The MRL/MpJ-lpr (MRL-lpr) mouse develops spontaneous inflammatory Genes from the MRL strain are necessary for this synovitis since lpr since lpr congenics, including C57BL/6J-lpr (B6-lpr), AKR/J-lpr and not manifest arthritis. Preliminary studies using F1 crosses between MRL- crosses between MRL-lpr and B6-lpr mice indicate that the inheritance of semidominant. In order to identify the number of genes, the chromosomal chromosomal location of the arthritis susceptibility gene(s) and determine relationship between synovitis and functional and serologic abnormalities, abnormalities, we will analyze backcross and/or F2 intercrosses utilizing BL/6-lpr parental strains. The histology of the hind limb knees of these knees of these mice will be scored and the results correlated with rheumatoid factor, anti-DNA antibodies, and Ig levels including IgG3. DNA including lgG3. DNA from each of the progeny will be examined for throughout the mouse genome at approximately 15 centi-Morgan intervals. Morgan intervals. Microsatellite polymorphisms that are detected by and restriction fragment length variants will be used to accurately define used to accurately define haplotypes. The segregation of loci that affect determined using computer programs that are designed to analyze complex analyze complex genetic diseases. Since the mouse and human genomes are multiple chromosome segments that have been conserved over evolution, these evolution, these studies have the potential to identify putative genetic the inheritance and pathogenesis of human inflammatory arthropathies. arthropathies. Therefore the proposed studies may suggest candidate genes critical to the development of disease in both mice and humans. As part of As part of this effort, human families with rheumatoid arthritis will also to determine whether disease segregates with candidate loci including those including those suggested by the MRL study. We will use an affected that does not presuppose a mode of inheritance. The proposed studies have proposed studies have the potential to identify non-major important in the pathogenesis of inflammatory arthropathy. inflammatory arthropathy.

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