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146 Cards in this Set
- Front
- Back
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Can a Class II MHC molecule present self-peptides?
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Yes
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Where might the self-peptides that can be presented on Class II MHC molecules originate?
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- From proteins / cellular debris engulfed by phagocytic cells
- From proteins in lumen of lysosome |
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How many gene products can our genome encode? Why is this problematic for the immune system?
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- ~25,000 gene products
- Need to be able to recognize millions of different antigens that we encounter on virtually any pathogen by generating antigen receptors for them |
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Class I MHC molecules present peptides from where?
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Cytosol - degraded by proteasome
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What do T cell receptors (TCRs) recognize?
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Combination of self MHC molecule and peptide
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What are the three possibilities for the affinity between the T cell receptor (TCR) and the MHC molecule / peptide complex during develpment?
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- No affinity = T cell 1 (doesn't bind MHC or peptide)
- High affinity = T cell 2 (binds both MHC and peptide) - Weak/Moderate affinity = T cell 3 and 4 (binds only MHC or only peptide) |
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What are the implications of no affinity between the T cell receptor (TCR) and the MHC/peptide complex during development?
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T cell dies - death by neglect (#1)
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What are the implications of high affinity between the T cell receptor (TCR) and the MHC/peptide complex during development?
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T cell dies - too strong of a bond (#2)
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What are the implications of weak/moderate affinity between the T cell receptor (TCR) and the MHC/peptide complex during development?
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T cell lives to leave the thymus and populate the periphery (#3 and 4)
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What is alloreactivity?
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- Reactivity of T cells (or B cells) to non-self (allogenic) MHC class I or II molecules (Green MHC from transplanted tissue - recognizes self peptide as non-self)
- Some of the remaining T cell receptors may bind strongly to NON-SELF MHC and SELF-PEPTIDES (*principle behind allotypic graft rejection*) |
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What are sources of foreign peptides?
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Infections
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What are the sources of foreign MHC molecules?
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Transplanted tissue
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What are the implications of a high affinity interaction in the periphery?
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Killing of target cell
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How does a T cell know whether it is seeing self or foreign peptide?
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- During development, we generate a population of newborn T cells that have the capacity to recognize everything, including self-peptide + MHC
- Then we eliminiate the T cells that recognize self-peptide + self-MHC - Therefore, your remaining T cells would never form a high affinity bond with the self-peptide + self-MHC because they were eliminated! - Only can form high affinity bonds w/ foreign peptides + self-MHC |
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What are the two types of T cells?
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- CD4+ T Helper Cells
- CD8+ T Cytotoxic Cells |
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What kind of T cells recognize Class I MHC molecules?
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CD8+ T cytotoxic cells
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What kind of T cells recognize Class II MHC molecules?
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CD4+ T helper cells
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During a viral infection, what kind of T cells do you need? Why?
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- CD4+ T helper cells help kickstart the production of antibodies
- CD8+ T cytotoxic cells are the effector cells that kill virus-infected cells |
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If you have never been exposed to a virus, what is absent during the first exposure?
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Virus-specific T cells are absent
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How long does it take to generate virus-specific T cells?
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3-7 days
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After an initial infection w/ a virus, what happens to the virus?
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- The virus is engulfed by phagocytic cells (dendritic cell) at the site of infection
- Phagocytic cells migrate to nearby lymphoid organ (lymph node) containing B and T cells - Antigen presenting cells that have engulfed pathogen present it on class II MHC molecules, which activates CD4+ cells - Via cross-presentation, class I MHC molecules can also present extracellular peptides, thus activating CD8+ cells - Normally, class I MHC molecules present cytosolic peptides (and so unless the virus infected the cell, it would be unable to activate CD8+ cells) |
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Lymph nodes capture antigen from what tissues?
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Epithelia and connective tissue
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The spleen captures what kind of antigens?
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Blood-borne antigens
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Class I MHC molecules usually present what kinds of peptides?
