Outcome 3 Flashcards
(159 cards)
1
Q
discuss the inheritance of the MHC genes
A
MCH class I and II molecules are co-dominantly expressed, Thus every nucleated cell expresses up to six different HLA class I and six different HLA class II molecules. One set is inherited from each parent. MHC genes are highly polymorphic, preventing two individuals from having the same MHC genes
2
Q
state the other common name the MHC complex is known by
A
Human Leukocyte Antigen Complex (HLA)
3
Q
discuss where MHC class I and class II molecules are located
A
MHC I: Expressed on nearly all nucleated cells (important to note RBCs do not have a nucleus and therefore do not display MHC I). Neurons and sperm cells at certain stages of differentiation appear to lack MHC I.
MHC II: APCs
4
Q
explain how antigens are processed and presented with MHC class I molecules (endogenous)
A
Endogenous antigen processing occurs inside of the cell and happens when the endogenous antigen is bound to the class I MHC molecule on the cell’s surface. This signals that the cell has been infected and requires help.
- Digestion of the antigen into peptide fragments.
- Synthesis of MHC class I molecules.
- Binding of peptide fragments to MHC class I molecules.
- Packing of the Ag-class I MHC molecule.
- Insertion of Ag-class I MHC complex into the plasma membrane.
Cytotoxic T lymphocytes (CD8) are activated and destroy the cell.
5
Q
explain how antigens are processed and presented with MHC class II molecules (exogenous)
A
Exogenous antigen processing occurs outside of the cell. Antigens that are present in extracellular fluid are ingested by APC by endocytosis or phagocytosis.
- Ingestion of antigen
- Digestion of Ag into fragments
- Synthesis of class II MHC molecules
- Packaging of class II MHC molecules
- Fusion of vesicles
- Binding of peptide to class II MHC molecules
- Insertion of Ag-class II MHC complex into the plasma membrane.
APC is not destroyed, the T helper cell (CD4) activates macrophages, and B cells (to produce an antibody response)
6
Q
explain MHC restriction
A
A T cell response is only generated if a peptide created during the processing of an antigen is bound to an MHC molecule. All peptides can fail to bind to an MHC molecule, and no T-cell response will occur.
This occurs in vaccination, as some peptide fragments are too small, and therefore not recognized by the individual.
7
Q
discuss the role of MHC in transplantation
A
MHC class I and II molecules will respond to the non-host MHC molecules on the graft, starting an immune response and graft rejection.
8
Q
Define Polygenicity
A
MHC class I and II molecules are coded for by multiple independent genes.
9
Q
Define Polymorphism
A
Multiple stable forms of each MHC gene exists in the population.
10
Q
differentiate between humoral and cell-mediated immunity
A
Humoral Immunity: Immune responses that involve antibodies. Can be transferred to another individual using an antibody-containing serum. Occurs when an antigen is found within an extracellular fluid.
Cell-mediated Immunity: Immune responses mediated by T cells. Occurs when the antigen is found within body cells.
11
Q
identify the effector cells of adaptive immunity
A
B lymphocytes
T lymphocytes
APCs
12
Q
explain clonal expansion/selection
A
When a lymphocyte identifies an antigen, the lymphocyte with proliferating and differentiates to respond to the specific antigen. The result is thousands of lymphocytes specialized for the antigen within secondary lymphatic organs.
Two populations of cells are created - effector and memory cells. Effector cells will perform the immune response functions, and memory cells will circulate and remember the antigen for future infections.
13
Q
define and state the purpose of the MHC classes
A
MHC I: The major function is to present peptide antigens to Tc Cells (CD8). Additionally MHC I molecules will prevent NK cells from killing normal host cells.
Helps the immune system identify host cells from antigens.
MHC II: The main function is to present peptides to T Cells (CD4).
Helps the immune system to identify antigens.
MHC III: Genes encode products that have immune functions (complement, cytokines, and TNF).
14
Q
identify the MHC class present on APCs
A
MHC I and MHC II
15
Q
describe antigen processing
A
Antigens must be processed with the APC and presented to specific T cell receptors (TCRs) on the T cell.
16
Q
differences between MHC classes and what is the end result of antigen processing.
A
MHC I: Occurs inside of the cell, and ends in cell death. CD8 cells. HLA-A, HLA-B, HLA-C.
MHC II: Occurs outside of the cell, and ends in an antibody response. CD4 cells. HLA-DP, HLA-DQ, HLA-DR.
17
Q
define and differentiate between antigens and immunogens
A
Antigens: Any agent capable of binding specifically to components of the immune system. Can be complete (immunogen) or incomplete (hapten).
Immunogen: Any agent capable of inducing an immune response (Production of antibodies)
All immunogens are antigens, but not all antigens are immunogens.
