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A Receptor Presentation Hypothesis for T Cell Help That Recruits Autoreactive B Cells¹

Department of Immunology, National Jewish Medical and Research Center, and the University of Colorado School of Medicine, Denver, CO 80206

To uncover mechanisms that drive spontaneous expansions of autoreactive B cells in systemic lupus erythematosus, we analyzed somatic mutations in variable region genes expressed by a panel of (NZB x SWR)F₁ hybridomas representing a large, spontaneously arising clone with specificity for chromatin. A single mutation within the J intron that was shared by all members of the lineage indicated that the clone emanated from a single mutated precursor cell and led to the prediction that a somatic mutation producing a functionally decisive amino acid change in the coding region would also be universally shared. Upon cloning and sequencing the corresponding germline V_H gene, we found that two replacement somatic mutations in FR1 and CDR2 were indeed shared by all seven clone members. Surprisingly, neither mutation influenced Ab binding to chromatin; however, one of them produced a nonconservative amino acid replacement in a mutationally "cold" region of FR1 and created an immunodominant epitope for class II MHC-restricted T cells. The epitope was restricted by IA^q (SWR), and the SWR MHC locus is associated with systemic lupus erythematosus in (NZB x SWR)F₁ mice. These, and related findings, provoke the hypothesis that autoreactive B cells may be recruited by a "receptor presentation" mechanism involving cognate interactions between T cells and somatically generated V region peptides that are self-presented by B cells.

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