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84 Cards in this Set
- Front
- Back
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What do T and B lymphocytes develop from? Where?
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- Originate from common lymphoid precursor in bone marrow (derivative of hematopoietic stem cell)
- B cells develop in bone marrow - T cells develop in thymus |
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What are the characteristics and implications of antigen receptors on B and T cells?
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- Bind epitopes in highly specific manner (capable of distinguishing between closely related ligands)
- Trigger responses in lymphocytes in which they are expressed |
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How are antigen receptors distributed? What does this mean?
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- Antigen receptors are clonally distributed
- Cells of each clone have a unique antigen receptor expressed many times on their surface - Clones all express the same antigen receptor |
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What do B cell receptors bind?
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Undegraded antigens of many types (proteins, lipids, carbohydrates, nucleic acids, etc)
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What do T cell receptors bind?
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Bind complexes of MHC molecules and peptides (degraded fragments of proteins)
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What do antigen receptors require to transmit signals to the interior of the cell?
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Require additional components to which they are non-covalently linked; forms B cell receptor complexes and T cell receptor complexes
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What are the domains of the antigen receptors of lymphocytes?
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- Variable domains - form antigen binding site
- Constant domains - maintain overall structure |
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Where are immunoglobulins?
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- Membrane bound
- Secreted |
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Where are T cell receptors?
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- Membrane bound
- NOT secreted |
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What are the effector functions of secreted antibodies?
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- Complement fixation
- Phagocyte binding |
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What are the forms of the epitopes recognized by antibody/immunoglobulin vs T-Cell receptors?
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- Ab: conformational and linear epitopes
- TCR: linear epitopes |
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What are the forms of the antigens recognized by antibody/immunoglobulin vs T-Cell receptors?
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- Ab: macromolecules (proteins, polysaccharides, lipids, nucleic acids), small chemicals
- TCR: peptides displayed by MHC molecules on APCs |
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What is the potential for diversity of antibody/immunoglobulin vs T-Cell receptors?
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- Ab: potential for >10^9 distinct specificities
- TCR: potential for >10^11 distinct specificities |
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What is antigen recognition mediated by for antibody/immunoglobulin vs T-Cell receptors?
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- Ab: variable (V) regions of heavy and light chains of membrane Ig
- TCR: variable (V) regions of α and β chains |
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What are the signaling functions mediated by for antibody/immunoglobulin vs T-Cell receptors?
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- Ab: proteins (Igα and Igβ) associated w/ membrane Ig
- TCR: proteins (CD3 and ζ) associated w/ TCR |
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What are the effector functions mediated by for antibody/immunoglobulin vs T-Cell receptors?
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- Ab: constant (C) regions of secreted Ig
-TCR: does not perform effector functions |
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What ist he organization of an Immunoglobulin?
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- 1x Light chain
- 2x Heavy chains - Both light chains and heavy chains have variable regions and constant regions - Fab region = variable regions + constant region of light chains + first constant region of heavy chains - Fc region = constant region of heavy chains |
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What is the Fab region?
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- Variable regions (Vh and VL) of the heavy and light chains
- Constant region (CL) of light chain - First constant region (CH1) of heavy chains |
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What is the Fc region?
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Constant region of two heavy chains (Ch)
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How many classes of antibodies are there?
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5 different classes (isotypes)
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How many types of light chains are there?
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2: Kappa (κ) or Lambda (λ)
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Do kappa (κ) and lambda (λ) light chains change during class switching?
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No
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Each immunoglobulin variable region (heavy and light chain) has how many regions of hypervariability? What are these regions called?
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3 regions of hypervariability (complementarity-determining = CD regions)
-CDR1, CDR2, CDR3 |
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What are the contact sites for the epitope in the antigen binding site?
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The 3 regions of hyper-variability: CDR1, CDR2, and CDR3
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Secreted forms of:
- IgA - IgD - IgE - IgG - IgM |
- IgA - monomer, dimer, or trimer
- IgD - none - IgE - monomer - IgG - monomer - IgM - pentamer |
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Functions of:
- IgA - IgD - IgE - IgG - IgM |
- IgA - mucosal immunity
- IgD - naive B cell antigen receptor - IgE - mast cell activation (immediate hypersensitivity) and defense against helminthic parasites - IgG - opsonization, complement activation, Ab-dependent cell-mediated cytotoxicity, neonatal immunity, feedback inhibition of B cells - IgM - naive B cell antigen receptor, complement activation |
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What are the secreted forms of IgA?
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- Monomers
- Dimers - Trimers |
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What are the functions of IgA?
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Mucosal immunity
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What are the secreted forms of IgD?
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None! - it is only membrane bound
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What are the functions of IgD?
