immuno
What ABs neutralize toxins and protects cells from their damaging action?
IgG
Activation of complement is triggered by binding of?
IgG or IgM to the surface of a pathogen
Describe ILCs
Lack B and T cell receptors Respond to infection Provide help similar to CD4 T cells but also have features of NK cells
What happens if there is deposition of immune complexes in the renal glomerulus?
Renal failure; as seen in systemic lupus erythrematosus
What are functions of the Secretory Component?
Retains secreted IgA in the mucous layer on the luminal surface through binding to mucins Protection from cleavage of Ig by proteases
The tonsils and adenoids form a ring of lymphoid tissues called ___________ around the entrance of the gut and the airway
Waldeyer's Ring
Infant response to TI ab response to polysaccharide antigens?
Weak response (Mostly immature B cells)
Intestinal lymphocytes carry out ____________
effector functions
Where are the muscosal tissues
eye, mouth, breast, urogenital tract
What are the four signs of infection?
-Dolor -Calor -Rubor -Tumor
What are the 2 conformations of IgM?
-Planar -Staple
3 Functions of IgG and IgA?
-neutralization of bacterial toxins -prevent virus binding -block adherence of bacteria to host cells
Protective immunity consists of
1)Preformed immune reactants 2)Immunological memory
What 3 kinds of signals do APCs deliver to naive T cells?
1-Activation 2-Survival 3-Differentiation
What is the course of a typical acute infection that is cleared by an adaptive immune response?
1-establishment of infection 2-induction of adaptive immune response 3-adaptive immune response 4-immunological memory
T cell memory half life after small pox vaccination *ABs show no significant decline *Restimulation by antigen not needed for memory maintenance
8-15 years
Which Igs are in the breast milk
A
Naive T cell
A naïve T cell is a T cell that has differentiated in bone marrow, and successfully undergone the positive and negative processes of central selection in the thymus. Among these are the naïve forms of helper T cells (CD4+) and cytotoxic T cells (CD8+). A naïve T cell is considered mature and, unlike activated or memory T cells, has not encountered its cognate antigen within the periphery
What ABs are used for protection of newborns?
A thru the breast milk E thru the placenta
2 Properties of of TD antigens?
AB response in infants Primes T cells
General functions of Fc Receptors?
Activation of accessory cells to attack pathogens Negative regulation of B cells, mast cells, macrophages and neutrophils by adjusting their threshold for activation Facilitate ingestions of antigen:AB complexes
Name some muscosal infections
Acute respiratory infection Diarrheal disease HIV/AIDS Tuberculosis Measles Hep B
Both the ___________ and _____________ of AB increase with repeated immunization
Affinity Amount
What is flowctyometry
Allows individual cells to be identified by their cell surface antigens (and sorted by FACS) -
Fc Receptors:
An Fc receptor is a protein found on the surface of certain cells - including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells - that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc (Fragment, crystallizable) region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection
Distinctive features of the mucosal immune system
Anatomical features Effector mechanisms Immunoregulatory environment
What is ADCC?
Antibody Dependent Cell Mediated Cytotoxicity - it is when AB coated target cells can be killed by NK cells
T cell dependent activation
Antigens that activate B cells with the help of T-cell are known as T cell-dependent (TD) antigens and include foreign proteins.[1] They are named as such because they are unable to induce a humoral response in organisms that lack T cells.[1] B cell response to these antigens takes multiple days, though antibodies generated have a higher affinity and are more functionally versatile than those generated from T cell-independent activation.[1] Once a BCR binds a TD antigen, the antigen is taken up into the B cell through receptor-mediated endocytosis, degraded, and presented to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane.[15] T helper (TH) cells, typically follicular T helper (TFH) cells, that were activated with the same antigen recognize and bind these MHC-II-peptide complexes through their T cell receptor (TCR).[16] Following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21.[16] CD40L serves as a necessary co-stimulatory factor for B cell activation by binding the B cell surface receptor CD40, which promotes B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as sustains T cell growth and differentiation.[1] T cell-derived cytokines bound by B cell cytokine receptors also promote B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as guide differentiation.[16] After B cells receive these signals, they are considered activated.[16] Now activated, B cells participate in a two-step differentiation process that yields both short-lived plasmablasts for immediate protection and long-lived plasma cells and memory B cells for persistent protection.