SOMATIC ORIGIN OF T-CELL EPITOPES WITHIN ANTIBODY VARIABLE REGIONS - SIGNIFICANCE TO MONOCLONAL THERAPY AND GENESIS OF SYSTEMIC AUTOIMMUNE-DISEASE

During an immune response, specific antibody variable region genes are diversified by a somatic point mutation process that generates de nov o ''foreign'' V-region sequences. This creates an interesting problem in immune regulation because B cells are highly proficient at self-pre senting V-region peptides in the context of class II MHC. Though our s tudies indicate that the corresponding T-cell repertoire attains a sta te of tolerance to germline-encoded antibody V-region diversity, ii is presently unknown whether the same is true of mutationally generated diversity. On the basis of immunoregulatory considerations, we hypothe size that contact exclusion or tolerance normally precludes T cells fr om helping B cells via self-presented mutant V-region peptides. The la ck of recurrent somatic mutations that create known T-cell epitopes in antibody V regions lends some support to this idea. In contrast, our studies of spontaneously autoreactive B cells in systemic autoimmune d isease strongly suggest that precursors of such cells are recruited by T-cell help directed to self-presented mutant idiopeptides. Failures in tolerance or contact exclusion mechanisms may be responsible for th is apparently abnormal event. In addition to their importance in immun e regulation, somatic mutations or other differences from germline-enc oded V-region sequence may be largely responsible for undesirable pati ent responses to therapeutic monoclonal antibodies. These reactions mi ght be averted or diminished by inducing tolerance in the T-cell reper toire with synthetic peptide correlates of non-germline-encoded V-regi on sequences in humanized antibodies.