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Flashcards in Antibody Diversity Deck (16)
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1

describe the steps in B-cell development

2

describe the function of IL-7

3

describe negative vs. positive selection in B-cells (the checkpoints)

4

describe the steps in heavy chain rearrangement

5

describe class switching

  • during class switching, the antigenic specificity (or V protein domain) is preserved and only the constant domain changes
    • therefore different antibody classes will have the same antibody binding properties
  • variety of diverse B-cell repertoire (as well as T cell) is generated through V-D-J somatic recombination before the B-cells meet any antigen
  • once a particular B-cell clone encounters an antigen, it becomes active, proliferates and secretes first IgM 
  • under the influence of cytokines, the B-cell clone will undergo further gene rearrangement and be able to produce other Ig classes (G, A, E)

6

describe light kappa chain rearrangement

  • Pre-B cells go through another gene rearrangement round to generate light k (kappa) chain from chr. 2
  • variable domain of light protein chains is coded by 2 gene segments: Vk (variable) and Jk (joining) genes
  • the constant region has only one gene segment: Ck
  • if the newly generated immature B-cell has high affinity to self-antigens, the rearrangment process may be reactivated to act upon lambda (λ) light chain genes 

7

describe allelic exlusion and light chain exclusion

  • allelic exclusion: suppression of the recombination from the second chromosome therefore only one allele (maternal or paternal) will be expressed in a single clone
    • single antibody can combine heavy chain from maternal gene origin with a light chain from paternal gene origin
  • light chain exclusion is the process of either k or λ chain synthesis, but never both of them in a single B cell

8

describe the BCR associated membrane proteins

  • cell surface Ig molecules (BCR) function is to:
    • recognize foreign antigens
    • send signal to intra-cellular components (tyrosine kinase) which initiates the B-cell activation cascades
  • the trans-membrane region of the Ig anchors the molecule on the cell membrane
  • signaling requires 2 adaptor surface glycoprotein molecules which are associated with the BCR
    • Iga (CD79a)
    • IgB (CD79b)

9

describe the combinatorial diversity seen through random joining

10

describe the function of TdT (terminal deoxynucleotidyl transferase)

  • TdT adds random non-germline coded nucleotided to V-D and D-J junctions
    • the amount of newly added nucleotides increases with the individual's age

11

describe somatic hypermutation and AID

  • somatic hypermutation is used in the process of affinity maturation initiated during the secondary stimulation
    • antibodies produced during primary exposure (immunization) have relatively low affinity compared to antibodies produced after secondary infection (boosting)
  • somatic hypermutation is facilitated by activation-induced cytidine deaminase (AID) 

12

13

describe the function of AID

  • AID is only expressed in activated B-cells and it works on:
    • immunoglobulin V regions hypermutation
    • the region which initiates antibody class switch
  • the enzyme deaminates the cytidine to uridine only in a ssDNA
  • such nucleotide conversion activates DNA mismatch and/or base excision repair mechanisms stabilizing the initial B cell mutation
  • defects in AID will interfere with antibody maturation process and will prevent class switching, limiting antibody production predominantly to low variability IgM = hyper IgM syndrome

14

describe the activation of B-cells by T-helper cells and cytokines

  • B-cell activation
    • clustering of antigen receptors by binding of multiple IgV receptors
    • Iga and IgB signaling modulates gene expression in lymphoid follicles of lymphoid tissues
    • B-cell presents antigen to T helper cell which secretes cytokines that binds to cytokine receptors on B cells
    • CD40,  CD40L and cytokines induce isotope switching in B cells and B cell proliferation

15

describe the generation of TCR diversity

  • analogous to BCR diversity
    • multiple germ-line segments
    • combinatorial V-D-J joining (random rearrangement)
    • junctional flexibility: imprecise joining at junctions
    • P-region nucleotide addition
    • N-region nucleotide addition
    • combinatorial association of a-chains with B-chains or γ- and δ-chains
  • the B-gene rearrangement (D-J joining, then DJ-V joining) occurs first in pre-T cells
  • followed by the a-chain rearrangement (V-J) joining in the immature T cell
  • rearrangement of both γ- and δ- genes appear to occur simultaneously
  • TCR does not exhibit somatic hypermutation

16

summarize the mechanisms for generating receptor diversity between B-cells and T-cells