Immunology

MHCI

(major histocompatibility complex): Short chains of amino acids (proteins) produced in(endogenous proteins) and displayed on healthy nucleated cells (not red blood cells). Communicates locally. Forskellige personer har forskellige MHC alleler, men de kan det samme Og hver MHC kan have tusindvis af subunits

Erythrocytes

Transport oxygen by hemoglobin

Inflammatory response

Uses chemicals to alarm in case of infection. Causes redness, swelling, heat(fever), and pain. - Mast cells in connective tissue send out histamine molecules. Causes vasodilation (creates redness and heat at site of injury). Heat increases the cells metabolic rate=faster repair. - Other inflammatory chemical signaling molecules include fatty acid prostaglandins, kininogen, and other plasma proteins, complement blood proteins and cytokines (CD8). - Histamine and other inflammatory chemicals also increase the permeability of blood vessels, causing nearby capillaries to release protein-rich fluids, that causes swelling. The leaked protein helps clot blood and form scabs, while lymphatic systems sucks up and filters that extra fluid, thus cleaning it before in enters back into the bloodstream. Local phagocytes and lymphocytes escape leaking capillaries and help destroy pathogens and cleaning up dead-cell.

Interferon

When a cell is infected with a virus, it excretes interferon (IFN), that another healthy cell binds on its receptors. The healthy cell then produces inactive enzymes, ready to take action if the cell is invaded by a virus (inactivation of replication).

Innate immunrespons on introducing bacteria in endothelia cells

When a endothelia cell gets infected by bacteria the local macrophage and mast cell gets activated by the chemical signals in the plasma saying "Hey! We got infected!". The macrophage recognize bacteria and the complement system get activated and produces C3a and C5a which stimulates the mast cell to degranulate and thereby release chemicals and histamin which make the membrane dilation and more permable. This results in increased flow of plasma in to the tissue. The macrophage releases chemicals which also makes the membrane more permable and makes the endothelia cells express adhesion molecules and CD8. The cytokines from the macrophage releases into the blood stream and the neutrofile cells receptors bind to these and stops for attacking by following the gradient of CD8. The neutrofile cells come in large number into the tissue to attack the bacteria. Here after the monocytes arrive in to the tissue and while they move through the epithelia cell they become macrophages. The influx of plasma induces the swelling.

Viral infection

When a virus infects a cell, the viral DNA will be replicated, and initiation of production of interferon. After replication of viral DNA, the Virus spreads to other cells and the first cell dies. The interferon is also transferred to other cells. And cells with interferon will not replicate the virus, but starts apoptosis.

Hypersensitivity

When immune reactions against antigens cause harmful tissue damage The mechanisms creating the damage can be divided into 4 types: I-IV

Hypersensitivity type 2 (cytotoxic) (IgG)

Works just like when any other pathogen comes into the body. E.g. when a person is given the wrong blood at a transfusion the body will treat the wrong blodtype like a pathogen because the body dont have antibodies for the antigens in the new blood. IgG antibodies

Bacteria may survive a macrophage attack by:

a: inhibiting of chemotaxis b: covering themselves with a non-immunogenic polysaccharide layer c: inhibit fusion of phagosome with lysosome d: being resistant towards lysosomal contents e: escaping into the cytoplasm f: changing the macrophage, so that it is no longer responsive to IFN-γ and cannot become activated

B cell receptor (BCR)

consists of an antigen-binding part: a monomeric immunoglobulin (Ig) unit (IgM or IgD in a naïve cell) and a signal transducing complex: CD79α + CD79β The Ig unit is fixed in the membrane by an extra, hydrophobic stretch of peptide All BCRs on the same cell has the same specificity

T cell receptor (TCR)

consists of an antigen-binding part: the TCR proper: a dimer consisting of an α and a β chain and a signal transducing complex: CD3 (consisting of four different chains: δ,ε,γ,ξ). The binding cite is at the top of the α and β chain. Bind to an antigen bound to MHCII on another cell membrane. There are two types of TCR receptors: CD4+-receptor, that binds to MHCII, and CD8+-receptor that binds to MHCI.