[12] The first step, known as the extrafollicular response, occurs outside of lymphoid follicles but still in the SLO.[12] During this step activated B cells proliferate, may undergo immunoglobulin class switching, and differentiate into plasmablasts that produce early, weak antibodies mostly of class IgM.[17] The second step consists of activated B cells entering a lymphoid follicle and forming a germinal center (GC), which is a specialized microenvironment where B cells undergo extensive proliferation, immunoglobulin class switching, and affinity maturation directed by somatic hypermutation.[18] These processes are facilitated by TFH cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells.[12] Resultant plasma cells secrete large amounts of antibody and either stay within the SLO or, more preferentially, migrate to bone marrow.[18]
T cell independent activation
Antigens that activate B cells without T cell help are known as T cell-independent (TI) antigens[1] and include foreign polysaccharides and unmethylated CpG DNA.[12] They are named as such because they are able to induce a humoral response in organisms that lack T cells.[1] B cell response to these antigens is rapid, though antibodies generated tend to have lower affinity and are less functionally versatile than those generated from T cell-dependent activation.[1] As with TD antigens, B cells activated by TI antigens need additional signals to complete activation, but instead of receiving them from T cells, they are provided either by recognition and binding of a common microbial constituent to toll-like receptors (TLRs) or by extensive crosslinking of BCRs to repeated epitopes on a bacterial cell.[1] B cells activated by TI antigens go on to proliferate outside of lymphoid follicles but still in SLOs (GCs do not form), possibly undergo immunoglobulin class switching, and differentiate into short-lived plasmablasts that produce early, weak antibodies mostly of class IgM, but also some populations of long-lived plasma cells
Where do antigen binding B cells meet T cells?
At the border between the T cell area and a B cell follicle in secondary lymphoid tissue
B cell activation
B cell activation occurs in the secondary lymphoid organs (SLOs), such as the spleen and lymph nodes.[1] After B cells mature in the bone marrow, they migrate through the blood to SLOs, which receive a constant supply of antigen through circulating lymph.[10] At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR.[11] Antigen is presented to lymphocytes by APCs such as macrophages or dendritic cells (DCs),[11] and include proteins, glycoproteins, polysaccharides, whole virus particles, and whole bacterial cells.[1] Of the three B cell subsets, FO B cells preferentially undergo T cell-dependent activation while MZ B cells and B1 B cells preferentially undergo T cell-independent activation.[12] B cell activation is enhanced through the activity of CD21, a surface receptor in complex with surface proteins CD19 and CD81 (all three are collectively known as the B cell coreceptor complex).[13] When a BCR binds an antigen tagged with a fragment of the C3 complement protein, CD21 binds the C3 fragment, co-ligates with the bound BCR, and signals are transduced through CD19 and CD81 to lower the activation threshold of the cell
Describe lymphocyte entry into lymphoid tissues
Circulating lymphocytes enters the high endothelial venule in the lymph node Binding of L selectin allows rolling interaction LFA-1 activated by chemokines bound to ECM Activated LFA-1 binds tightly to ICAM-1 Lymphocyte migrates into the lymph node via diapedesis
Describe how an infection triggers an inflammatory response?
Bacteria trigger macrophages to release cytokines and chemokines Vasodilation and increased vascular permeability causes redness, heat, and swelling Inflammatory cells migrate into tissue releasing inflammatory mediators that cause pain
Most common diseases are caused by?
Bacterial toxins
What are FDCs?
Follicular Dendritic Cells; they are of non-hematopoietic origin; also non-phagocytic
T cells differentiate into central and effector memory subsets distinguished by expression of the chemokine receptor __________.
CCR7
____________ are required for the development of functional CD8 memory cells
CD4 T cells
Reduced protection against HCV reinfection in the absence of __________
CD4+ T cells
What are 2 ways that TI-2 antigens activate mature B cells?
Can signal B cells to produce pentameric igM ab Activated DCs can release a cytokine BAFF that aids production of ab against TI-2 antigens and induces class switching (M-->G)
What is the secretory component?
Cleavage of the extracellular domain of pIgR (polymeric immunoglobulin receptor) during the 2nd part of transcytosis
________________ to detect anti-Rh antibodies
Coombs test
How is B cell activation by TI-2 antigens enhanced (or what is required)?
Cytokines
What is the differentiation of naive CD4 T cells into subclasses of effector T cells influenced by?
Cytokines elicited by the pathogen
What activates Innate Lymphoid Cells ILCs?
Cytokines produced by innate sensor cells
Parameters influencing memory maintenance?
