V(D)J hypermutation and DNA mismatch repair: vexed by fixation.

Abstract

The immune system has adopted a remarkable series of genetic tricks to cope with pathogens, extant and possible. For example, diverse sets of Ig heavy- and light-chain genes are generated by specific DNA recombinations in the developing B lymphocytes present in bone marrow. This process of V(D)J recombination can generate >107 distinct antibody V regions from relatively few (≈102) genetic building blocks and is driven by the punctuated expression of the recombination activating genes Rag1 and Rag2 during B cell genesis (1). Maturing B cells leave the bone marrow and travel to peripheral lymphoid follicles, where they become competent to respond to an antigen. The antigen activates B cells by binding to membrane Ig, inducing migration from follicles into adjacent zones of T lymphocytes and a concerted up-regulation of surface molecules that mediate T and B cell collaboration (2). In the T cell zone, activated antigen-specific B cells provide and receive survival and proliferation signals; the progeny of these cells subsequently specialize to become antibody-secreting plasmacytes or return to the follicle and initiate the germinal center (GC) reaction (2, 3). GCs support another trick for generating Ig diversity: V(D)J hypermutation. B cells in GCs accumulate high frequencies of point mutations (and, less commonly, deletions and insertions); the rate of mutation in the Ig V region is thought to be ≈1 mutation/103 bp/cell division, a rate 106-fold above that for other gene loci. Ig hypermutation usually is restricted to GC B cells and exhibits a distinctive pattern of nucleotide misincorporations by favoring transition mutations and strand polarity (1, 4). The small, GC B cell population undergoes repeated rounds of hypermutation, selection, and proliferation. In this darwinian microcosm, mutations that better the ability of the B cell to bind …