Exogenous antigen in the MHCII pathway

happens when a protein comes in through the cell membrane e.g. a virus protein from a vaccine. the protein is then processed in to peptides in vesicles (acidic). In the ER the synthesis of MHCII is finished and the MHCII is assembled through the ER and golgi, from where it is released to the cytoplasm in a vesicle. Here MHCII bounds to the matching peptide and is transported through the membrane to present a peptide for CD4+ T cells (helper).

Cytokines

influence itself, neighboring cells or distant cells

Phagocytosis

is performed by the phagocytes. The pathogen adheres to the phagocyte. The plasma membrane engulfs the phagocyte and thereby creates a phagosome. The phagosome fuses with a lysosome to form a phagolysosome. The enzymes from the lysosome digests the pathogen. The indigestible material forms a residual body, that is discharged from the phagocyte.

The anaphylatoxins, C3a and C5a

-Increase vascular permeability -Mediate contraction of smooth muscles -Are chemotactic for neutrophils and monocytes/macrophages -Initiate killing mechanisms in neutrophils, eosinophils and macrophages -Stimulate degranulation of mast cells, that release histamine to make the membrane more permeable.

Role of complement system in the innate system

-initiates inflammation when an infection starts -recruits leukocytes to the infection focus -recruitment of phagocytes -enhance uptake and killing of microorganisms by phagocytes -kills Gram-negative bacteria -removes soluble immunocomplexes from the circulation

The three steps in the innate immune system

1) Fever 2) Chemical signals 3) Inflammation

Bone marrows role in the immune system

1) Produces all blood cells (also T cells, but these are matured in the thymus) 2) Maturation of B cells. - The b cells express (get) their individual BCR. - All B cells that react with self-antigens will be induced to undergo apoptosis in the bone marrow or become defunct. - Only mature B cells can leave the bone marrow (where they are activated in the lymph nodes)

Cytotoxic T cells

that kill the infected cells (Tc may also produce IFN-γ)

Recruitment of phagocytes to a site of inflammation

A passing phagocyte cell grabs onto e-selektin on the surface of the blood vessel and rolls. Here it is activated by C8 binding to the receptor on the phagocyte. It stops, and slips through the blood vessel and into the tissue. Here it attacks (kemotaksi)

Endogenous (Virus) antigen in the MHCI

A virus infects the cell and a viral protein(endogenous antigen) is synthesised. Proteasomes break down the protein into peptides, that via a peptide transporter in the ER membrane gets attached to a newly synthesised MHCI. The peptide presenting MHCI is transported to the cell membrane through Golgi apparatus. The MHCI molekyle then present a CD8 for the CD8+ T cells (cytotoxic)

Activation and proliferation of the CD4+ helper T cell

Activated CD4+ T cell synthesizes and secretes IL-2 and synthesizes the IL-2 receptor α chain. The interaction of IL-2 and the high-affinity IL-2 receptor results in proliferation of CD4+ T-cell clone. Which in the end leads to differentiation into T-effector cells. Activation of CD4+ helper T cells leads to different functions of the cell depending on the cytokine received from the dendritic cell.

Antibody (humoral component)

Activates by the B cells and binds to the phagocyts cell membrane/cell wall, opsonize the bacteria, block bacterial adhesion, activate complement system, neutralize toxins Consist of immunoglobulins which have a double Y-shape consting of an antigen binding site at the top where the rest of the Y are where there are the biological activity. The bottom strings are the Fc region and the top string are the Fab regions. The bottom and the inner string at the top are the heavy chain and the outer string in the top are the light chain (see pic) There are 5 immunoglobulin classes, IgG, IgE, IgD, IgA and IgM. IgA and IgM consist of 5 Ig subunits in their heavy chains while the three others only have 4.