Cytokines: Yes e.g. IL-7, IL-15 MHC peptide interactions? Less dependent CD4 T cell help? Yes
Cytotoxic T cell
Cytotoxic T cells (TC cells, CTLs, T-killer cells, killer T cells) destroy virus-infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells since they express the CD8 glycoprotein at their surfaces. These cells recognize their targets by binding to antigen associated with MHC class I molecules, which are present on the surface of all nucleated cells. Through IL-10, adenosine, and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which prevents autoimmune diseases
What are the differences in the Ig isotypes?
Differences in: -the number and location of di-sulfide bonds -the distribution of N-linked carbohydrates -number of C domains -length of the hinge region
What is transcytosis?
Dimeric IgA is transported into the gut lumen through epithelial cells at the base of the crypt Dimeric IgA binds to the layer of mucus overlaying the gut epithelium IgA in the gut neutralizes pathogens and their toxins
The generation of 2ndary AB responses from memory B cells is __________ from the generation of the primary AB response
Distinct
What do surviving germinal center B cells differentiate into?
Either plasma cells or memory cells
The mucosal immune systems consists of two distinct compartments, the _________ and the ______________
Epithelium and the Lamina propria
What helps to clear immune complexes from circulation?
Erythrocyte CR1
What mediates the perinatal transfer of IgG?
FcRn (Fc Receptor neonatal) --MHC class I like molecule
Describe the process of antigen binding B cells and T cells meeting
Follicular B cells activated by antigen express CCR7 and migrate to boundary of the follicle and the T cell area T cells activated by antigen express CXCR5, migrate towards the follicle, and encounter activated B cells Activated B cells migrate to form a primary focus and differentiate into plasmoblasts
Where do ILCs originate?
From CLP (common lymphoid precursors)
Which Igs are given from Mother to child as maternal ABs
G
Which Igs are in extracellular fluids
G/A
Which Igs are in the blood
G/M
What is GALT
Gut associated lymphoid tissue The following comprise lymphoid tissue in the gut: Tonsils (Waldeyer's ring) Peyer's patches Lymphoid aggregates in the appendix and large intestine Lymphoid tissue accumulating with age in the stomach Small lymphoid aggregates in the esophagus Diffusely distributed lymphoid cells and plasma cells in the lamina propria of the gut
What is linked recognition?
Helper T cells activate B cells that recognize the same antigen: 1) B cells bind virus through viral coat protein 2)Virus particle is internalized and degraded 3) Peptides from internal proteins of the virus are presented to the T cell which activates the B cell 4)activated B cell produces ab against the viral coat protein
Expression of the ________ indicates which CD8 effector T cells can generate robust memory responses
IL7R
What AB cross linking on mast cell surfaces leads to a rapid release of inflammatory mediators?
IgE
Difference between mature and immature B cells?
Immature B cells are those still in final stages of development within the red bone marrow. Naive B cells are those which have left the bone marrow, before they bind to the antigen for which they're specific. These are, as you note, both IgM and IgD positive. Even after being stimulated by their specific antigen and secreting specific IgM to it, B cells aren't considered mature until they differentiate into clones of daughter cells, most of which become plasma cells. A small percentage of each clone of daughter cells become memory cells, which account for the phenomenon of immunologic memory.
How do DCs initiate adaptive immune responses?
Immature DCs reside in peripheral tissues DCs migrate via lymphatic vessels to regional lymph nodes Mature DCs activate naive T cells in lymphoid organs
What type of B cells can TI-1 antigens activate?
Immature and mature B cells
Infection and Response Stages
Local infection, penetration of epithelium Protection against infection: Wound healing induced antimicrobial proteins and peptides, phagocytes, and complement destroy invading microorganisms Local infection of tissues Protection against infection: Complement activation; DCs migrate to lymph nodes; phagocyte action; NK cells activated; Cytokines and chemokines produced Lymphatic Spread Protection against infection:Pathogens trapped and phagocytosed in lymphoid tissues; adaptive immunity inititated by migrating DCs Adaptive Immunity Protection against infection: Infection cleared by specific AB, T cell dependent macrophage activation and cytotoxic T cells
Which tissue homing receptors are induced during T cell priming depends on the _________________, which itself is influenced by _______________________.