18
Q
the requirements for immunogenicity
A
Foreignness, size, complexity, degradability
a. Foreignness
The molecule must be recognized as nonself, the more foreign the more immunogenic.
b. size (mw)
The larger the molecule the more immunogenic. Carrier molecules can be added to increase molecular weight.
c. complexity
The more complex the molecule the more immunogenic. Large simple molecules will be less immunogenic than small complex molecules. Proteins elicit the best response, followed by carbohydrates. Lipids/nucleic acids elicit a poor response. particulate/aggregated antigens yield better responses than soluble antigens.
d. degradability (APC uptake and processing)
The antigen must be susceptible to enzymatic degradation. Molecules that cannot be phagocytosed or processed by APCs cannot stimulate an immune response.
Two factors must generally exist for an antigen to be degradable.
1. The antigen must be stable so that it can exist long enough to interact with a B or T cell to initiate an immune response.
2. The antigen must be susceptible to enzymatic degradation so that the antigen can be processed by APCs.
19
Q
list host factors that may influence immune response to an antigen
A
Host factors can prevent an immune response even if all the properties of immunogenicity are present in an antigen.
The genotype of the host affects the type and degree of the immune response. MHC gene products play a role in determining the degree to which the host will respond to an antigen.
Age - very young and elderly individuals have decreased immune system function due to immaturity or degeneration.
Health- illness can contribute to weaker immune responses.
Stress
Nutrition
20
Q
define epitope/antigenic determinants
A
They are the only immunologically active portions of antigens. Meaning they are where receptors on lymphocytes or antibodies bind, and they stimulate the activation and clonal expansion of antigen-specific T cells. Antigens can have multiple epitopes, and B and T cell receptors may recognize different epitopes on the same immunogen. As both B and T cells can recognize epitopes both humoral and cell-mediated responses can be mounted.
21
Q
Epitopes recognized by B cell
A
Membrane-bound antibodies on B cells recognize and bind to free antigens in solutions. These antigens generally have epitopes on the outside of their cell, making the epitopes accessible for interactions with the BCR on b-cell antibodies.
22
Q
Define conformational or Discontinuous epitopes
A
Epitopes that are non-contiguous residues along a polypeptide chain are brought together by the folded conformation of the protein.
B cell recognized epitopes.
23
Q
Epitopes recognized by T cells
A
T cells are unable to bind to soluble antigens. For TCRs to interact with epitopes the antigen first go through antigen processing by an APC to degrade the polypeptide chain into smaller peptide chains.
24
Q
Define continuous or linear epitopes
A
Epitopes are small peptide chains created during antigen processing.
T cell TCRs recognized epitopes.
25
define hapten
A substance that is capable of reacting with an antibody but cannot induce antibody formation unless it is bound to a carrier molecule. Haptens that are not bound to carrier molecules have too low of a molecule weight and are too chemically simple to induce an immune response.
26
identify the major classes of antigen composition
Protein, carbohydrates, lipids/nucleic acids.
Particulate/aggregate and soluble
27
discuss cross-reactivity
Cells/Antibodies may be able to react with two different molecules (two different antigens) that share epitopes.
When antibodies/cells with specificity to one epitope bind to another epitope that is not identical. (antibody/cell binds to an antigen it is not specific to). The epitopes must be structurally similar. The “wrong” epitope will elicit a weaker bond than the “correct” epitope.
Heterophilic Antigens - When cross-reacting substances are unrelated to each other. ABO blood group system is an example.
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toxoid
An inactivated toxin whose toxicity has been suppressed by chemical or heat treatment while immunogenicity is maintained. - Altered form of toxins secreted by bacteria.
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heterophile antigen
A cross-reacting antigen expressed by widely different species including humans and bacteria.
30
define adjuvants
Substances that enhance the immunogenicity of an antigen and are used in vaccine preparations.
Effects:
Prolong antigen persistence (increases half-life of antigens)
Enhance costimulatory signals
Increase local inflammation by converting soluble proteins into particulate forms - enhance phagocytosis.
Improve antigen delivery and processing.
increases the production of local inflammatory cytokines
31
describe the factors that affect immunogenicity: Route of administration.
Various routes of administration will influence which immune organs and cell populations will be involved with the response.
Subcutaneous/Intramuscular - high immune response due to dendritic cells processing and transporting antigens to lymph nodes.
Intravenous - Moderate/low immune response. Antigens are carried to the spleen.
Intragastric - Low, mainly a local response is elicited. Often induces tolerance.
Intranasal - Low immune response. Mainly allergic reactions.
32
describe the factors that affect immunogenicity: Dosage
Too little or too much of the antigen may induce tolerance in the host, preventing an immune response. Various routes of administration will influence which immune organs and cell populations will be involved with the response.
33
Define Immunogenicity
The ability to produce a cell-mediated or humoral response.
34
Define Antigenicity
The ability to combine specifically with the final products of the immune response.
35
Define Tolerance
The ability to distinguish between self and non-self
36
Freund’s complete adjuvant
The most common adjuvant - consists of mineral oil, lanolin, and heat-killed Mycobacterium tuberculosis (TB). Allows the antigen to be released slowly and continuously, prolonging antigen exposure.
