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

Human IgG structure n 2 heavy chains + 2 light chains n Constant, variable and hypervariable regions n The conundrum: to account for ~10 11 different IgG specificities - cannot be separate gene for each (i.e., more different antibodies than base pairs in genome!)

The solution: combinatorial diversity n Mechanisms: in B cells, somatic “rearrangement” (or recombination) involving splicing as well as somatic mutation n 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)

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

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

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