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Naive B cell antigen receptor
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What are the secreted forms of IgE?
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Monomer
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What are the functions of IgE?
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- Mast cell activation (immediate hyper-sensitivity)
- Defense agains helminth parasites |
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What are the secreted forms of IgG?
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Monomer
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What are the functions of IgG?
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- Opsonization
- Complement activation - Antibody-dependent cell-mediated cytotoxicity - Neonatal immunity - Feedback inhibition of B cells |
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What are the secreted forms of IgM?
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Pentamer
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What are the functions of IgM?
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- Naive B cell antigen receptor
- Complement activation |
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Which antibody forms the naive B cell antigen receptors?
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- IgD
- IgM |
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If a dog is immunized with human Ig, what happens?
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- They will generate an Ab response to the non-self protein
- Abs directed against common epitopes on a given isotype will react with the same isotypes from any human |
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Where are there polymorphic residues within antibodies? How big? Function?
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- Within light and heavy chain constant regions - single amino acid interchanges (allotypic difference)
- May serve as epitopes (the part of an antigen molecule to which an antibody attaches itself) |
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What is the term for antibodies that can distinguish immunoglobulins from two individuals that have single amino acid interchanges on their light and heavy chain constant regions?
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Anti-allotypic
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When are anti-allotypic antibodies common?
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Patients with rheumatoid arthritis
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What is the term for antibodies that can distinguish immunoglobulins from two individuals that have single amino acid interchanges on their variable regions?
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Anti-idiotypic
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What is the difference between isotypic, allotypic, and idiotypic differences?
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- Isotypic: IgG vs IgA (different heavy chains)
- Allotypic: individual differences within constant region of the same heavy chain - Idiotypic: differences within variable region / binding specificities |
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What is the structure of the T cell receptor?
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- α chain
- β chain - Each has a variable and a constant region, connected to one another with disulfide linkages |
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What are the antigen binding characteristics of an Ig vs TCR?
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- Ig: 3 CDRs in Vh and 3 CDRs in VL
- TCR: 3 CDRs in Vα and 3 CDRs in Vβ |
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What is the structure of antigens bound to Ig vs TCR?
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- Ig: linear and conformational determinants of macromolecules and small chemicals
- TCR: only 1-3 aa residues of a peptide and polymorphic residues of of MHC molecule |
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What is the affinity of antigen binding to an Ig vs TCR?
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- Ig: Kd = 10^-7 to 10^-11 M; average affinity of Igs increases during immune response
- TCR: Kd = 10^-5 to 10^-7 M; no change to affinity during immune responses |
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What are the on-rates and off-rates of Ig vs TCR?
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- Ig: rapid on-rate and variable off-rate
- TCR: slow on- and off-rate |
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What are the accessory molecules involved in binding an Ig vs TCR?
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- Ig: none
- TCR: CD4 or CD8 simultaneously binds MHC molecule to stabilize binding interaction |
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What is the difference between Affinity and Avidity
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- Affinity: binding strength of a single interaction
- Avidity: combined strength of binding by many different interactions |
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What is the term for the binding strength of a single interaction?
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Affinity
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What is the term for the combined strength of binding by many interactions?
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Avidity
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How does the number of peptides in the binding site differ for CD4 and CD8 T cells?
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- CD4: larger peptides (14-24 aa)
- CD8: smaller peptides (8-10 aa) |
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It is estimated that there are how many distinct antibody specificities in a given individual?
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More than a billion
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How can you generate so much T cell and B cell receptor diversity?
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- Rearrangement of genomic gene segments between variable gene and J-region segment
- This construct then pairs with a constant region gene segment (Ig light chains and TCR α-chains) - Same process occurs in Ig heavy chains and TCR β-chains w/ addition of D-region |
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What is the sequence of Ig and TCR gene rearrangement events?
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- 1st: recombination of heavy chain D and J
- 2nd: recombination of V with DJ - 3rd: VDJ recombines with a constant region gene segment - 4th: heavy chain transcript VDJC is processed and expressed within cell, and then at cell surface with a surrogate light chain - 5th: Ig light chain (or TCR α-chain) V and J recombine - 6th: VJ recombines w/ C segment to form transcript for the light chain - 7th: light chain transcript VJC is translated and expressed in combination with heavy chain to form intact protein |
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For Immunoglobulins, where do they get most of their diversity?
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* Heavy chain and κ chains get most of diversity from number of V gene segments
* Heavy chain gets some diversity from D (diversity) gene segments - Heavy chain and κ chain get mild amount of diversity from joining (J) gene segments |
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For T Cell Receptors , where do they get most of their diversity?
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* α and β chains get most of their diversity from V gene segments and joining (J) gene segments
- D (diversity) gene segments do not contribute (much) |
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Diversity (D) gene segments provide diversity to what?