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Cytosolic
(& extracellular via cross-presentation) |
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Class II MHC molecules usually present what kinds of peptides?
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Extracellular
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On what kind of cells does cross-presentation happen? What does this mean?
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- Specialized antigen-presenting cells
- Class I MHC molecules can also present extracellular peptides (in addition to cytosolic) |
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How can extracellular peptides access Class I MHC molecules?
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- Viral peptides somehow get into the cytosol
- It is unclear how this happens! |
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What neutralizes extracellular virus particles?
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Antibodies made by B cells
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What are the insufficiencies of antibodies from B cells?
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- They neutralize extracellular virus particles
- Unable to eliminate the source of the virus |
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If you take antibodies (produced by B cells) specific to a virus and transfer them to a non-infected mouse and then infect the mouse w/ the virus, what will happen?
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The mouse will be protected from the virus - passive immunity
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What is passive immunity?
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Transfer of active humoral immunity (antibodies from B cells) from one individual to another
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Under what circumstances is the idea of "passive immunity" utilized as a treatment?
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- Gamma-globulin (IgG) injection for HIV patients
- Hepatitis B antibodies to prevent infection even after exposure - This is expensive because the half-life is ~30 days! |
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If you take T cells specific to a virus and transfer them to a non-infected mouse (genetically identical) and then infect the mouse w/ the virus, what will happen?
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- Yes because genetically identical
- T cells will divide, don't have to worry about half-life |
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If you take T cells specific to a virus and transfer them to a non-infected mouse (not genetically identical) and then infect the mouse w/ the virus, what will happen?
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- Not protected
- T cells always recognize foreign antigen in the context of self - New strain of mouse has different "non-self" MHC molecules presenting the antigen which won't bind to the transferred T cells |
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What is "MHC restriction"? How does it apply to the transfer of T cells between genetically different mice?
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- T cell receptors are specific for a type of virus antigen
- But they are restricted by self-MHC, so they don't protect a mouse with different genes |
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What happens when you transplant tumors from one strain of mice into the same inbred strain (syngeneic/same genes) mice?
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Tumors fluorished and killed these mice
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What happens when you transplant tumors from one strain of mice into a different strain (allogeneic) mice?
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Tumors were quickly rejected w/in 2 weeks post transplant
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What did the studies of transplanting tumors into genetically similar (syngeneic) and dissimilar (allogeneic) mice tell us about tissue rejection?
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- Genetically heritable trait
- Genetic locus responsible for tissue rejection = Major Histocompatibility Complex |
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What is the Major Histocompatibility Complex genetic locus?
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- The area on chromosome 6 that is responsible for tissue rejection
- Over 200 genes, spans ~7 million bp - Contains class I and class II genes |
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Are tumor rejection genes dominant/recessive/codominant?
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Codominant - A and B are both dominant alleles
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If you are AB for tumor rejection genes, what kind of tumors will not be rejected?
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A/A or B/B because you express both A and B
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What genes on the Human MHC locus of chromosome 6 are important for Class I molecules?
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HLA-A, -B, -C ("heavy chains")
(HLA = Human Leukocyte Antigen) *Beta-2-m is not encoded on MHC gene locus* |
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What genes on the Human MHC locus of chromosome 6 are important for Class II molecules?
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HLA-DR, -DQ, -DP (heterodimers - alpha/beta chains)
(HLA = Human Leukocyte Antigen) HLA-DM and TAP *Note that alpha and beta chains are encoded by different genes* |
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What is the function of the HLA-DM gene?
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Bumps Invariant Chain (Ii) out of the binding site of Class II molecules
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What are the most polymorphic (many alleles at each locus within the population) genes in the genome?
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MHC class I and class II genes on MHC locus (chr 6)
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What characteristics about MHC molecules lead to such diverse recognition of foreign antigens?
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- Polygenic - 3 genes for Class I
- Codominant - gene product from mother and father are equally expressed (6 Class I molecules) - Polymorphic - multiple alleles at each locus within the population |
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What molecules are responsible for transplant rejection?