37
Freund’s incomplete adjuvant
Consists of mineral oil and lanolin.
38
Antigen Recognition
The more epitopes that are processed the more diverse the immune response will be.
B cells bind to soluble antigens, these tend to have accessible epitopes and consist of proteins, polysaccharides and lipids.
T cell epitopes are derived from internal amino acid sequences that have been enzymatically digested during antigen processing and then bound to MHC molecules allowing them to be recognized by T cell receptors. Can only recognize proteins.
39
Binding of antigens
Binding occurs through electrostatic interactions (hydrogen bonding), hydrophobic interactions, and Van Der Waals forces. Binding does not involve covalent bonds.
40
Define Signal Transduction
Lymphocyte receptors with other molecules deliver intracellular signals that activate the cell to respond.
41
Define Carrier
A high molecular weight compound to which a hapten combines. Makes the hapten immunogenic.
42
List the major classes of antigens.
1. Carbohydrates (polysaccharides): Only immunogenic when associated with protein carriers. ABO blood group is an example.
2. Lipids: Rarely immunogenic unless bound to protein carriers. Cab be regarded as a hapten.
3. Nucleic acids: Poor immunogens, become immunogenic when they are bound to protein carriers.
4. Proteins: Virtually all proteins are immunogenic. The greater the degree of complexity of the protein the greater the immune response. Proteins contain multiple epitopes.
43
Define Homologous
Denotes that the antigen and the immunogen are the same.
44
Define Heterologous
Denotes that the substance used to induce the immune response is different from the substance that is used to react with the products of the induced response.
45
Define exogenous antigens
Antigens that come from outside a host cell and are taken inside, normally by endocytosis or phagocytosis. Interacts with MCH class II/CD4 cells.
46
Define endogenous antigens
Proteins are synthesized inside a cell and are generally derived from pathogens that have infected a host cell. Interacts with MHC class I/CD8 cells.
47
Define superantigen
Exotoxins produced by pathogenic bacteria that bind ti MHC class II. Activating huge numbers of CD4 T cells which secrete high levels of cytokines into circulation. This exaggerated release of cytokines ca cause fever, shock, or death.
48
Discuss the general characteristics of an immunoglobulin.
Immunoglobulins are produced by plasma cells and can be either membrane-bound (B-cells), or soluble molecules that are secreted into plasma and body fluids.
They will have two major functions:
1. Binding of foreign antigens.
2. Mediating effector functions to neutralize or eliminate foreign invaders.
49
Fab
Binds to antigens and marks it for the immunological attack. Additionally activates nonspecific defence mechanisms that can destroy the antigen. Each antigen has two fab fragments.
50
Fc
Crystallizable portion. Does not bind antigens, but mediates binding to host cell receptors, and additionally contains the biological functional portion of the antibody. The first component of the complement system. Allows different antibodies to carry out the same functions even with different epitope binding specificities.
51
Light chains
There are two types of light chains. Normal antibodies will only have one type of light chain. Light chains that are produced in excess are excreted in urine (called Bence-Jones proteins).
Kappa: 60% of light chains in humans.
Lamda: 40% of light chains in humans. Four subtypes exist (λ1,λ2,λ3,λ4), with the difference being amino acid substitutions.
52
Heavy chains
There are five isotypes of heavy chains, and they relate to antibody specificity. IgG, and IgA have subtypes, which differ in the number and arrangement of the interchain disulphide bonds and alterations in structural features producing changes in functional properties.
53
variable domain
The V of the VDJ chain.
54
Constant domain
where isotype switching occurs, and the area on a chain that tells you if it is a light or heavy chain. Causes antigen specificity.
55
CDR
Complementarity-determining regions. The region that forms the antigen binding site of the antibody. There are three CDRs on both heavy and light chains (6 CDRs per antibody). CDRs are unique to each antibody and are responsible for antibody specificity. Located in loops that connect VH and VL domains. Provides diversity of the shape of the binding site to create ABs of different specificities.
56
hinge
The extended peptide sequence that connects the CH1 and CH2 domains. Provides flexibility between the two fab arms of the Y-shaped antibody. Allows the two Fab arms to open and close to accommodate binding to two identical antigenic epitopes.
57
V region
The variable region- consists of the first 110 amino acids of both the light and heavy chains. The v regions amino acid sequence determines the antigen specificity of the antibody
58
C region
The constant region - occurs after the v region. This region remains constant and is the site of attachment for carbohydrates. The C region on heavy chains determines the effecter function of the antibody.
59
J Chain
The Joining chain- a small glycoprotein that is found in IgM and IgA. It joins monomers of the basic immunoglobulin unit.
60
IgG
The most abundant immunoglobulin in plasma is mainly produced following secondary exposure to an antigen (typically bacterial infections).
- Consists of 2 gamma heavy chains, and two light chains (kappa or lambda).
- Contains two antigen-binding sites
- Can cross the placenta, providing passive immunity to the fetus and newborn.
Most effective in activating complement.
