Hypermutation, somatic

Epitopes presented in constrained scaffolds may be prevented from optimal interactions with their target by local deleterious charge, hydrophobic, hydrophilic or steric interactions. Methods have, therefore, been developed which introduce hypervariability, not only into the highly variable epitopes but also into the framework which carries them. This has been achieved by the use of error-prone PCR or, more recently, in vivo hypermutation. Ouellette and Wright [100] in their review of PCR amplifiable DNA and RNA ligands, 

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Somatic hypermutation High frequency of mutation that occurs in the gene segments encoding the variable regions of antibodies during the differentiation of B lymphocytes into antibody-producing plasma cells. 

Wang L, Jackson WC, Steinbach PA, Tsien RY (2004) Evolution of new nonantibody proteins via iterative somatic hypermutation. Proc Natl Acad Sci USA 101 16745-16749... 

Somatic hypermutation Mutations occurring in the variable region genes of the light and heavy chains during the formation of memory B cells. Those B cells whose affinity is increased by such mutations are positively selected by interaction with antigen, and this leads to an increase in the average affinity of the antibodies produced. 

As compared to DCs, B cells are very poor APCs and play a major role as source for antibodies. Upon stimulation by antigens and in the presence of T cells at the border of the T-cell-B-cell area, adjacent to follicles, B cells become antibody-secreting cells and eventually form a germinal center (GC) response. GCs are specialized follicles for B-cell expansion, somatic hypermutation, and class switch recombination, processes that are regulated by T cells, follicular DCs, and other cells. In this process of B-cell maturation, Tregs seem to play a critical role, as in several immune diseases, which are characterized by aberrant antibody... 

With one exception, all the mechanisms used by B cells to generate antibody diversity are also used by T cells to generate T-cell receptor diversity. The one mechanism that does not appear to operate in T-cell receptor diversification is somatic hypermutation. This is presumably because mutation would be likely to generate killer T cells that would wantonly attack self-molecules. This is much less of a problem for B cells, since most self-reactive B cells could not be activated without the aid of specific helper T cells. 

Somatic Hypermutation in Clonally Related B Cell Products Changes in Antibody Affinity... 

The molecular mechanism of somatic hypermutation is not yet understood, nor have the enzyme(s) involved been identified. Nevertheless, a considerable amount of descriptive information about the process has accumulated (see reviews by Milstein and Neuberger, 1996 Storb, 1996). 

Somatic hypermutation has been studied in detail in mice and humans, but no doubt operates in a similar fashion in a variety of other species, modifying the repertoire that is initially established by V(D)J recombination before the introduction of antigen. In the case of V regions of K light chains in sheep, somatic hypermutation also contributes toward the generation of the preimmune repertoire in an antigen-independent process (Reynaud et al., 1991, 1995). 

Allen, D., Cumano, A., Dildrop, R., Kocks, C., Rajewsky, K., Rajewsky, N., Roes, J., Sablitzky, F., Siekevitz, M. (1987). Timing, genetic requirements and functional consequences of somatic hypermutation during B-cell development. Immunol. Revs. 96, 5-22. 

Betz, A.G., Milstein, C., Gonzilez-Femindez, A., Pannell, R., Larson, T., Neuberger, M.S. (1994). Elements regulating somatic hypermutation of an immunoglobulin k gene critical role for the intron enhancer/matrix attachment region. Cell 77,239-248. 

Brezinschek, H.-P., Foster, S.J., Brezinschek, R.I., Domer, T., Domiati-Saad, R., Lipsky, P.E. (1997). Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5+/IgM+ and CD57IgM+ B cells. J. Clin. Invest 99,2488-2501. 

Kim, N., Kage, K., Matsuda, F., Lefranc, M.-P., Storb, U. (1997). B lymphocytes of xeroderma pigmentosum or Cockayne syndrome patients with inherited defects in nucleotide excision repair are fully capable of somatic hypermutation of immunoglobulin genes. J. Exp. Med. 186,413-419. 

Kim, S., Davis, M., Sinn, E., Patten, P., Hood, L. (1981). Antibody diversity somatic hypermutation of rearranged VH genes. Cell 27, 573-581. 

Klobeck, H.-G., Combriato, G., Zachau, H.G. (1987). N segment insertion and region-directed somatic hypermutation in a Kappa gene of a t(2 8) chromosomal translocation. Nucleic Acids Res. 15,4877-4888. 

O Brien, R.L., Brinster, R.L., Storb, U. (1987). Somatic hypermutation of an immunoglobulin transgene in k transgenic mice. Nature 326,405-409. 

Peters, A. Storb, U. (1996). Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity 4, 57-65. 

Somatic hypermutation, 41-51 Southern blots, 7,22, 33 Strand breaks in DNA, 129, 132... 

The final stage of B cell differentiation where the BCR repertoire is shaped is the germinal centre (GC) reaction. In the T cell dependent GC reaction, the BCR is adapted for its cognate antigen by somatic hypermutation (SMH) and class switch recombination (CSR), both of which are driven by activation induced cytidine deaminase (AID). Since AID induces targeted point mutations in the CDRs of the Ig HCs and Ig LCs, this can dramatically alter the BCR affinity or even its specificity. As AID activity may also result in the formation of an autoreactive BCR, a stringent counterselection of such self-reactive B cells is required. By analysis in human of the BCR repertoire of post-GC IgG+ memory B cells, it was demonstrated that indeed new auto-reactive B cells develop by SHM whereas 20% of naive B cells is self-reactive, up to 40% of the IgG+ memory B cells expressed a true de novo created self-reactive BCR. Apparently, lack of T cell help prevents activation of these self-... 

Low, N. M., ffolliger, P. H., and Winter, G. (1996). Mimicking somatic hypermutation affinity maturation of antibodies displayed on bacteriophage using a bacterial mutator strain. J. Mol. Biol., 260, 359-368. 

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