Antigen Recognition in the Adaptive Immune System Flashcards Preview

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Flashcards in Antigen Recognition in the Adaptive Immune System Deck (22)
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1

describe B-cells receptors (BCRs)

  • BCRs are antibodies
  • BCRs recognize a broad range of chemical structures: proteins, lipid, carbohydrates, and nucleic acids
  • B cells can recognize microbes and toxins in their native form
  • antibodies exist in 2 forms:
    • membrane-bound antigen receptors on B-cells
    • secreted proteins
  • both forms of antibodies recognize antigen by their variable domains
  • the constant region of some secreted antibodies can also participate in antigen elimination

2

describe the B-cell receptor: immunoglobulin

  • composed of 4 polypeptide chains:
    • 2 identical heavy chains (H)
    • 2 identical light chains (L)
  • end of the fork formed by light and heavy chains contain a wide range of variable antigen binding sites
  • V = variable regions
  • C = constant regions

3

describe the light chain (red)

  • comprises 2 domains:
    • the amino (N) terminal domain is variable and the site of antigen binding
    • the constant domain at the carboxy (C) terminal; it can be kappa or lambda

4

describe the heavy chain (blue)

  • it has a variable domain attached to several constant domains
    • the heavy chain determines the 5 classes of Ig: G, A, M, E or D
  • constant region (C): nearly invariant; not involved in antigen binding
    • AA sequence defines the five heavy chain classes

5

describe the variability in different regions of the Ig

6

name the 5 classes of immunoglobulins

  • IgG: monomer, produced by plasma cells (primary response) and memory cells (secondary), most prevalent
  • IgA: monomer circulates in blood, dimer in mucous and serous secretions
  • IgM: five monomers, first class synthesized following Ag encounter
  • IgD: monomer, serves as a receptor for antigen on B cells
  • IgE: involved in allergic responses and parasitic worm infections

7

describe the antigen/antibody interaction for the B-cell receptor

  • the antigen binds to the antibody by non-covalent interactions
    • strengths of the interaction: affinity
    • with repeat stimulation, the affinity increases: affinity maturation
    • avidity refers to the accumulated strength of multiple affinities of individual non-covalent binding interactions (10 for IgM compared to 2 for IgG)
    • cross-reactivity: one antibody, different epitopes

8

BCR (B-cell receptor) recognizes ___ but can not transmit signals on its own

signaling functions are mediated by __ and __ associated with membrane Ig

BCR (B-cell receptor) recognizes antigen but can not transmit signals on its own

signaling functions are mediated by Igα and Igβ associated with membrane Ig

9

describe T-cell receptor (TCR)

  • TCR heterodimer recognizes peptides displayed by MHC molecules
  • composed of 2 chains: α and β, each with a variable (V) and a constant (C) region
    • there are 3 hypervariable or complementary determining regions with V
    • like in antibodies CDR3 is the most variable
  • TCRs are not produced in a secreted form
  • TCRs do not undergo class switching

10

describe lymphopoiesis

  • B-cell production occurs throughout life; does not wane as does T cell production
  • about 5 million produced per day
  • about 10% of B cells mature
  • naive B cells survive about 1 week
    • undergo negative selection

11

describe B-cell development (3 stages)

  • goal: production of plasma and memory cells
  • process if divided in 3 stages:
    • generation of mature immunocompetent cells (antigen-independent phase)
    • activation of mature cells (antigen-dependent phase)
    • differentiation of active B cells into plasma and memory cells

12

describe the pro B cells (antigen-independent phase of B cell maturation)

  • Pro B cells
    • expression of CD45R and CD19
    • requires the bone marrow stromal cells to develop into a pre-B cells
      • cytokines (IL-7) support the process
  • rearrangement of Ig heavy chain genes
    • successful rearrangement = pre-B cells 
    • unsuccessful = apoptosis
  • the enzyme terminal deoxyribonucleotidyl transferase (TdT) is expressed: catalyzes insertino of N-nucleotides at the heavy chain coding (only)