- Can neutralize bacterial toxins or inactivate some venoms.
-Play a role in cell-mediated cytotoxicity - The Fab portion binds with the target cell and the Fc portion binds with specific receptors that are found on NK cells
61
IgM
The largest immunoglobulin. It is found in intravascular space, and on the surface of B cells where it serves as a BCR. It is generally the first antibody produced following exposure to an antigen and the first one synthesized in neonates.
- A pentamer molecule (10 mu heavy chains, and 10 kappa or lambda light chains)
- Contains up to 10 antigen binding sites
- High IgM levels usually follow a recent infection or exposure to an antigen.
- Efficient in agglutination due to their pentameter form.
- Most efficient initiator of complement (because complement activation requires at least two Fc regions)
- Most common surface Ig bound on B lymphocytes.
62
IgA
The major immunoglobulin found in body secretions, and the most abundant immunoglobulin in the body. It is found in two forms: 1. Monomeric (plasma) 2. Dimeric (secretions)- allows it to cross-link large antigens with multiple epitopes.
- Consists of two alpha heavy chains, and two kappa or lambda chains.
- The secretory component is produced by epithelial cells of mucous membranes.
- IgA-secreting plasma cells are concentrated along mucosal membrane surfaces.
- Cannot activate complement - therefore cannot cause bacterial lysis.
- Secretory IgA can bind to bacterial and viral surfaces to prevent the attachment of pathogens to mucosal cells.
- Offers protection against infections in newborns during the first few months of life.
63
IgE
Found in very low concentrations in plasma. Mediates the immediate hypersensitivity reactions seen in allergies.
- Consists of two epsilon heavy chains, and two kappa or lambda light chains.
- Cross-linkage of receptor-bound IgE by an antigen induces the degranulation of basophils and mast cells.
- Protects against infection by releasing mediators that attract eosinophils to the site of infection.
- Increased levels in plasma are seen during roundworm infections.
64
IgD
Has an unknown function, but most likely serves in the regulation of lymphocyte activation and suppression with IgM and IgD.
- Consists of two delta heavy chains, and two kappa or lambda chains.
- Membrane-bound immunoglobulin is expressed by mature B cells along with IgM.
65
agglutination
The formation of clumps when an insoluble/particulate antigen interacts with an antibody.
66
opsonization
Leads to enhanced phagocytosis by neutrophils and macrophages. Phagocyte membranes contain Fc receptors which will bind to antibodies that have an antigen bound to its Fab portion. This interaction secures the antigen to the phagocyte and results in cross-linking between FcR and multiple Fc regions. This causes a signal-transduction pathway that ends in phagocytosis.
Phagocyte Fc receptor + (antibody bound to an antigen) = phagocytosis of the antibody-antigen complex
67
complement activation
IgM and IgG can activate complement via the classical pathway. IgM is more effective due to its pentameric form that allows a single IgM immunoglobulin to activate the pathway. Results in the MAC complex, and cell lysis.
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ADCC
Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Fc receptors on cells allow the linking of an antibody to a target cell, allowing for cytotoxic activities of the effector cell against the target cell. Generally occurs when a host cell is infected with a virus. Antibody enables the attacking cell to recognize and kill the target cell.
69
neutralization
Antibodies can block the attachment of toxins or venoms- neutralizing/inactivating them. IgG is very efficient at neutralizing toxins and the inactivation of venoms. IgM can also neutralize viruses by binding to them so they can no longer bind to host cells.
70
discuss CDRs and their role in antibody specificity for antigen recognition
Specificity of TCR and BCRs are attributed to the CDR, by forming the antigen binding site.
71
discuss the factors that affect the binding of an antigen to an antibody
Antigens and antibodies binding does not involve covalent bonds, inherently making the bond weak. Van der Waals forces, electrostatic forces, and hydrophobic forces all require very close proximity, like a lock and key to bind antigens to antibodies.
Forces that can break these bonss are:
Low or high pH
High salt concentrations
Chaotropic ions
72
isotype
The class of immunoglobulin: IgG, IgA, IgM, IgE, IgD.
The constant region determinants define each heavy and light chain. Each isotype is encoded by a separate constant region gene.
If an antibody from one species is injected into another species the isoty[pic determinant will be recognized as foreign and induces an antibody response (IgG).
All antibodies produced from the original plasma cell can bind to the same epitope regardless of the isotype.
73
allotype
Allotypes are inherited and thus vary between individuals to do populations having multiple alleles for the gene. The allotypes occur mainly as variants of heavy chain constant-region genes.
This type of antibody develops following blood transfusions. Allotypic determinants are produced when antibodies from one individual are injected into another individual from the same species.
74
idiotype
The individual antigenic determinants of the variable region (which has unique amino acid sequences) are referred to as the idiotope. The sum of all the individual isotopes is called the idiotype of the antibody.
Usually specific for an individual clone of an antibody.
75
differentiate between avidity and affinity
They are both measures of binding strength.
Affinity: The measure of the binding strength at a single binding site.
