregs can suppress the activation and effector function of other immune cells, including self-reactive T cells. Tregs can do this by releasing inhibitory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which can inhibit the activation and proliferation of effector T cells. Cell-to-cell contact: Tregs can also exert their function through direct cell-to-cell contact with other immune cells. Tregs express high levels of cell surface molecules such as CTLA-4 and PD-1, which can bind to co-stimulatory molecules on other immune cells and prevent their activation. Metabolic disruption: Tregs can also exert their function by disrupting the metabolism of effector T cells. Tregs can consume IL-2, which is a growth factor that is critical for the activation and proliferation of effector T cells, thereby limiting their expansion. Cytotoxicity: Some Tregs, such as CD8+ Tregs, can also directly kill target cells through the expression of cytotoxic molecules such as perforin and granzyme.

How can regulatory T cells exert their function?

Autoimmune diseases can be classified based on the immunological reaction patterns they exhibit. The three main patterns of autoimmune diseases are: Organ-specific autoimmune diseases: In these diseases, the immune response is targeted against antigens specific to a particular organ or tissue. Examples of organ-specific autoimmune diseases include type 1 diabetes, in which the immune system attacks pancreatic beta cells, and Hashimoto's thyroiditis, in which the immune system attacks the thyroid gland. Non-organ-specific autoimmune diseases: In these diseases, the immune response is not restricted to a specific organ or tissue, but rather targets antigens that are widely distributed throughout the body. Examples of non-organ-specific autoimmune diseases include systemic lupus erythematosus (SLE), in which the immune system attacks a variety of self-antigens, and rheumatoid arthritis, in which the immune system attacks joint tissue. Immune complex-mediated autoimmune diseases: In these diseases, the immune system produces antibodies that form immune complexes with self-antigens, leading to tissue damage. Examples of immune complex-mediated autoimmune diseases include systemic lupus erythematosus (SLE), in which immune complexes can deposit in various tissues and organs, and glomerulonephritis, in which immune complexes deposit in the kidneys and cause damage.

How can the immunological reaction patterns of autoimmune disease be classified?

Intracellular microbes can stimulate the activity of T cells by presenting microbial antigens, producing pro-inflammatory cytokines, cross-presenting antigens, and releasing danger signals. These mechanisms help to activate and coordinate the immune response against intracellular infections.

How do intracellular microbes stimulate the activity of T cells?

If recognizes MHC 1 then CD8 cell, if MHC2, CD4 cell

How does MHC recognition by the T cell receptor regulate positive selection of CD4 or CD8- positive T cells in the thymus?

There are two types of MHC molecules: MHC class I and MHC class II. Peptides bind to these molecules in slightly different ways. The binding of a peptide to an MHC class I molecule occurs in the following steps: 1. Inside the cell, the protein to be presented is broken down into short peptide fragments by proteasomes. 2. The peptide fragments are transported into the endoplasmic reticulum, where they encounter MHC class I molecules that are waiting to be loaded with peptides. 3. The MHC class I molecule undergoes a conformational change, creating a binding groove that can accommodate peptides that are usually 8-10 amino acids long. 4. The peptide binds to the groove of the MHC class I molecule through a combination of hydrogen bonds, electrostatic interactions, and van der Waals forces. 5. The peptide-MHC class I complex is transported to the cell surface, where it is presented to cytotoxic T cells. 6. The binding of a peptide to an MHC class II molecule occurs in the following steps: 1. Antigen-presenting cells phagocytize foreign substances and degrade them into peptides. 2. The peptides are loaded onto MHC class II molecules in vesicles called endosomes. 3. The MHC class II molecule undergoes a conformational change, creating a binding groove that can accommodate peptides that are typically 13-25 amino acids long. 4. The peptide binds to the groove of the MHC class II molecule through a combination of hydrogen bonds, electrostatic interactions, and van der Waals forces. 5. The peptide-MHC class II complex is transported to the cell surface, where it is presented to helper T cells. It is possible for a single Major Histocompatibility Complex (MHC) groove to bind many different peptides because the groove is flexible and can accommodate peptides of different sizes and shapes. Additionally, the amino acid residues that line the groove can form different interactions with the peptide backbone and side chains, allowing for a wide range of peptide sequences to bind

How does a peptide bind to a MHC molecule? How is it possible that a single MHC groove can bind many different peptides?

Complement activation is an important mechanism of the innate immune system that helps to eliminate pathogens through a variety of effector mechanisms. One of the ways in which complement activation promotes B cell activation is through the generation of complement fragments that act as opsonins, which enhance the recognition and phagocytosis of pathogens by phagocytic cells such as macrophages and neutrophils. In addition to opsonization, complement fragments such as C3d can also directly activate B cells by binding to complement receptors on the surface of B cells. The binding of C3d to complement receptors on B cells enhances the recognition of antigen by the B cell receptor (BCR) by stabilizing the interaction between the BCR and antigen. Furthermore, complement fragments such as C3a and C5a can act as chemoattractants and recruit immune cells such as B cells, T cells, and dendritic cells to the site of complement activation. This recruitment of immune cells can enhance the interaction between B cells and T cells, which is required for effective B cell activation and differentiation.

How does complement activation promote B cell activation? Which part of the receptor complex that is involved in this process can bind Ag? Which part binds C3d? And which components transmit the signal intracellularly? Is CR2 a co-receptor or a co-stimulatory molecule?

Most effector cells die a few days after, however some become memory cells.

How does the generation of memory cells occur?

A MHC complex is on the end of a dendritic cell and contains a specific antigen. The T-cell recognises both the MHC peptide complex and the antigen. The T-cell receptor interacts with the MHC molecule and is activated.

How is a T-cell activated?

Depending on the pathogen present, a dendritic cell will activate a specific cytokine to then activate a specific T-cell that will destroy that pathogen.

How is is decided which the cytokine is activated?

When an antigen-presenting cell (APC) presents an antigen to a naive T cell, it provides signals that lead to the activation of the T cell. The cytokine environment at the site of infection or inflammation plays a crucial role in determining the type of Th cell that will be differentiated from the activated T cell. For example, the presence of IL-12 and IFN-gamma promotes the differentiation of Th1 cells, while the presence of IL-4 promotes the differentiation of Th2 cells. The antigen-presenting cells also provide co-stimulatory signals to the T cell, which are essential for its activation and differentiation. The co-stimulatory signals are provided by the binding of molecules such as CD80 and CD86 on the APC to the CD28 receptor on the T cell.

How is the differentiation of naive T cells into different Th subsets regulated?

The release of soluble antibody, which mediates the humoral immune response through pathogen neutralization, opsonization, and complement fixation. B lymphocytes have little cytoplasm and scanty organelles while plasma cells which differentiate from B cells have an abundance of rough endoplasmic reticulum

If a resting B lymphocyte is activated by an antigen, what will happen to this cell? Can plasma cells be distinguished from B cells based on their morphological characteristics?

When an infectious microorganism passes the epithelium, the first line of defense is the innate immune system, which includes various types of immune cells and molecules that respond rapidly to invading pathogens. These immune cells produce cytokines, which are signaling molecules that regulate the immune response and coordinate the activities of immune cells. The specific cytokines that are produced first in response to an invading microorganism can vary depending on the type of pathogen and the location of infection. However, some of the most common cytokines produced in the early stages of infection include: Interleukin-1 (IL-1), Tumor necrosis factor alpha (TNF-alpha), Interleukin-6 (IL-6), Interferon gamma (IFN-gamma), Interleukin-12 (IL-12)

If an infectious microorganism passes the epithelium, which cytokines will be produced first? And by which cells will these cytokines be produced?