There is an overlap between Vh segments encoding antibodies involved in secondary immune responses against exogenous antigens and those few that are expressed in fetal, autoreactive, and/or CD5 B cells. Consequently, the proposed functions for such 'core' antibodies might be related. This idea predicts that the origin of autoimmunity is linked to mechanisms that regulate primary Vh repertoire development. One such stage and tissue-restricted mechanism is the programmed recombination of targeted Vh genes. A proposed determinant of the targeting event is chromatin accessibility, potentially generated by prior germline transcription of the specified Vh. We propose to study this mechanism and its consequences for autoantibody production primarily in transgenic mice that contain human sequence IgH miniloci sufficient to direct VDJ recombination. Vh genes employed in the miniloci satisfy the above core criteria of expression in fetal B cells, autoreactive B cells and CD5 B cells. Our plan includes in vivo expression studies in normal and autoimmune strains and in vitro cell culture experiments aimed at dissecting cis/trans/acting regulators of germline transcription and chromatin accessibility.
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