Antigen Receptor Genes and Antibody Diversity

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Antigen Receptor Genes and Antibody Diversity

• Lecture 14

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Overview of B Cell Development,
Activation, Antibody Production
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The expression of antigen receptor genes is the
Key event in lymphocyte Development/Maturation

• Functional Ag. Receptor Created in Immature
  Lymphocytes
• B Cells Bone Marrow
• T Cells Thymus

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The expression of antigen receptor genes is the
Key event in lymphocyte development/maturation

• Required for
• Generation of Diverse Repertoire
• Selection Against lymphocytes that are Self
  Reactive-NEGATIVE SELECTION
• Selection for Lymphocytes With Useful
  Specificities-POSITIVE SELECTION

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Formation of Functional Antigen Receptor Genes in
Lymphocytes
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Overview of B Cell Development,
Activation, Antibody Production
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Heavy Chain

• Variable Region
• Region Encoded for by 3 separate gene segments
• VH (Variable)
• DH (Diversity)
• JH (Joining)
• Constant Region
• C Gene Segments

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Light Chain

• Variable Region
• Encoded for by 2 separate gene segments
• VL (Variable)
• JL (Joining)
• Constant Region
• C (CL) Gene Segment

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Complete Variable Regions are Generated by the
Somatic Recombination of Separate Gene
Fragments-Gene Rearrangement
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Gene Rearrangement

• Occurs in Bone Marrow
• Antigen-Independent
• Before Antigenic Exposure.

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How to code for different antibodies?

• A few groups of gene segments, combining 1 gene
  segment from each group to form a complete Ab

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Recombination and Expression of Ig Genes
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Recombination and Expression of Ig Genes(Contd.)
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Gene Rearrangement(Heavy chain)

• In the course of differentiation, a B cell
  rearranges its DNA so as to join one VH gene
  segment to one DH segment and one JH segment.
  The joined VDJ unit codes for the entire variable
  region of the heavy chain.
• Mediated by Recombinases
• Recombination Signal Sequence (RSS)

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Antibody Diversity

• Combinatorial Diversity (V-D-J joining)
• Combinatorial association of heavy and light
  chains
• Junctional Diversity
• Somatic Hypermutation

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Combinatorial Diversity

• The ability to create many different
  specificities by making many different
  combinations of a small number of gene segments.
  (2005)(1006)(200126)

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Combinatorial Diversity
2.3 X 107
Specific antibody
14,400
VH
VL
1600
V 200
D 12
J 6
?
600
?
1000
V 200
J 5
V 100
J 6
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Junctional Diversity
Joining of V and the J, or V, D and J segments To
form CODING JOINT is Imprecise Addition and
Deletion of Nucleotides Diversity of the
Hypervariable region 3 (CDR3)
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Mechanisms of Diversity in Antigen Receptors
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Deletions
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Additions
Terminal deoxyribonuceotidyl transferase (TdT)
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Allelic Exclusion
Monospecificity Of B Cells