Anti-Sm antibodies are a highly specific marker for the diagnosis of SLE in humans and in certain SLE mouse strains. The expression of these autoantibodies is under genetic control in mice, although the nature of this control is not at present understood. In addition, the expression of anti-Sm antibodies in a genetically predisposed mouse depends on stochastic processes. The current studies are organized around the working hypothesis that the initiation of the anti-Sm response in individually genetically predisposed animals results from the rearrangement or somatic mutation of unique variable region genes (either light chain or heavy chain). Once the response is initiated, it is amplified by an (?abnormal) antibody-mediated positive feedback mechanism which results in an enhancement of the response and a diversification, either through somatic mutation or through the recruitment of new clones. The genetic predisposition to the anti-Sm response probably relates to a susceptibility to severe SLE, even through the antibody itself is not directly pathogenic. In the current proposal, we will investigate the genetics of the anti-Sm response by crossing anti-Sm positive and anti-Sm negative SLE mouse strains. We will breed anti-Sm positive and anti-Sm negative congenic mouse strains. We will compare the spontaneous anti-Sm response to the passive antibody-induced anti-Sm response, as well as to anti-Sm response induced by the injection of purified Sm in adjuvant. We will also investigate the control of expression of the anti-Sm trait in genetically predisposed strains by determining the repertoire of immunoglobulin variable region genes utilized in this response, and the role that somatic mutation plays. We will look at the expression of anti-Sm antibodies in allotype heterozygous animals in order to determine clonality of the anti-Sm response and changes in clonality over time. Finally, we will study an unusual system of positive feedback caused by passive administration of anti-Sm antibody, which may be important in the development of the high titer anti-Sm response seen in individual positive animals.
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