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MHC Class I and Class II molecules
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What are the odds that a sibling will match for all 10 products (assuming no recombination between loci)?
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1:4
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What are the 10 products that need to match for someone to be a good bone marrow donor?
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HLA-A, -B, -C x2 (class I)
HLA-DQ, -DR x2 (class II) (HLA-DP isn't involved in transplant rejection) |
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On what types of cells are Class I MHC molecules expressed?
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All nucleated cells
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On what type of cells are Class II MHC molecules expressed?
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Only on specialized antigen-presenting cells
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Which of the gene products of MHC Class II molecules is the most polymorphic?
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HLA-DR beta
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What does the T cell receptor recognize?
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Combination of both peptide and class I/II helices
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What are the common sites of polymorphisms/mutations on Class I MHC molecules?
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- Peptide-binding cleft
- On alpha helices and beta sheets of bed of heavy chain |
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What are the common sites of polymorphisms/mutations on Class II MHC molecules?
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- Peptide-binding cleft
- On alpha helices and beta sheets of bed of beta chain |
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What do the polymorphisms on the bed of the peptide-binding cleft affect?
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Which peptides can bind within this groove
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How can 6 distinct class I molecules and 6 distinct class II molecules be sufficient to handle all viruses and infections?
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- Range of sizes (8-10 resis for class I; 12-16 resis for class II, but up to 30+)
- Structural similarities of residues (e.g. peptide backbone, N-term, C-term) - Each class 1 molecule can bind >1000 peptides, and each type binds unique sets |
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How many distinct peptides can bind to each class I MHC molecule?
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>1000
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What constraints are there on the amino acid residues of the peptides that bind to MHC molecules?
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- Certain AA residues are anchor residues (blue)
- The rest can vary |
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Which peptides (class I vs class II) are anchored at the ends?
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Class I peptides are anchored
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How many copies of each Class I molecule are there?
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10^5 (100,000) copies of each
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Why are cheetahs highly susceptible as a population to certain pathogens?
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They do not have polymorphic MHC alleles
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What percentage of people do not respond to the Hepatitis B vaccine? Why?
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- 5-15%
- They are homozygous for HLA-DR3 and -DR7 - Maybe these don't present the antigens for Hep B very well |
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What is Ankylosing Spondylitis? What gene is common to it?
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- Inflammatory, possibly autoimune disease of vertebral joints
- HLA-B27 is found in 6% of the population, but approximately 93% of individuals w/ AS have HLA-B27 |
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How does the gene HLA-B27 predisopse people to Ankylosing Spondylitis?
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Having tissue type does not mean an individual will have AS, but it increases the chances of having AS by ~100-fold (it is currently being studied what the activating agent may be that triggers AS)
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What is the basic structure of a B cell receptor (BCR)?
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- Shape of a Y - membrane Ig (immunoglobulin) - integral membrane receptor
- Signal is transmitted through cytoplasmic tails of two associated proteins, Ig-alpha and and Ig-beta |
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What is the basic structure of a T cell receptor (TCR)?
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- TCR is embedded in membrane with area for antigen binding
- Associates with several CD3 Dimers (together called the TCR complex) - Signaling is transmitted through CD3 chains |
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How many classes of antibodies (isotypes) are there? Names?
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5: IgM, IgD, IgE, IgA, IgG
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How do the five different classes of antibodies differ structurally?
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- Differ within their heavy chain (blue or read) constant regions (Fc)
- Light chains (green) are either kappa or lambda) |
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How many molecules assemble to form an antibody?
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- 2 heavy chains (blue and red)
- 2 light chains (green) |
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What structural components of the antibody should we know?
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- CH# = # constant region of heavy chain (CH1 found in Fab and CH2/3 found in Fc region)
- VL/H = Variable region of Light/Heavy chain, parts that contact the antibody - Fc Region - base or tail of Y, only made of heavy chains - Fab Region - limbs of Y, made of heavy and light chains - business end |
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What are B cell receptors in their secreted, soluble form called?