13

describe the development of pre-B cells (antigen-independent phase of B-cell maturation)

  • Pre-B cells
    • presence of Igμ heavy chain in cytoplasm
    • few expressed on cell surface associate with a surrogate light chain and Igα/β
    • signal:
      • induce recombination of Igk light chain locus (failure will bring about recombination of λ light chain) (V to J joining)
      • RAG1 and RAG2 are expressed in Pro and Pre-cell development
      • allelic exclusion (no Ig heavy chain recombination on second allele)

14

describe the development of immature B-cells (antigen-independent phase of B cell maturation)

  • immature B cells
    • IgM expressed on surface
    • functional B cell receptor appears
    • negative selection (clonal deletion) occurs

15

describe further maturation and development of naive B cells (antigen-independent phase of B cell maturation)

  • further maturation: bone marrow or spleen
    • expression of IgM and IgD = mature B-cell (follicular B cells)
    • this process involves a change in RNA processing on the heavy chain
  • naive B cells
    • migrate out of bone marrow 
    • quiescent; no dividing; G0
    • has not encountered antigen

16

summarize B-cell development

17

describe targets for treatment during B-cell maturation

  • dysregulated B-cell receptor (BCR) signaling is a key driver of B-cell malignancies
    • kinases downstream of the B-cell receptor, such as SYK, PI3K and Bruton Tyrosine Kinase (BTK) are clinical targets for treatment of B-cell malignancies
  • CD20 is expressed on all stages of B-cell development except the first and last; it is present from pre-B cells through memory cells, but not on either early pro-B cells or plasma cells
    • CD20 is the target of the monoclonal antibodies: rituximab, obinutuzumab, ibritumomab, and tositumomab, which are all active agents in the treatment of all B cell lymphomas and leukemias
    • function: enable optimal B-cell immune resposne, specifically against T-independent antigens

18

give an overview of thymocyte development

  • hematopoietic stem cells (HSC)
    • bone marrow
  • common lymphoid progenitor
    • migrates to thymus
    • thymus is the maturation site
    • proliferation: IL-7 (common lymphoid only)
  • T-cell precursor
    • pro-T cell
    • no TCR, no CD3 expressed

19

describe the double negative cells (pre-T cells) in thymocyte development

  • double negative cells: Pre-T cells
    • no expression of CD4 or CD8
    • rearrangement of TCR beta genes
    • loss of stem cell markers
      • c-kit, CD44
    • expression of pre-TCR (if TCR beta genes rearrangement is successful)
      • beta chain plus pre alpha chain
    • signals:
      • proliferation
      • allelic exclusion
      • alpha chain rearrangements CD4, CD8 expression

20

describe positive selection during thymocye development

double positive cells (CD4+, CD8+)

  • positive selection:
    • DP thymocytes interact with cortical epithelial cells
    • cells that do bind moderately to MHC molecules become single positive (CD4 or CD8)
      • TCRs recognize class I MHC-peptide complexes: preserve the expression of CD8
        • capable of becoming CTLs on activation
      • TCRs recognize class II MHC-peptide complexes: preserve the expression of CD4
        • T cell/thymocyte or T helper cells
    • ensures self-MHC restriction

21

describe negative selection during thymocyte development

  • negative selection
    • elimination of any CD4 or CD8 cells that have high affinity to self-MHC alone or to self MHC-self epitope complexes
    • these cells are programmed to die (apoptosis)
    • ensures self-tolerance

22

describe AIRE

  • autoimmune regulator (AIRE): transcription factor expressed in the medulla of the thymus
    • controls a mechanism that prevents the immune system from attacking the body
    • AIRE drives negative selection of self-recognizing T cells
    • through the action of AIRE, medullary thymic epithelial cells (mTEC) express major proteins from elsewhere in the body ("tissue-restricted antigens" - TRA) and T cells that respond to those proteins are eliminated through apoptosis
  • when AIRE is defective, this can result in a variety of autoimmune diseases
    • hypoparathyroidism, primary adrenocortical failure, chronic mucocutaneous candidiasis