A novel mechanism for rescuing autoreactive B cells generated in vivo by somatic mutation
Ray, Subhransu Kumar
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The ultimate success of the immune system resides in its ability to discriminate between small molecular differences that distinguish foreign from self epitopes. This is a daunting task when one considers the magnitude of epitopes encountered by the immune system. During a response to foreign antigen, somatic hypermutation occurring in peripheral lymphoid organs alters the expressed antibody specificities. A process of positive selection leads to the survival of B cells producing higher affinity antibodies to the eliciting antigen. However, based on the random nature of the mutational process, we reasoned that the response to foreign antigen may introduce extensive autoreactivity into the immune repertoire. To explore this hypothesis, I have developed a unique myeloma fusion partner that forms stable hybridomas with B cells destined for apoptosis. I have used this cell line to examine the immunized B cell repertoire of non-autoimmune mouse strains and to characterize those B cells that are not normally selected to contribute to the expressed antibody repertoire.;B cell proliferation and diversification following antigenic stimulation occurs in germinal centers. The majority of these B cells undergo apoptosis. Survival of an antigen specific subpopulation is associated with the expression of Bcl-2, a gene known to interfere with the process of apoptosis. I have designed a cell line, which, by expressing Bcl-2, is able to rescue B cells that were previously inaccessible by somatic cell fusion.;Utilizing this fusion partner, we have demonstrated that a significant proportion of the antibody response to the foreign antigen, PC, is cross-reactive with the self antigen, double-stranded DNA (dsDNA). In addition, we have demonstrated that some of these cross-reactive antibodies are able to deposit in renal glomeruli, similar to the anti-dsDNA antibodies involved in systemic lupus erythematosus. These data support the existence of negative regulatory pressures in peripheral lymphoid organs, which act to prevent the activation of deleterious B cell clones that would transform an otherwise protective antibody response into one that would be pathogenic to the host. As these cross-reactive antibodies have characteristics similar to those involved in autoimmune disorders, we speculate that peripheral dysregulation may be a central factor in autoimmunity.