Avidity: The measure of the total binding strength.
76
differentiate between a primary and secondary immune response
The first encounter with an antigen is the primary response, the immune response is slow to develop, short lived, and “weak”.
Subsequent exposure to the antigen creates a secondary response, the immune response is rapid, and “strong”.
77
differentiate between monoclonal and polyclonal antibodies
Monoclonal antibodies: Have a single antigen epitope specificity.
Polyclonal antibodies: Different antibodies are produced with specificity to the various epitopes on a single antigen.
78
Primary Response Phases
Lag/Latent Phase: Antibodies are not detected until 1-2 weeks following the initial exposure. IgM is the first antibody detected. IgG may be present in small amounts as well.
Exponential Phase: The level of antibodies increases in the plasma.
Steady State: Production and degradation rates of the antibodies are balanced.
Declining Phase: The immune response begins to slow and the concentration of antibodies in the plasma is rapidly decreased.
79
Secondary Response process
The Lag/Latent Phase is 1-3 days and the magnitude and length of antibody production is greater than then seen in the primary response. IgG is the most produced antibody. Affinity maturation also occurs.
80
Define Antibody
A protein (immunoglobulin) that is produced by B cells. Antibodies are able to recognize and bind to a single epitope on an antigen, causing cell lysis. Occurs in two forms.
1. Bound on the surface of B cells (Surface Ig = part of BCR)
2. Secreted and circulating in the blood, lymph, or mucosal surfaces.
Additionally, antibodies are able to mediate biological functions that eliminate antigens.
81
Define Antibody Specificity
Refers to what antigen (epitope) the antibody binds to/ It is possible for two antibodies with different amino acid sequences to have the same specificity to the same epitope.
82
Define Hypervariable region
CDR- The area of the light and heavy chains that have the greatest variability.
83
Define redundancy
The ability of a single antibody to cross-react with multiple epitopes. Can reduce the number of antibodies needed to defend an individual against the range of antigenic challenges.
84
Define binding affinities
When two antibodies with different amino acid sequences have the same epitope specificity, the strength of the bond between antigen and antibody will vary depending on the number and types of binding forces available to each antibody.
85
Differentiate between isotype, allotype, and idiotype.
Isotype: The differences between constant regions due to different heavy and light chain constant region genes.
Allotype: Differences due to different alleles of the same constant region gene.
Idiotype: Differences due to particular rearranged VH and VL genes.
86
Discuss the general structure of an immunoglobulin
All classes of immunoglobulins have the same four-chain structure, two heavy chains and two light chains. Through disulfide bonds, each light chain is linked to a heavy chain, and the two heavy chains are additionally linked to each other.
87
define BCR
B Cell receptor. A transmembrane protein on the surface of B cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. Has two antigen binding sites.
88
define gene rearrangement
Immunoglobulin genes can rearrange themselves within the genome of a differentiating cell.
There are separate genes that code for a single heavy and light Ig chain. Gene segments code for the variable and constant regions for each light and heavy chain. These gene segments in B cell maturation are rearranged into different combinations to form functional antibodies.
89
where do B cells develop
The bone marrow is where B cell development and gene rearrangement occur.
90
B cell markers
CD19 - On all B cells, in all stages except for Plasma cells.
CD20- Expressed after light chain rearrangement. Seen on mature B cells.
91
which gene segments are involved in heavy chain rearrangement
V (variable), D (Diversity), J (Joining), and C (constant).
D+J
DJ+ V
92
which gene segments are involved in light chain rearrangement
V (variable), J (Joining), and C (constant).
93
discuss antigen-independent phase (stages of somatic recombination) – steps, order
1. VDJ gene is transcribed into RNA (includes exons and introns of the VDJ gene)
2. The first two C genes (code for mu or delta heavy chains) downstream from the VDJ are also transcribed
3. RNA is spliced, to remove introns and make mRNA, only one of the mu or delta genes will be retained.
4. mRNA is translated to produce functional Ig protein (H chain) of either IgM or IgD
5. Functional Heavy and Light chains are made
6. Antibody is assembled and expressed on the B cell surface
Stem cell - Pro-B - Pre-B - Immature B = Mature B - (Memory B or Plasma Cell)
94
Rearrangement of which chain is involved with class switching
The heavy chains constant region. It generally occurs in the germinal center of a secondary lymphoid organ, and occurs after antigen stimulation, under the influence of cytokines released by T cells. Specificity remains the same.
95
identify which Ig are co-expressed for a mature B cell
IgM and IgD
96
junctional diversity
Nucleic acid sequences can be changed when the selected gene segments are cut and joined together, during this process nucleotides can be added (by enzyme TdT) or lost (removed by exonucleases). These sequences code for CDR Loops.
Increases antibody diversity by amplification.
97
non-productive recombination
Gene sequence rearrangements do not always result in a functional Ig protein. If there is no Ig protein to display on the B cell's surface the cell dies by apoptosis. ⅔ of gene arrangements are non-productive.
