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IgGs: Somatic recombination and combinatorial diversity

IgGs: Somatic recombination and combinatorial diversity. Immune system - recognition of “self” vs. “non-self” Hallmarks of immune response specificity memory Ig class switching. Human IgG structure. 2 heavy chains + 2 light chains Constant, variable and hypervariable regions

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IgGs: Somatic recombination and combinatorial diversity

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  1. IgGs: Somatic recombination and combinatorial diversity • Immune system - recognition of “self” vs. “non-self” • Hallmarks of immune response • specificity • memory • Ig class switching

  2. Human IgG structure • 2 heavy chains + 2 light chains • Constant, variable and hypervariable regions • The conundrum: to account for ~1011 different IgG specificities - cannot be separate gene for each (i.e., more different antibodies than base pairs in genome!)

  3. The solution: combinatorial diversity • Mechanisms: in B cells, somatic “rearrangement” (or recombination) involving splicing as well as somatic mutation • 4 families of elements: V (variable), D (diversity), J (joining) and C (constant) • H chain: ~200 V genes, 20 D genes, 6 J genes (plus constant region genes for each isotype)

  4. Antibody diversity: A combination of mechanisms • Combination of different V, D and J regions • Junctional diversity in splicing these regions together - imprecise joining with random insertion of nucleotides • Somatic mutation within V region genes • Finally, combinations of pairing of H chain isotypes and L-chain subtypes (kappa and lambda)

  5. Additional genetic mechanisms governing Ig expression • Isotypic exclusion: each B cell expresses only a single H-chain isotype and single L-chain subtype (IgM, IgG, IgA, IgD, IgE) • Allelic exclusion: only 1 of 2 possible alleles is expressed

  6. Diversity of the TCR (T-cell antigen receptor) • TCR: a highly variable transmembrane heterodimeric glycoprotein that plays a role in antigen recognition • Structure is similar to Igs • Combinatorial diversity generated in similar manner • Ig and TCR genes appear to be part of immunoglobulin gene superfamily with shared ancestry

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