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Heavy chains of Ig
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What is the extent of combinatorial diversity from V-(D)-J combinations alone?
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- Ig: ~10 million
- TCR: ~3 million |
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What is the extent of combinatorial diversity from V-(D)-J combinations in addition to Junctional Diversity?
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- Ig: ~10^11
- TCR: ~10^16 |
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What is junctional diversity? Function?
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- Nucleotides randomly removed or added from Ig and TCR
- Form of adding diversity to Igs and TCRs |
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What are the mechanisms of generating antigen receptor (Ig and TCR) diversity?
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1. Combinatorial (multiple gene segments; V-(D)-J)
2. Junctional diversity 3. Mix and match pairing of light and heavy chains 4. Somatic hyper-mutation (only for B cells) |
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What happens in somatic hyper-mutation? Function?
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- CDR regions in Ig can have additional random mutations that can increase affinity over time = AFFINITY MATURATION
- Leads to much higher binding affinity for Ig * Does not occur in TCRs |
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What is necessary for an Ig or TCR to be expressed?
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- All recombination events must be in the proper reading frame
- Once an in-frame transcript is translated, no further recombination of that chain will occur |
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How do you know when no further recombination of a chain will occur?
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Once an in-frame transcript is translated (no further recombination of that chain will occur)
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What is allelic exclusion? Function?
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- Expression of the heavy chain gene product of EITHER the maternal or the paternal chromosome, but NOT BOTH
- Ensures clonal specificity |
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What are the implications of mutations in the recombination enzymes (VDJ recombinase; RAG-1 and RAG-2)?
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Profound negative consequences such as:
- Autosomal SCID (severe combined immune deficiency) - Both "arms" (B cells and T cells) of the adaptive immune system are impaired |
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What are the steps in the maturation of lymphocytes?
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1. Proliferation
2. Pre-B/T antigen receptor expression (one chain of antigen receptor) 3. Proliferation 4. Antigen receptor expression (complete antigen receptor) 5. Positive and negative selection |
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What induces proliferation of Pro-B/T cells in the first step of maturation of lymphocytes?
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IL-7
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What can cause failure of the maturation of lymphocytes?
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- 1st checkpoint: Failure to express pre-lymphocyte receptors
- 2nd checkpoint: Failure to express antigen receptor |
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What are the components of positive and negative selection of lymphocytes?
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- Positive selection: weak self antigen recognition
- Negative selection: strong self antigen recognition - Failure of positive selection: no self antigen recognition |
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What happens if the lymphocyte has weak self antigen recognition?
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Positive selection - forms mature T/B cell
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What happens if the lymphocyte has no self antigen recognition?
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Failure of positive selection - cell dies
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What happens if the lymphocyte has strong self antigen recognition?
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Negative selection - cell dies
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What are the names of the B cells as they progress from a stem cell to a mature B cell?
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- Stem cell
- Pro-B - Pre-B - Immature B - Mature B |
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What Ig DNA and RNA is present in the following stages:
- Stem cell - Pro-B - Pre-B - Immature B - Mature B |
- Stem cell: germline DNA
- Pro-B: germline DNA - Pre-B: recombined H chain gene (VDJ); µ mRNA - Immature B: recombined H chain gene, κ or λ genes; µ and κ or λ mRNA - Mature B: alternative splicing of primary transcript to form Cµ and Cδ mRNA |
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What Ig expression is happening during the following stages:
- Stem cell - Pro-B - Pre-B - Immature B - Mature B |
- Stem cell: none
- Pro-B: none - Pre-B: cytopasmic µ and pre-B receptor associated µ - Immature B: membrane IgM (µ + κ or λ light chain) - Mature B: membrane IgM and IgD |
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Where do B cells go after maturing? Function?
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- Go to peripheral lymphoid tissues
- When antigen encounter activates BCR the activated B cells secrete antibodies |
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How do you get rid of B cells that react with self molecules (auto-reactive)?
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Removed or functionally inactivated by Negative Selection
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What happens in positive selection of T cells?
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Thymocytes reactive w/ self-MHC molecules are expanded following interaction w/ self-MHC peptide complexes int he thymus
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What happens in negative selection of T cells?
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Self-reactive thymocytes are eliminated, either physically or functionally, following interaction of the T cell antigen receptor w/ self MHC-peptide complexes
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What determines the T cell repertoire in an individual?
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Result of positive and negative selection during T cell maturation in thymus
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What are the regions of the Thymus? What happens in these locations?
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- Cortex: location where T cell precursors set up and rearrange α and β chains - location of positive selection
- Medulla: rich in APCs, this is where negative selection occurs |