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Immunoglobulins (Ig) or antibodies
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What components of an antibody form the business end?
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Fab region = CH1 and VL/H and CL
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Name letters A, B, C?
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A = VL (variable region of light chain)
B = CL (constant region of light chain) C = VH (variable region of heavy chain) |
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Name letters, D, E, F?
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D = CH1 (constant region 1 of heavy chain)
E = CH2 (constant region 2 of heavy chain) F = CH3 (constant region 3 of heavy chain) |
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Name letters A, B, C?
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A = VL (variable region of light chain)
B = CL (constant region of light chain) C = VH (variable region of heavy chain) |
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Name letters, D, E, F?
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D = CH1 (constant region 1 of heavy chain)
E = CH2 (constant region 2 of heavy chain) F = CH3 (constant region 3 of heavy chain) |
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What is the name of the structure boxed in yellow? Orange?
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Yellow - Fab region
Orange - Fc region |
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What are the CDRs on an antigen?
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The portions of the antibody that contact the antigen; these are the portions that vary
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How many CDRs are there on an antigen? Where are they located?
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- 3 for the heavy chain variable region (VH)
- 3 for the light chain variable region (VL) - CDR = complementarity-determining regions |
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How are IgA and IgM similar (and different from the other antibodies)?
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- They are not secreted as the typical Y-shaped antibody
- IgA is a dimer - IgM is a pentamer |
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What joins the IgA and IgM antibodies?
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J-chain joins the dimers or pentamers
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What is avidity? What increases the avidity of IgA and IgM?
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- Avidity = strength of multiple bond interactions
- Multimeric features of IgA (dimer) and IgM (pentamer) increases avidity |
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What is the difference between affinity and avidity? Example?
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- Affinity - strength of a single bond
- Avidity - strength of multiple bonds - IgM has a low affinity for its epitopes but 10 low-affinity interactions leads to a high avidity |
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Which antibody isotypes are monomers with the classic Y shape?
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IgE and IgG and IgD
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What are Isotypes?
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Differences in heavy chains (IgG vs IgA vs IgE vs IgD vs IgM)
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What are allotypes?
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Differences in a single AA (there are a few polymorphic residues) on the same antibody
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What are Idiotypes?
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Differences that happen between two of the same type of antibody in the same person within the variable region
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What is the structure of the T cell antigen receptor?
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- Like MHC and Ig molecules, the TCR also contains Ig domains
- "Business end" which can recognize >10^11 distinct specificities is at the top (most membrane-distal region) - 2 similar chains, α and β, which form heterodimer - Each chain has a Variable and Constant region - Most membrane-distal ends have the CDRs - hypervariable regions |
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What do antibodies recognize?
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Anything - chemicals, proteins, phosphorylated proteins, carbohydrates
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How can the many proteins (billions) of differing specificities be synthesized without using a large percentage of our DNA to encode them?
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- Rearrangement of genomic gene segments where one of a large number of Variable gene segments rearranges to pair w/ a J-region segment
- Construct is spliced w/ a Constant region gene segment (immunoglobulin light chains and TCR α chains) - Same process occurs with Ig heavy chains and TCR β chains w/ addition of D-region segment |
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What are the gene segments that recombine during cellular differentiation and maturation on the Variable Region of the Heavy Chain of the TCRβ and Ig VH?
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V, D, and J
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What are the recombination events that take place on the variable region of the heavy chain of TCRβ and Ig VH?
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1. Recombination of Heavy chain D and J
2. Recombination of V (variable region) with DJ 3. After transcription, VDJ is spliced w/ a μ Constant region gene segment 4. Later after B cell matures it can be spliced with δ gene segments 5. Cell expresses IgM and IgD 6. Once B cell has seen antigen in lymphoid organ, class switching (recombination again) can occur 7. Heavy chain transcript (V(D)JC) is then expressed within the cell, and then at the cell surface w/ a surrogate light chain |
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What are the gene segments that recombine during cellular differentiation and maturation on the Variable Region of the Light Chain of the TCRα and Ig VL?
