We have identified three chromosomal segments, apart from the MHC complex, which contain genes that independently regulate progression of the pancreatic autoimmunity and beta-cell loss in non-obese diabetic (NOD) mice. Two of these genes, found on chromosomes 4 and 11, co-localize with chromosomal segments associated with one or more aspects of lupus-like disease in the NZB/NZW F1 model. This observation led to our first hypothesis: that genes located on chromosomes 4 and 11, which control- diabetes-susceptibility in NOD mice, promote the development of lupus-like disease in mice. We propose to define the location of lupus-susceptibility genes on chromosomes 4 and 11 in a recombinant-inbred mouse model of SLE, NZM2328. This will be accomplished by inhibiting disease expression with defined intervals of chromosome 4 and 11 taken from the non-autoimmune C57L/J strain and correspond to the locations of the chromosome 4 and 11 genes in autoimmune diabetes (Specific Aim 1). Using targeted breeding, we will then determine directly whether homologous NOD interval can reestablish disease expression after replacing C57L/J segments in this model (Specific Aim 2). Taken together, the results of the proposed experiments in Aims 1 and 2 will test the hypothesis that the lupus- susceptibility genes identified on chromosomes 4 and 1 represent """"""""autoimmunity genes"""""""" common to at least two distinct models of spontaneous autoimmunity in mice. In addition to protection from insulitis, we show that introduction of C57L/J derived alleles into a defined segment of chromosome 11 supports normalization of defective immune responses and protection from invasive insulitis in NOD mice. These observations suggest the second hypothesis: that this region of chromosome 11 plays a fundamental role in the regulation of specific immune reactivity, with particular relevance to autoimmunity. In order to test this hypothesis, we will determine the mechanism of action of the chromosome 11 gene(s) in an induced model of autoimmunity resulting from immunization with Ro60 antigen (Specific Aim 3). These studies will allow us to define the genetic relationship between pathogenic immune responses and the regulation of inflammatory responses by genes on chromosome 11. The results of these experiment will provide insight in disease pathogenesis in lupus-like autoimmunity in mice, particularly in dependence regulation of immune responses and inflammation. In addition, they will determine whether common """"""""autoimmunity genes"""""""" control the development of disease in two autoimmune disease with different manifestations. We postulate that genes of this type are very likely to have homologues in human autoimmune disease.
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