Somatic Hypermutation: Another piece in the hypermutation puzzle

Another piece in the hypermutation puzzle Studies with transgenic mice are beginning to define the minimal requirements for the somatic hypermutation of immunoglobulin genes that is critical in the production of high-affinity antibodies. One of the hallmarks of an advanced vertebrate immune system is the ability of the body to remember an invading organism, and to educate itself to respond more vigorously upon a second 'antigenic' challenge by the same organism. After first contact with an antigen, a portion of the responding B cells migrate to the germinal centers of lymphoid organs, where they undergo a fantastic evolution. The B cells hypermutate their rearranged immunoglobulin variable genes and undergo a process of natural selection, whereby the clones that produce anti-bodies with the highest affinity survive while other clones die [1]. This results in 'memory' B cells, which have 102 to 10 3 times higher affinity for the cognate anti-gen than do the cells in the original clone. In two weeks, this breathtaking process creates a million years' worth of mutation and selection in a somatic recapitulation of evolution. Over the last decade, our knowledge of this process has grown considerably, although often the results may seem confusing or contradictory. The published data are like pieces of a dauntingly complex biological puzzle; only recently have a few pieces, here and there, begun to fit together to give us a view of the molecular mechanism driving hypermutation. We now know that the hypermutation occurs only at the 5' end of immunoglobulin genes, centering on the rearranged variable (V), diversity (D) and joining J) gene segments. The mutations appear to be randomly distributed over a 2 kb region with a well-defined 5' end, starting in the promoter region, and an amorphous 3' end trailing into the intron downstream of the V(D)J coding region [2]. Work from several laboratories [3-7] has linked the immunoglobulin-gene mutation frequency with the presence of both the intronic transcriptional 'enhancer' element between the V(D)J and constant (C) regions and the 3' enhancer downstream of the C region (Fig. 1). This suggests that mutation correlates with an 'open' DNA structure, associated with the potential for transcription. There is, however, no evidence directly connecting hypermutation to the transcription rate. Furthermore, hypermutation appears to occur only in germinal-center B cells [8], which express low levels of immunoglobulin mRNA and cytoplasmic immunoglobulin [9,10]. The role of the enhancers and transcription may therefore be …