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V and J
(**No D - diversity segment) |
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Which loci contain the D segment? How many?
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Ig VH has n=23 D segments
TCRβ has n=2 D segments TCRα does not have any D segments |
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What are the recombination events that take place on the variable region of the heavy chain of TCRα and Ig VL?
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1. V and J recombine
2. VJ recombines with a C segment to form a transcript for the light chain 3. Translated and expressed in combination w/ Ig heavy chain (or TCR beta chain) to form intact BCR or TCR (expressed on cell surface) |
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What enzymes are responsible for recombination of immunoglobulin and TCR molecules? Location of expression?
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- Recombination Activating Genes (RAG-1 and RAG-2)
- Expressed in lymphocytes only |
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What are the functions of RAG-1 and Rag-2?
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- Work together
- Recognize recombination signal sequences (RSS) - Induce double-stranded breakage of DNA |
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Where are Recombination Signal Sequences (RSS) found? What recognizes them?
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Flank V and D sequences - recognized by RAG proteins, which induce double-stranded breaks in DNA
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Once DNA is cleaved by RAG-1 and RAG-2, what happens?
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- Recombination even
- Break is repaired by ubiquitously expressed DNA-repair enzymes - Including: DNA-PK (Protein Kinase) |
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What is the role of DNA-PK (Protein Kinase)?
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- DNA repair enzyme
- Phosphorylates an enzyme (Artemis) that opens up hairpins |
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What are the two types of diversity that contribute to the diversity of antigen receptors?
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- Combinatorial Diversity - V(D)J Recombination
- Junctional Diversity - enzymes that alter the junctions between the gene segments |
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What are the 3 enzymatic mechanisms by which the junctions between the gene segments are altered (to increase diversity of antigen receptors)?
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1. Breakage of hairpins to generate Palindromic sequences = "P-nucleotides"
2. Addition of Non-templated nucleotides to sites of V(D)J recombination, catalyzed by TdT, forms "N-regions" 3. Exonucleases remove nucleotides from V, D, and J gene segments at time of recombination |
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How many possibilities are there for all of the Ig V(D)J combinations? TCR V(D)J combinations?
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Ig: ~10^6 (1 million)
TCR: ~3x10^6 (3 million) |
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What is the total potential repertoire of Ig combinatorial + junctional diversity combinations? TCR?
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Ig: ~10^11
TCR: ~10^16 |
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What is the chain of events that occurs to create P-nucleotides (first step of generating junctional diversity)?
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1. Recombination Signal Sequences (RSS) on different V, D, or J sequences are recognized and brought together randomly
2. RAG complex (RAG-1 and RAG-2) generates double-stranded breaks 3. Hairpins form 4. Artemis:DNA-PK complex opens hairpins to generate Palindromic "P-nucleotides" |
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What is the chain of events that occurs to add N-nucleotides (second step in generating junctional diversity)?
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1. N-nucleotide (non-templated nucleotide) addition by TdT to P-nucleotides
2. Weak pairing of strands |
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What is the chain of events that occurs to complete junctional diversity?
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1. Unpaired nucleotides removed by exonucleases
2. Gaps filled in and ligated |
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What is the "cost" of generating junctional diversity?
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- Because this is a random process of nucleotide addition/excision, only 1 in 3 receptors will be in-frame
- Other 2/3 of receptors will be out of frame (useless) antigen receptors - Hopefully the other chromosome will have an in-frame receptor locus |
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What are the mechanisms of generating antigen receptor diversity?
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1. Combinatorial (multiple gene segments; VDJ)
2. Junctional Diversity 3. Mix and Match Pairing of Light and Heavy Chains 4. Somatic Hypermutation (discussed in another lecture) |
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What is meant by allelic exclusion?