Activation of B cells

Activation needs 3 signals: Signal 1: Antigens bind to BCR and is engulfed by an endosome. The endosome fuses with a lysosome, and break down of the proteins happens. A vesicle from the Golgi, containing a newly synthesised MHCII fuses with the lysosome/endosome and MHCII binds peptides. The peptide binding MHCII is then moved to the surface to present the antigen. Signal2: CD40 on the B cell, bind CD40L on a T-helper cell. This up regulates the cytokine receptor on the B-cell. Signal3: Binding of cytokines from the T-helper cell. This makes the B-cell divide uncontrollably. It is also possible for the B-cell immunoglobin class to switch.

Physical barriers

All epithelia cells (skin and stoach lining) Mucus, movement of cilia Tears and Urin

Development of memory B cells

An activated B cell makes a switching of immunoglobin class. By doing this, it can transform into a memory B-cell. Memory B-cells can live for many years, and present the antigen for as long. It can also transform into a plasma cell, that produces antibodies.

Immunological synapse

An area in the T cell that is filled with T-cell receptors.

Hypersensitivity Type 3 (IgG)

An exess of antigens present in the body, will produce antibody-antigen complexes, that will bind complement-molecules and produce inflammation in places that is not necessary is infected, that will kill healthy cells. If immune complexes are present in the blood the most vulnerable organs are the kidneys where the blood is filtered. IgG antibodies

Paratitic infection

Antigens from the parasite binds to IgE antibodies bound on the mast cell. This makes the mast cell degranulate to release Histamine and signals for granulocytes (CD8) to arrive at the crime scene. The parasite is then coated in IgG and IgE antibodies and bound to granulocytes, which either hurts the parasite or in some cases excrete it.

Activation of T cells

Best activating cell is dendritic cells, then comes macrophages, monocytes (that turn into macrophages) and the least effective activator is B cells, that only activate itself. Gives increased glucose uptake, activation of the actin system and gene transcription, which leads to cell cycle. Within the immune synapse formed between APCs and T cells, three signals are required for antigen-specific T cell activation. Signal 1 comprises the presentation of antigen peptide, in the context of MHC molecules, which is recognized by the antigen-specific TCR. Signal 2 involves the stabilization of the synapse through adhesion molecules and the generation of signals via costimulatory molecules present on the surface of APCs and T cells. CD80/CD86 on APCs interact with their receptor, CD28, on T cells to generate activatory signals, while interaction with cytotoxic T lymphocyte-associated protein 4 (CTLA4) generates inhibitory signals (not shown). Signal 3 is produced by the secretion of cytokines by APCs, which signal via cytokine receptors on T cells in order to polarize them toward an effector phenotype. Ag, antigen.

Macrophages

Bigger, derived from monocyte white-blood cells that have moved out of the blood stream and occupies tissues. Uses cytoplasmic extensions to capture pathogens and bacteria, consumes, digests and spits the rest out. During digestion, the macrophages take tiny pieces of the pathogen and displays them on their outer membrane (MHCII). Can do this many times, lives longer. Is able to duplicate to get larger numbers. o Free types: Patrol tissues looking for pathogens o Fixes types: Fixed to fibers in specific organs, consuming anything suspicious passing by. (Ex. Stellate macrophages in the liver) If the macrophages can't kill the bacteria cell it can keep inside it self and then it activates a helper T cell to come and kill it.

Target killing by CD8+ effektor T cell (cytoxic T cell)

Binding of the of the Tc to the infected cell (i.e. recognition by TCR og a suitable virus Ag/MHC I complex on the cell surface) triggers the CTL to release perforins (pore-forming proteins) and granzymes (proteolytic enzymes). Granzymes pass through the pores and activate the enzymes that lead to apoptosis, a programmed suicide of the infected cell. Apoptosis occurs when certain granzymes activate a group of protease enzymes inside the target cell called caspases that destroy the protein structural scaffolding of the cell, degrade the cell's nucleoprotein, and activate enzymes that degrade the cell's DNA. As a result, the infected cell breaks into membrane-bound fragments that are subsequently removed by phagocytes. An advantage to killing infected cells by apoptosis is that the cell's contents, including viable virus particles and mediators of inflammation, are not released as they are during cell lysis.

