One of the unique features of the immune system is that it has evolved to raise antibodies against an unlimited number of antigens. The number of different antibodies raised in the lifetime of an organism is too large to be encoded in the genome. Instead, the immune system has evolved specific mechanisms that create a large number of diverse antibody specificities starting from a limited amount of genetic material. Our laboratory studies the different processes which are employed by B lymphocytes to generate this diversity.

Two processes generate the diversity of lymphocyte specificities. Initially, antigen receptor genes are generated by the somatic recombination of a small number of Variable, Diversity and Joining gene segments [V(D)J recombination]. The combinatorial diversity of this step alone is enough to generate up to 10⁷ different antibody specificities.

Antibodies generated through V(D)J recombination generally have low affinity for many different antigens. Fine tuning of the affinity of a particular antibody to a particular antigen is driven by a process called somatic hypermutation. Somatic hypermutation occurs when B cells respond to antigen and involves the introduction of point mutations into the variable regions of immunoglobulin genes. Some of the mutagenized antibodies will have a higher affinity for the antigen. Cells harboring these higher affinity antibodies proliferate and survive preferentially. Successive cycles of mutation and selection lead to the generation of B cells with very high affinity antibodies, a process known as affinity maturation.

As it is a highly mutagenic process, somatic hypermutation must be spatially and temporally regulated, but what targets it to the appropriate areas of the genome at the right time remains unknown and is of great interest to our lab. In addition, the molecular mechanism of somatic hypermutation is very poorly understood. None of the protein factors involved have been identified and no steps in the reaction have been characterized. We have recently obtained evidence that suggests that DNA double strand breaks are created during the reaction. We are currently establishing in vitro assays for somatic hypermutation, setting the stage for molecular and biochemical studies of the reaction mechanism, and hence for the identification of the key molecular players in the reaction.

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