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- Expression of heavy chain gene product of either the maternal or paternal chromosome, but not both
- Ensures clonal specificity - each B cell produces only a single, unique receptor |
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What is clonal specificity?
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Each B cell produces only a single, unique receptor
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If the first heavy chain recombination event occurs on the maternal chromosome and is successful, what happens to the paternal chromosome?
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Heavy chain on paternal chromosome will not rearrange and the cell will express the maternal gene product only
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If the first heavy chain recombination event occurs on the maternal chromosome and is unsuccessful, what happens to the paternal chromosome?
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- Rearrangement of heavy chain on the paternal chromosome will occur
- If successful, paternal heavy chain will be expressed - If unsuccessful, cell will die |
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Does recombination begin on the maternal or paternal chromosome always?
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No - it's a random process and may begin on either maternal or paternal chromosome
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What is required for an immature B cell to recognize an antigen?
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Once it expresses a completed antigen receptor on its cell surface
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Are all of the B cell receptors on a given B cell identical?
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Yes!
- The BCR is the product of a chromosomal rearrangement - Only one allele is expressed and the other is shut down (allelic exclusion) |
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What types of antigens will a naive B cell encounter in the bone marrow?
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Self cells - largely bone marrow stromal cells
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What happens when a BCR recognizes an antigen in the bone marrow with high affinity? Why?
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- It is recognizing a self-antigen
- Leads to a signaling cascade that triggers apoptosis - BUT: It can turn on its RAG recombinases to rearrange its other light chain and try again for a BCR that does not possess high affinity for self-antigens in bone marrow |
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What happens to B cells during negative selection?
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BCRs that react tightly with antigen die through a process called "negative selection"
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What percent of B cells survive selection and exit the bone marrow? What happens to the remainder?
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Only 10%
(90% of B cells are negatively selected because of high affinity bonds to self antigens) |
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What are the steps in maturation and selection of B lymphocytes?
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- Stem cell - contains germline DNA for Ig, no expression
- Progenitor-B - rearranges first heavy chain (VDJ) - Pre-B - recombined H chain gene (VDJ) and assembles with surrogate light chain; this indicates that it was successful - Immature B - recombined H chain gene and recombined light chain - Mature B - alternative splicing to form δ mRNA; membrane IgM and IgD |
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What happens to the progenitor B cell?
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- Recombination of D and J heavy chains, followed by V and D heavy chains
- If allele #1 is successful forms productive Pre-B cell w/ productive μ heavy chain (inhibits rearrangement of allele #2 and induces κ light chain rearrangement) - If unsuccessful, try allele #2 - If allele #2 is also unsuccessful, leads to cell death |
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What happens to the pre-B cells that have a productive μ heavy chain from either allele #1 or #2?
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- Vκ recombines with Jκ on allele #1
- If productive μ + κ chains inhibit rearrangement of κ allele #2 and λ rearrangement (forms immature B cell) - If unproductive, Vκ recombines with Jκ on allele #2 - If productive μ + κ chains inhibit λ rearrangement (forms immature B cell) - If unproductive, λ rearrangement |
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What happens to a pre-B cell with unsuccessful recombination of the κ light chains on both alleles?
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- Recombination of Vλ with Jλ on allele #1
- If successful, μ + λ chains inhibit λ rearrangement of allele #2 (forms immature B cell) - If unsuccessful, recombination of Vλ with Jλ on allele #2 - If allele #2 is successful, form immature-B cell (w/ μ + λ chains) - If λ allele #2 is also unsuccessful --> cell death |
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Which chain is recombined first in a B cell? Then?
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- Heavy chain
- Light chain (μ or λ) |
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Why are the progenitor T "Pro-T" cells referred to as "double-negative"?
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They do not express the T cell co-receptors CD4 or CD8
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What do progenitor T cells first express? What happens to it?
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- Pre-TCR - analogous to surrogate light chain that assebles with the first rearranged BCR μ heavy chain
- Can pair with a rearranged TCRβ when first expressed |
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What happens to a progenitor T cell if a productively rearranged TCRβ is not expressed?
