Systemic lupus erythematosus (SLE) is a serious autoimmune disease of which the etiology and mechanisms of pathogenesis are incompletely understood. It is clear that there is an important genetic component to lupus. High titers of autoantibodies, which may include anti-Sm and anti-RNP are characteristic of lupus. Recent work shows that the natural history of these autoimmune responses is to increase in complexity by involving additional structures of the autoantigen in the autoimmune response. This process is termed epitope spreading detected in this proposal as added antigenic spine specificity through time. A similar phenomenon in T cell epitopes is very important in other models of disease, such as experimental autoimmune encephalitis. The applicants suspect that this process is also very important in lupus pathogenesis. Recently a new model of lupus autoimmunity was discovered by this group induced by immunization with a short sequence from Sm B/B'. This new model of induced SLE presents opportunities to explore the genes involved in B cell epitope spreading as well as the autoimmunity of lupus. Work here with the AKXL recombinant inbred set of mouse strains has preliminarily established linkage on chromosome 4 at B cell marker 72. They propose to apply the impressive tools of mouse genetics to identify the genomic region and perhaps the specific genes associated with anti-Sm B cell epitope spreading. They will subsequently explore the syntenic regions and homologous genes in human lupus. The goals of this proposal are to analyze genetic contributions to epitope spreading and recombinant inbred strains of mice and to confirm the findings by classical genetic approaches. It will seek to confirm and narrow the region of chromosome 4 by classical back cross experiments. Simultaneously the investigators will evaluate the candidate gene Cd72 for its potential role in the observed linkage. If Cd72 does not explain linkage in this recombinant inbred set, then confirmation of this region, and a search for different candidate genes will then pursue. They will then seek linkage in other recombinant inbred strains of mice and work to identify the responsible genes. Finally, linked regions and identified genes will be tested for their potential contribution to human lupus.