98
allelic exclusion
B cells have 2 chromosomes, if a B cell is successful in rearranging its DNA to make a functional antibody it shuts down the possibility of gene rearrangement on the other chromosome. This ensures that each B cell will produce antibodies that have a single specificity only.
The B cell will have many BCRs but of the same specificity.
99
negative selection
Mechanisms that ensure that mature B cells will produce antibodies against a forge antigen, and not host cells. Immature B cells with intact sIgM and sIgD are exposed to self-antigens in bone marrow, and B cells that bind to a self-antigen are destroyed.
Receptor editing can occur to save the cell, V(D)J recombinase complex can be activated, and an attempt to make a new light chain to produce a functional arrangement that is not self-reactive.
100
discuss the interaction with antigen to activate a B cell
* where does this interaction occur
Typically occurs in the secondary lymphoid organs, mainly the spleen and lymph nodes where the B cell can trigger B cells to proliferate.
101
discuss how activated B cells transform into plasma cells
When a mature B cell interacts with an antigen, IgM+IgD b cells proliferate and can differentiate into plasma cells or memory cells.
102
What is the first Ig class to be produced by plasma cells
IgM
103
hypermutation
Mutations that occur in V genes of heavy and light chains during the lifetime of B cell also increase the variety and affinity of antibodies produced by the B-cell populations.
104
affinity maturation
A phenomenon is that the average age affinity (binding constant) of the antibodies for te antigen increases as the secondary immune response develops.
105
class switching
Occurs in the secondary response, when there is a change in the type (IgG to IgM for example) of antibodies produced for the same antigen specificity.
106
explain the role of plasma/memory cells in adaptive immunity
* development (germinal centres)
Germinal centres are formed when a mature B cell encounters an antigen and helper T cells in a lymphoid organ. Germinal centres are the site of proliferation and differentiation (plasma and memory B cells).
107
explain the role of plasma/memory cells in adaptive immunity
* where cells migrate to
Plasma cells that secrete IgG migrate to the bone marrow.
Plasma cells that secrete IgA are found in mucosal tissue
Memory B cells reside in the dermis and can be reactivated locally by antigen
108
discuss the activation, proliferation and differentiation of B cells
* where does this occur
In the periphery.
109
discuss the activation, proliferation and differentiation of B cells
* role of T cells
T helper cells can interact with B cells in response to thymus-dependent (TD) antigens.
110
what is primary purpose of T-independent response
It is a first-line defence against systemic infections, as the response is rapid. Antigens that induce the T-independent response are composed of polysaccharides, lipids, and other non-protein molecules that have repeating structures. (LPS of gram-negative organisms). These antigens do not bind to MHC molecules and therefore are not “seen” by the T cells.
111
discuss thymus-independent antigens
* type of antigens and B cells involved
There are two groups of antigens that are thymus-independent.
TI-1: Mitogenic, LPS from gram negative bacteria, and protein coats of viruses. Binds to BCR and TLR on the surface of B cell.
TI-2: Not mitogenic: Bacterial and fungal polysaccharides. Can activate the cell directly by binding to adjacent sIg receptors. BCRs are crosslinked, initiating an antibody response.
The B cells involved are marginal-zone b cells in the spleen, and B-1 cells.
112
discuss thymus-dependent antigens
* discuss the interaction between B and T cells
B cells will interact with CD4 T cells in the presence of an antigen. The CD4 T cell will release cytokines to influence the B cell to class switch. A germinal center will form, creating the site of plasma and memory B cell production.
TD antigens generally involve the creation of antibodies of more than one isotype.
113
Pro-B cell
When the V binds to the DJ complex. Attempts to create a functional heavy chain. Light chain has not been created yet, so a “surrogate light chain” is used. The surrogate light chain will signal that heavy chain rearrangement was successful and to move on to the light chain rearrangement.
114
Immature B cell
When light chain rearrangement occurs, the kappa will have two attempts, if they both fail lambda will get two attempts.
115
Mature B cell
IgM and IgD are both expressed on the cell. Cells will now undergo negative selection in the bone marrow. If it survives negative selection the mature B cell will then migrate into the lymph nodes and wait for its cognate antigen.
116
Memory B cells
Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response.
117
Plasma Cells
Secrete antibodies.
118
Mitogenic
Stimulate the proliferation of B cell clones and produce antibodies.
119
RAG-1 and RAG-2
Cleave repair and join the V(D)J on BCR and TCR.
120
Define Pre-B cell receptor
When heavy chain rearrangement is productive, the heavy chain and surrogate light chains are expressed on the cells surface, This shuts down heavy chain rearrangement, and initiates light chain rearrangement. If the Pre-BCR is not made the cell dies by apoptosis.
121
Define Marginal-Zone B cells
Long-lived populations of mature B cells in the spleen that participate in the production of IgM in response to TI antigens.
122
Define B-1 Cells
Subpopulation of B cells in the peritoneal and pleural cavities. Minor population in the spleen and lymph node. B-1 cells synthesize low-affinity IgM polyspecific antibodies (antibodies that are reactive to many antigens).