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Cell dies
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What signals are released from the pre-TCR/TCRβ complex? What do they signal?
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Cell survival signals - signal for TCRα gene recombination and inhibits further recombination at TCRβ locus (allelic exclusion)
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What happens if there is a failure to express a productively rearranged TCRα/TCRβ complex?
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Cell death
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T cells that survive (have productively rearranged TCRα/TCRβ complex) will express what? What are they called?
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T cell coreceptors CD4 and CD8 = Double-Positive Immature T cells
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What leads to the proliferation and expansion of immature T and B cell progenitors?
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Cytokine IL-7
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Where is cytokine IL-7 produced? Purpose?
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- Thymus for T cells
- Bone marrow for B cells - Causes proliferation/expansion of immature T or B cell progenitors |
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Do all of the T cell receptors on a given T cell have identical specificities?
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Yes
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What types of antigens will the T cell encounter in the thymus?
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Only self - thymic epithelial cells and other T cells
*But thymic epithelial cells express a transcription factor called "Aire"* |
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What is the significance of the transcription factor "Aire" (autioimmune regulator)?
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- Turns on expression of many genes that are expressed elsewhere in the body - urinary tract, kidney, pancreas, Paneth cells, etc.
- Mainly turns on expression of tissue-specific genes, note genes that are expressed in every cell - This allows the T cells in the thymus to recognize additional self peptides and destroy those T cells that bind tightly to self |
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What kind of double-positive immature T cells survive in the thymus?
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Those that have "positive selection" - weak recognition of class II MHC + peptide or class I MHC + peptide
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What kind of double-positive immature T cells do not survive in the thymus?
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- Those that fail to undergo positive selection (death by neglect) caused by no recognition of MHC + peptide
- Those that undergo negative selection due to a strong recognition of Class I or Class I MHC + peptide |
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How is immature T cell selection different from B cell selection?
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T cells must recognize peptides in the context of MHC molecules (self MHC molecules)
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What is the "T cell repertoire"?
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- Total number of antigen specificities exhibited in a single individual as determined by antigen-specific T cell receptors
- Each T cell displays receptors of a single specificity |
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An inactivating mutation in which gene(s) could be responsible for a patient having essentially undetectable T cells or B cells, but normal numbers of NK cells?
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- RAG-1 or RAG-2 - expressed only in T and B cells; recognizes the RSS and generates double stranded DNA breaks; leads to absence or deficiency of T and B cells and Ig
- Artemis - failure to resolve hairpins during V(D)J recombination; leads to reduced Ig and absence or deficieny of T and B cells - DNA-PK - identical to Artemis (works w/ Artemis to resolve hairpins) |
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What are the implications of an inactivating mutation in RAG-1 or RAG-2?
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- SCID: Severe Combined Immunodeficiency - both B and T cell deficient, reduced serum Ig ("Bubble Boy Syndrome")
- Omenn Syndrome: RAG deficiency can be "leaky" and result in low rather than absent B and T cells - these patients develop a combination of immunodeficiency and autoimmunity |
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What are the implications of an inactivating mutation in Artemis?
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- SCID: Severe Combined Immunodeficiency - absence or deficiency of T and B cells and reduced serum Ig
- Caused by failure to resolve hairpins during V(D)J recombination *Identical to mutation of DNA-PK because they work together* |
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What are the implications of an inactivating mutation in TdT?
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- Adds completely new non-template nucleotides after breaks have been made but before they have been repaired
- Without this there would be a less diverse repertoire of B and T cell receptors (only have combinatorial diversity ~10^6) |
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What are the implications of an inactivating mutation in DNA-PK?
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- SCID: Severe Combined Immunodeficiency - absence or deficiency of T and B cells and reduced serum Ig
- Caused by failure to resolve hairpins during V(D)J recombination *Identical to mutation of Artemis because they work together* |
