Historically, a major goal of my research program has been to reveal the cellular and molecular basis of antibody formation and the development of memory B cells. Somatic hypermutation plays a critical role in these processes by altering the sequences of antibody variable (V) genes while B cells respond to foreign immunogen in germinal centers. Selection pressures normally favor the continued participation of rare B cell clones expressing mutant receptor antibodies that bind immunogen with improved affinity. As such, the memory B cell repertoire is normally established.
More recently, my laboratory has taken an interest in elucidating the etiology of autoantibody formation in systemic autoimmune diseases such as lupus (SLE). Although it plays a decisive role in acquired immunity, SHM is a potentially dangerous process and one that we suspect is critical for the generation of such pathological autoantibodies. Conventional wisdom holds that newly minted B cells emerging from the bone marrow with an autoreactive receptor sometimes escape the self-tolerance mechanisms that normally censor the repertoire and that following activation by self-antigen, such B cells acquire somatic mutations that may improve the affinity with which their receptor antibodies bind self-antigen. Alternatively, SHM may be playing a much more decisive role by actually creating autoreactive B cell clones de novo from nonautoreactive antecedents. Our studies to date support the latter of these two alternatives. As such, we are building a new model to examine self-tolerance in B cells and their escape from self-tolerance at the post-mutational, germinal center stage of activation. We are also investigating the possibility that spontaneous somatic mutagenesis in genes that regulate the immune system is the ultimate cause of autoimmunity.
In order to participate in autoimmune response, B cells must receive help from αβ T cells. But the origin and antigenic specificity of this help are unknown. One possibility we are exploring is that somatic hypermutation creates new T cell epitopes within the B cell receptor that enable the autoreactive B cell to obtain T cell help. This is plausible because B cells not only process and present peptides from foreign immunogen in the context of class II MHC, they also process and present peptides derived from their receptor antibody. We refer to this idea as the “receptor presentation” hypothesis. We are looking at this from two perspectives. On the one hand, we are testing the idea that receptor presentation ultimately provides the major avenue of help to pathological autoreactive B cells. On the other, we are determining how receptor presentation is normally precluded under physiological circumstances. We assume that specialized tolerance mechanisms must normally regulate this avenue of help, otherwise autoimmunity would be the rule not the exception. To test our ideas, we have developed transgenic lines of mice that carry B cells expressing mutant antibody molecules with defined T cell epitopes and corresponding transgenic lines that carry corresponding αβ T cells that react to these epitopes.