123
define TCR
T-cell receptor - Recognizes and binds to processed antigen peptides presented on self-MHC molecules only. Enhances signal transduction into the cell. Has one antigen binding site.
Each TCR is composed of an alpha chain and a beta chain. Each chain has a variable and constant region. Additionally, each variable region has 3 CDRs, and forms the antigen binding site for the epitope.
124
where do T cells originate and where do they mature
T cells originate from progenitor cells in the bone marrow, and then migrate to the thymus. The thymus is the site where T cells proliferate, differentiate and undergo a selection process into mature cells.
125
discuss double-negative and double-positive T cells
Double Negative: Progenitor cells that have not yet rearranged their TCR genes, and thus do not express the proteins necessary for rearrangement to occur. Do not have CD4 or CD8 markers. Ensure that the T cell will bind to foreign antigens and not self-cells.
Double Positive: Double negative cells that have received both CD4+ and CD8+ markers. Ensures that the T cell can recognise self MHC.
126
discuss positive and negative selection of T cells
Progenitor cells will start off being double negative, then will receive both CD4 and CD8 markers to become double positive. Double-positive cells with affinity that are either too low or too high for self-MHC do not survive thymic selection. The cell will then go through “positive selection”, and the T cell will be educated to self-MHC and choose either CD4 or CD8. The cell is then called a single positive cell. Negative selection occurs next and is where T cells that bind too strongly with self-MHC will be eliminated. Only T cells that have TCRs with intermediate affinity for peptides are displayed on MHC.
Double negative, double positive, positive selection (single positive), negative selection, T cell is released from the thymus into the periphery.
127
discuss gene rearrangement involved with the T cell receptor (TCR)
TCR diversity is produced by the process of gene recombination of the alpha chain (VJ genes) and the Beta chain (VDJ genes). Beta chain (VDJ) recombination occurs first, and a surrogate alpha chain is used as a placeholder. At this stage, the cell is double positive.
VJ recombination of the alpha chain occurs next. The cell will undergo positive selection to produce a single positive cell (will obtain CD4 or CD8 markers)
128
discuss the role of CD3 in the TCR
CD3 is required for the transport of the newly synthesized TCR molecule through the cell to the cell surface. CD3 is the same on all cells and is always associated with TCR. Forms the antigen binding site of the TCR.
129
discuss single positive T cells
Single positive T cells have either CD8 or CD4 but not both. They undergo the selection process in the cortex of the thymus.
CD8: TCR recognizes MHC I
CD4: TCR recognizes MHC II
130
explain the CD that identifies T helper and T cytotoxic lymphocytes
CD4 = T helper cells - synthesize cytokines that affect the activity of many other cells.
CD8 = T cytotoxic cells - Predominantly result in the killing of the infected host cell.
131
discuss the interaction of T-helper and T-cytotoxic lymphocytes with the appropriate MHC class
T cytotoxic cells: CD8: TCR recognizes MHC I
T helper cells: CD4: TCR recognizes MHC II
132
explain what is meant by effector cells
Lymphocytes can mediate the removal of pathogens or antigens from the body without the need for further differentiation. They are distinct from naive lymphocytes, which need to proliferate and differentiate before they can mediate effector cell functions. Also distinct from memory cells, which must differentiate and sometimes proliferate before they can before effector cells.
Effector B cells: Plasma cells that secrete antibodies.
Effector T helper cells (CD4): Secrete cytokines.
Effector Cytotoxic T cells (CD8): Kill infected host cells.
133
identify the costimulatory molecules required for T cell activation (CD28-B7)
CD28 - Expressed on the T cells surface
B7 - A family of molecules expressed on APCs
CD40 Ligand - expressed on macrophages, dendritic cells, and B cells. Enhances the B7-CD28 co-stimulator interaction.
134
CD4+ lymphocytes:
* which MHC class do they interact with
Class II
135
what is the major effect of stimulation of CD4 cells
Proliferation, and differentiation of CD4 cells into effector cells.
136
discuss the four subsets of T-helper lymphocytes
TH1: Develop due to IL-12, which is released during IR to bacteria and viruses. Synthesizes IFN-y and IL-2. These cytokines activate macrophages, CD* T cells, and NK cells. Influences B Cell class switching to IgG.
TH2: Develop due to IL-4, which is released during IR to parasitic worms. Synthesizes IL-4, IL-5, and IL-13. Drives the development of TH2 cells, and promotes B cell class switching to IgE and IgG. Activates eosinophils.
TH17: synthesizes IL-17, IL-21, and IL-22. Proi=nflammatory. Activates osteoclasts which degrade bone and stimulate bone resorption.
Treg cells: Suppress the IR of other cells.
137
the process of CD4+ cell activation (signals, molecules, proliferation)
First signal: MHC class II + Peptide interacts with the T cells TCR
Second Signal: MHC Class II interacts withe with a co-stimulator (B7-CD28)
IL-2 is released, and influences CD4 cells to proliferate and differentiate into effector cells.