IgE

Binds to mast cells, the binding leads to release of mast cells inflammatory mediates.

IgD

Binds to the B cells

Alternative pathway

C3 is constantly spontaneously cleaved. C3b binds to the surface of cells, and will form the alternative C3-convertase, leading to further cleavage of C3. The activation of the alternative pathway is inhibited by binding of factor H, which mainly binds mammalian cells and not bacteria. Cleavage of C3 by the C3 convertase into the fragments C3a and C3b, leading to formation of the C5 convertase, which cleaves C5 into C5a and C5b. Binding of C5b to the cell surface leads to formation of the membrane attack complex (MAC).

Activation of CD8+ cells

CD8+ effector cells activates by a virus or another pathogen meet a immature dendritic cell who take up peptide from the pathogen which activates MHCI and MHCII. MHCII bind to a TCR on a helper T cell who then binds and signal to a CD8+ T cell. MHCI from the dendritic cell binds to the CD8+ T cell and togther with the binding from the helper T cell activates the CD8+ effektor cell.

Complement systems three pathways

Classical pathway MB-Lectin pathway Alternative pathway

Natural killer cells (NK cells)

Controls blood and lymph looking for abnormal cells. Can move from infected cell to infected cell (Can kill more than one cell). Can kill your own cells if they are infected with viruses or have become cancerous, this happens when MHCI is not present on the cell membrane. When the NK cells detects a defective cell (MHCI), it pokes it with an enzyme(perforins) that triggers apoptosis (programmed cell death). Is a lymphocyte that is bigger than B-cells and T-cells.

Cross-Presentation

Dendritic cells can take in exogenous antigens and present them on MHC I molecules.

Dendritic cells

Dendritic cells do not really belong to the adaptive immune system as they have no antigen-specific receptors. But since they are crucial to the activation of T cells they may be said to belong to both the innate and the adaptive immune system. Express MHCII molecules.

MHCII

Displayed on Macrophages, dendritic cells and B-cells. Binds to fragments of exogenous antigens, like a virus that's been consumed, broken up and displayed to get the attention of other cells. Communicates locally. Forskellige personer har forskellige MHC alleler, men de kan det samme Og hver MHC kan have tusindvis af subunits

Toll-like receptors (TLR)

Effects of TLR-ligand interaction: • Production of cytokines and inflammatory mediators • Increased cell migration • In antigen presenting cells (dendritic cells): increased antigen presentation • Increased phagocytosis

Innate immunesystem (nonspecific)

External barricades (first line of defence): 1)Skin 2)Mucus membrane Internal defenses(second line of defence): 1)Phagocytes 2)Antimicrobial proteins 3)Attack cells Uses physical and chemical barriers, killer cells, and fever to keep you healthy. Consists of these cells: Phagocytes (Neutrophils and Macrophages) Natural killer cells (NK cells) Dendritic cells Mast cells

Secondary respons of antibody (second time they meet the antigen)

Faster production of antibodies Much higher concentrations of antibody The immunoglobulin class composition of the antibody response is different (more IgG etc) Higher affinity of antibodies Can be induced by lower amounts of antigen

Fc and Fc receptor

Fragment of Ig molecules the vertical double heavy chain. The top of the heavy chains are bound togther by S-S bounds. A complement binding region but can not bind to antigens. The receptor binds to the Fc region of the antibody. Normally an antibody has to react with an antigen before the Fc part of the antibody achieve enough binding potential to bind to the Fc receptor. The Fc receptor is found on the phagocytic cells, B cells and NK cells. Binding of antibodies to the Fc receptors can have different physiological functions, where phagocytosis and cell activating are the most common.

Thromocytes

Help stop bleedings.

Anti-inflammatory cytokines

IL-10 TGFβ Poor production of anti-inflammatory cytokines leads to autoimmunity. Over-production of anti-inflammatory cytokines leads to severe and chronic infections.