Lymph node environment Tissue derived DCs
Talk about antigen uptake in mucosal tissue
M cells take up antigen by endocytosis and phagocytosis Antigen is transported across the M cells in vesicles and released at the basal surface Antigen is bound by DCs, which activate T cells
Expression of __________ alters when naive T cells become memory T cells
Many proteins
Memory B cell activation
Memory B cell activation begins with the detection and binding of their target antigen, which is shared by their parent B cell.[20] Some memory B cells can be activated without T cell help, such as certain virus-specific memory B cells, but others need T cell help.[21] Upon antigen binding, the memory B cell takes up the antigen through receptor-mediated endocytosis, degrades it, and presents it to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane.[20] Memory T helper (TH) cells, typically memory follicular T helper (TFH) cells, that were derived from T cells activated with the same antigen recognize and bind these MHC-II-peptide complexes through their TCR.[20] Following TCR-MHC-II-peptide binding and the relay of other signals from the memory TFH cell, the memory B cell is activated and differentiates either into plasmablasts and plasma cells via an extrafollicular response or enter a germinal center reaction where they generate plasma cells and more memory B cells.[20][21] It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs
Memory T cells
Memory T cells are a subset of infection- as well as potentially cancer-fighting T cells (also known as a T lymphocyte) that have previously encountered and responded to their cognate antigen; thus, the term antigen-experienced T cell is often applied. Such T cells can recognize foreign invaders, such as bacteria or viruses, as well as cancer cells. Memory T cells have become "experienced" by having encountered antigen during a prior infection, encounter with cancer, or previous vaccination. At a second encounter with the invader, memory T cells can reproduce to mount a faster and stronger immune response than the first time the immune system responded to the invader. This behaviour is utilized in T lymphocyte proliferation assays, which can reveal exposure to specific antigens
Secondary and subsequent responses are mainly attributable to __________________
Memory lymphocytes
How do monocytes circulating in the blood migrate into infected and inflamed tissues?
Monocyte binds adhesion molecules on vascular endothelium near site of infection and receives chemokine signal The monocyte migrates into the surrounding tissue Monocyte differentiates into a macrophage and migrates to the site of infection
Where is the human microbiota located
Moth, esophagus, stomach, skin, colon, vagina
The subsets of CD4 T cells each produce cytokines that can...
Negatively regulate the development of effector activity of other subsets
What do Fc and complement receptors do?
On phagocytes they trigger the uptake and degradation of AB coated bacteria
Where are intestinal immune cells located?
Organized lymphoid tissues -Mesenteric lymph nodes -GALT**see next slide Scattered lymphoid cells -in the epithelilum -in the Lamina propria
What induces changes in DCs stimulating them to migrate and initiate adaptive immunity?
PRRs sensing PAMPs (Pattern Recognition Receptors sensing Pathogen Associated Molecular Patterns)
Plasma cells
Plasma cells, also called plasma B cells, plasmocytes, plasmacytes, or effector B cells, are white blood cells that secrete large volumes of antibodies. They are transported by the blood plasma and the lymphatic system. Plasma cells originate in the bone marrow; B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell. Once released into the blood and lymph, these antibody molecules bind to the target antigen (foreign substance) and initiate its neutralization or destruction
What happens with a high concentration of TI-1 antigen?
Polyclonal B cell activation: nonspecific antibody response
SMALLPOX:Differences between Primary (unimmunized) and Secondary response (immunized)
Primary: IgM>igG; affinity of AB low; somatic hypermutation low 2ndary: igG,IgA; affinity of AB high; somatic hypermutation high
What does the muscosal immune system protect?
The internal surfaces of the body
Details on TI-2 antigens
Second group of TI antigens consists mainly of highly repetitive surface structures (epitopes) of encapsulated bacteria. They do not have an intrinsic B-cell activating activity. The activation of B lymphocytes is caused by cross-linking of a critical number of B cell receptors, which leads to accumulation of BCRs and cross activation of these receptors. It results in proliferation and differentiation of B lymphocytes and production of antibodies. TI-2 antigens can activate only mature B lymphocytes. Immature B cells are anergized, so they do not elicit any immune response. That may explain why children up to 5 years are not capable of producing effective antibodies against polysaccharide antigens. It might be because the majority of their B cell population is immature.[2] Even though the response on TI antigens is not dependent on T lymphocytes, there are some cytokines, produced mainly by T lymphocytes and natural killer (NK) cells, necessary for eliciting reaction against these antigens. The most necessary are interleukin 2 (IL-2), interleukin 3 (IL-3) and interferon γ (IFN-γ).[1] Moreover, additional stimulation by dendritic cells (DC) and macrophages is required
What is the major class of ab present in the lumen of the gut?