138
discuss how CD4 cells interact with B cells to produce antibodies
B cells will interact with an antigen, then peasant the MHC + peptide to a CD4 cell with the same specificity. This up-regulates T cell expression of Bcl-6. Bcl-6 activates CXCR5 expression. A germinal centre is formed. The B cell will undergo class switching, and produce antibodies.
139
CD8+ lymphocytes:
* which MHC class do they interact with
Class I
140
discuss the role of the following regarding CD8 cell activation: TH1, CD40, B7, CD28, IL-2.
TH1 cells - Secrete IL-2 which is crucial for CD8 activate.
CD40-CD40L - Enhances the
B7-CD28 co-stimulator interaction fro CD4 cells.
IL-2 - induces CD8 cell proliferation and differentiation.
141
discuss the role of CD178 (Fas ligand) with CD8 cells
FasL on CD8 T cells interacts with Fas expressed on host cells activating apoptosis of the target cells by the activation of caspases (proteolytic enzymes in the target cell).
142
discuss how CD8+ cells kill the target cell
Granule Exocytosis: The cytotoxic T cell will adhere to the target cell, and release cytotoxic proteins from its cytotoxic granules toward the cell. These granules are Perforin and Granzymes. DNA fragmentation will begin, and the cytotoxic T cell will detach from the target cell and bind to another target. Cell death generally occurs within a few hours.
Fas Receptor: Effector cytotoxic T cells express Fas ligand on their cell surface. Fas will bind to the corresponding receptor (CD95) on the target cell. A death signal will be sent to the target cell, triggering cell apoptosis.
143
list the major chemicals involved with cytotoxic destruction of target cells
* Perforin
Cytotoxic protein that forms a pore in target cell membranes.
* Granzymes (proteases)
Cytotoxin protein enters the target cell and activates the apoptotic pathway.
144
Differentiate between apoptosis and necrosis
* Necrosis
The whole cell is destroyed at once. Cellular debris is released into the extracellular environment and can initiate an inflammatory response. Tends to be sudden. DAMPs can cause necrosis.
* Apoptosis
Programmed cell death. Prevents release of inflammatory cellular elements so inflammation is not induced. Target cell DNA is fragmented, and then forms apoptotic bodies that will be phagocytosed by macrophages.
145
discuss the role/function of memory T cells
Long-lived T cells that are involved in the IR to secondary exposure of antigens. Subtypes are effector memory T cells, and central memory T cells.
146
Define the TCR complex
TCR (alpha and beta chains) are associated with accessory molecules that transmit signals across cell membranes. These molecules are CD3 and 2 zeta chains.
Complex forms 2 processes:
TCR recognizes and binds to peptides displayed on MHC,
CD3 and zeta perform signal transduction.
147
Define AIRE
Autoimmune regulator.
148
What is the role of AIRE in negative selection
Peptides outside of the thymus are expressed in medullary thymic epithelial cells. Transcription factor that allows non-thymus peptides to be produced by these cells so, during negative selection, T cells are exposed to peptides found all over the body.
149
Define Immunological Tolerance
The process by which adaptive immune cells learn to tolerate self-cells by teaching the cell to not react to host cells.
150
Natural Killer T cells
Respond to glycolipid antigens presented on CD1d. A regulatory cell that is involved in regulating autoimmune conditions, cancer, and infections.
151
Tregs
Regulatory T cells - CD4/CD25 - Actively suppress activation of the immune system and prevent pathological self-reactivity, Produce inhibitory cytokines. Maintain tolerance to self-antigens. Prevent autoimmune disease.
Two classifications: Natural and adaptive.
152
Natural Tregs
Produced by the thymus - auto-reactive T cells
153
Adaptive Tregs
are Formed by the differentiation of naive T cells outside of the thymus
154
Define T-cell homing
Once T cells are activated in the nodes, effector T cells and memory T cells change their pattern of expressing adhesion molecules and chemokine receptors, and migrate out of the nodes and generally take the T cell back to the site of its activation.
155
Define Pre-T cells
Double negative cells that have rearranged the beta chain successfully, and have a pre-T alpha chain.
156
Define Thymic Selection
The TCR complex plus CD4 and CD* are expressed by a thymocyte. The thymocyte will interact with MHC molecules and peptides that are expressed by thymic nonlymphoid cells. Two phases. Positive and negative selection.
157
Positive selection of T cells.
Occurs in the thymus, double-positive cells interact with epithelial cells in the thymic cortex that express MHC class I and II molecules. This “educates” the cell to self MHC, and depending on what class of MHC the cell has affinity for will determine if the cell will become a CD4 or CD8 T cell.
158
Negative selection of T cells
Thymocytes with too high or too low reactivity to self-MHC are removed.
159
Effector T cells
CD4: synthesize cytokines that affect the activity of cells.
CD8: Kill host cells infected by viruses.