Pro-inflammatory cytokines

INFγ TNF ILI-β Over-production of pro-inflammatory cytokines leads to autoimmunity. Poor production of pro-inflammatory cytokines leads to severe and chronic infections.

Hypersensitivity type 1 (IgE)

If the body is exposed to e.g. pollen the CD4 drives the B cells to produce IgE in respons to the pollen antigens which binds to the mast who the degranulates and releases histamin. At the second expose to pollen the body will have the B memory cells and antibodies so the mastcells will make a acute release of histamin.

Affinity maturation

In the germinal centers a process that improves antibody quality. Somatic hypermutation in the B cell genome in the area that contact the antigen (complementarity determining regions - CDRs) • Subsequent selection of the B cells having the BCR with the highest antigen affinity

Membrane attack complex (MAC)

Is activated through he complement system. Several proteins bind to the cell membrane of the pathogen and initiates apoptosis.

Hypersensitivity Type 4

Is mediated by lymphocytes, not antibodies. Is called "Delayed type hypersensitivity" because the typical reaction is delayed 24-72 hours. When Th1 cells are presented to an antigen, it excretes cytokines that activated macrophages. The macrophages kills the infected cells that presents the right peptide containing MHCI.

IgA

Is the most common in secretes. It is charateristic by not being in the inflammatory reaktion. Block adhesion molecules on the surface of virus particles.

Secondary lymphiod organs

Lymph nodes (encapsulated) - "Filtering" the lymph The spleen (encapsulated) - "Filtering" the blood Diffuse lymphoid tissue (without capsule) - Spread out in the lamina propria of the intestine, where invasion of pathogens can be expected - Also in the airways and the uro-genitalial tracts - Larger masses of cells: the tonsils, Peyer's patches in the intesBne, the appendix

Chemical barriers

Lysosomes Anti-bacterial peptides Acid in stomach

Receptors on phagocytes

MHCI TLR-receptor Cytokine receptor for CD8.

The thymus role in the immune system

Maturation of T cells - T cells arrive to the thymus through the blood - T cells express(get) their individual TCR - only survive if the TCR reacts with MHC (positive selection) - stop expressing CD4 or CD8 depending on whether the TCR reacts with MHC I or MHC II - only survive it they do not react strongly with self peptides on MHC (negative selection)

Adaptive immune system (specific)

Memorizing, attacking (efficient) and systematic. Important cell types: T cells B cells (dendritic cells) Humorale component: Antibodies

Neutophils

Most abundant type of white blood cells. Self-destruct after consuming a pathogen and turns into pus. Always present, first to arrive.

Mast cells

Only present in tissue, not in the blood. Is stimulated by C5a from the compliment system, or by antigens binding to their IGE-antibodies. When stimulated is releases chemicals, for example histamine.

Phagocytes

trace down intruders and consume them. Includes Neutrophils and macrophages

Lymphoid organs

Primary: The place where the cells of the immune system mature. Bone marrow for B cells, Thymus for T cells. Secondary: The place where antigen and the cells of the immune system interact. Lymph nodes, spleen and diffuse lymphoid tissue.

Apoptosis

Programmed cell death

Cytokine receptor 1 and 2

Receptor type 1 generally binds IL molekyles where receptor type 2 generelly binds IFN molekyle. They both work as a JAK/STAT pathway, where when STAT is phosphorylated it sends out a transcription factor.

Activation of B cells in lymph nodes

Recirculating "naïve" lymphocytes(B-cells) enter the lymph node from the blood (in the post-capillary venules) and leave by the efferent lymph. Antigen enters in the afferent lymph. If recognized by the B-cells, the cells proliferate. Ultimately, the cells leave the lymph node via the efferent lymph.

Blood components

Red blood cells: erythrocytes (one) Platelets: thrombocytes (one) White blood cells: leukocytes (the rest)

Antihistamine

Suppress histamine if it is triggering an unwanted immune reaction.

