The contribution of somatic hypermutation to the diversity of serum immunoglobulin: dramatic increase with age.

Although somatic mutation contributes to the diversity of only a minor fraction of B cells in mouse spleen or blood, its contribution to the diversity of serum immunoglobulin is unknown. We have devised an immunoassay to monitor mutated antibodies in serum using a monoclonal antibody that recognizes a VK only when mutated at its major intrinsic hot spot. Mutation makes essentially no contribution to the diversity of endogenous serum IgM, IgG, or IgA in young mice. However, in response to environmental antigens, the titer of mutated immunoglobulin in T cell-proficient mice rises strikingly with age, such that the major proportion of serum immunoglobulin in adults is somatically mutated, with the mutation load in IgG being some 10-fold greater than in IgM.