Secretory dimeric igA
What identifies effector CD8 T cells that give rise to long lived memory cells?
Selective expression of the interleuken 7 receptor
2 functions of the B cell receptor
Signaling Facilitates uptake of the bound antigen
How can you distinguish bound AB and free Ig?
State of aggregation -Free Ig doesnt cross link Fc Receptors leading to no activation of macrophage and no destruction of the bacterium -Aggregation of Ig on the bacteria surface allows cross linking of Fc Receptors leading to activation of the macrophage and destruction of the bacteria
Adult response to TI ab response to polysaccharide antigens?
Strong response
Helper T cells
T helper cells (TH cells) assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages. These cells are also known as CD4+ T cells because they express the CD4 glycoprotein on their surfaces. Helper T cells become activated when they are presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells (APCs). Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the active immune response. These cells can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, TH9, or TFH, which secrete different cytokines to facilitate different types of immune responses. Signalling from the APC directs T cells into particular subtypes
What happens with a low concentration of TI-1 antigen?
TI-1 antigen specific ab response
Details on TI-1 antigens
TI-1 antigens have an intrinsic B cell activating activity, that can directly cause proliferation and differentiation of B lymphocytes without T cell stimulation and independently of their BCR specificity. TI-1 antigens activate B-cells via Toll like receptors, which are, in human, expressed on the surface of B lymphocytes after BCR stimulation. In higher concentrations, TI-1 antigens bind to BCR and TLR of various clones of B lymphocytes, which leads to production of multiclonal antibodies. But when the concentration of TI-1 is lower, it can activate only B lymphocytes with specific binding of TI-1 on their BCR, and leads to production of monoclonal antibodies.[1] This part of immune response may be important in some early stages of infection by extracellular pathogens, because it is rapidly activated and does not require T cell help or clonal maturation and expansion. An example of TI-1 antigen is lipopolysaccharide (LPS) or bacterial DNA
Plasmablasts
The most immature blood cell that is considered of plasma cell lineage is the plasmablast.[3] Plasmablasts secrete more antibodies than B cells, but less than plasma cells.[4] They divide rapidly and are still capable of internalizing antigens and presenting them to T cells.[4] A cell may stay in this state for several days, and then either die or irrevocably differentiate into a mature, fully differentiated plasma cell.[4] Differentiation of mature B cells into plasma cells is dependent upon the transcription factors Blimp-1/PRDM1 and IRF4.
Where do most infections happen through?
The mucosal tissues
What do effector T cells change allowing them to home to sites of infection?
Their surface molecules
What are skin homing T cells?
They use specific combinations of integrins and chemokines to migrate specifically to the skin
What is the 2nd signal required for B cell activation
Thymus Independent Antigen (TI-1, TI-2) (T independent antigen elicits antibody production by B lymphocytes without T lymphocyte involvement. There are 2 distinct subgroups of TI antigens, different in mechanism of activating B lymphocytes. TI-1 antigen, which has an activity that can directly activate B cells and TI-2 antigen, which has highly repetitive structure and causes simultaneous cross-linking of specific B cell receptors (BCR) on B lymphocyte. The most commonly released isotype of antibodies in this type of immune reaction is low affinity IgM
Describe how ABs neutralize toxins and protects cells from their damaging action?
Toxin binds to cellular receptors Endocytosis of Toxin:receptor complexes Dissociation of toxin to release active chain, which poisons the cell AB protects cell by blocking binding of toxin
What enforces mutually exclusive B cell and plasma cell gene expression?
Transcriptional repression
T cell subpopulations
Within the overall memory T cell population, at least three distinct subpopulations have been described and can be recognised by the differential expression of chemokine receptor CCR7 and L-selectin (CD62L).[1] Stem memory TSCM cells, like naive cells, are CD45RO−, CCR7+, CD45RA+, CD62L+ (L-selectin), CD27+, CD28+ and IL-7Rα+, but they also express large amounts of CD95, IL-2Rβ, CXCR3, and LFA-1, and show numerous functional attributes distinctive of memory cells.[2] Central memory TCM cells express L-selectin and the CCR7, they secrete IL-2, but not IFNγ or IL-4. Effector memory TEM cells, however, do not express L-selectin or CCR7 but produce effector cytokines like IFNγ and IL-4.
Prevention of hemolytic disease by administration of ___________________
anti-Rh antibodies