Systematic type 1 reaction (anaphylaxis)

Systemic smooth muscle contraction, severe bronchiole constriction Systemic vasodilation leading to edema and a severe fall in blood pressure: anaphylactic shock Give adrenalin to reverse this.

Naïve T cells

T cells that have yet to meet an antigen. They are activated in secondary lymphoid tissue (dendritic cells with antigens travels to lymphoid cells and presents the antigen to the T cells)

Th1

T-helper cell (CD4+) produce IFN-γ, that activate the macrophages and make them able to kill the intracellular bacteria

CD4+ effector cells

Th1 secrete cytokines that activate macrophages and NK cells Th17 secrete cytokines that recruit and activate neutrophils and increase inflammation Other effector cells down-regulate the functions of other cells of the immune system (Treg)

IFN-γ

The IFN-γ cytokine released from T-helper cells, activate macrophages to kill an absorbed pathogen.

Classical pathway

The classical pathway is initiated when the C1 complex (C1q, C1r, C1s) binds to antibodies. This binding initiates the formation of the C3 convertase (C4bC2a). Cleavage of C3 by the C3 convertase into the fragments C3a and C3b, leading to formation of the C5 convertase, which cleaves C5 into C5a and C5b. Binding of C5b to the cell surface leads to formation of the membrane attack complex (MAC).

Central tolerance

The destruction of auto-reactive B cells in the bone marrow. The destruction of auto-reactive T cells in the thymus.

IgM

The first to be created by antigen stimulation, is a B cell receptor (BCR). Has good compliment binding properties and can make pentames with S-S binding. Block adhesion molecules on the surface of virus particles Agglutinate virus particles. Induce complement activation and thereby opsonization of virus through deposition of C3b (and iC3b, C3d).

MB-Lectin pathway

The lectin pathway is activated when a carbohydrate-binding complex (MBL or Ficolin) binds to polysaccharides on the bacterial surface, leading to formation of the C3 convertase. Cleavage of C3 by the C3 convertase into the fragments C3a and C3b, leading to formation of the C5 convertase, which cleaves C5 into C5a and C5b. Binding of C5b to the cell surface leads to formation of the membrane attack complex (MAC).

IgG

The most abundant Ig in the blood plasma, it is the most inporten in inflammatoric reaktions. Can cross the placenta from mother to fetes. Cover infected cells with antibodies allowing ADCC. Opsonize virus particles Block adhesion molecules on the surface of virus particles. Induce complement activation and thereby opsonization of virus through deposition of C3b (and iC3b, C3d).

B cells

The part of an antigen recognized by a B cell via its antigen-specific receptor (BCR) is called a B cell epitope B cells react on tertiary structure of proteins/antigen. B lymphocytes (B cells) respond to activation by differentiating into plasma cells and secreting antibodies (humoral immunity)

T cells

The part of an antigen recognized by a T cell via its antigen-specific receptor (TCR) is called a T cell epitope T cells react on small peptides from a degraded antigen (primary protein structure). T lymphocytes (T cells) cooperate with antigen-presenting cells on the recognition of antigen: activated T cells proliferate clonally and differentiate into effector cells (helper T cells (Th) or cytotoxic T cells (Tc)) There are two kinds of T cells: CD8 and CD4.

Leukocytosis

The release of neutrophils from the bone marrow into the bloodstream after chemical signals from site of injury. - Inflamed endothelial cells in the capillaries send out chemicals, so neutrophils cling to the capillary walls near injury, flatten themselves and squeeze through the vessel walls. - Monocytes arrive and transform into macrophages after leaving the blood, and basically takes over from neutrophils. - When there are too many pathogens, neutrophils and macrophages release pyrogen chemicals to the hypothalamus, that starts a fever to burn out the pathogens. - The fever increases metabolism of the cells, this makes healing go faster, and tells the liver and spleen to hold onto all of their iron and zinc to prevent bacterial growth. If this doesn't work, we call the adaptive immune defenses!