EFFECT OF GENETIC BACKGROUND ON THE CONTRIBUTION OF NEW-ZEALAND BLACKLOCI TO AUTOIMMUNE LUPUS NEPHRITIS

Autoimmune diseases such as systemic lupus erythematosus are complex g enetic traits with contributions from major histocompatibility complex (MHC) genes and multiple unknown non-MHC genes. Studies of animal mod els of lupus have provided important insight into the immunopathogenes is of disease, and genetic analyses of these models overcome certain o bstacles encountered when studying human patients, Genome-wide scans o f different genetic crosses have been used to map several disease-link ed loci in New Zealand hybrid mice. Although some consensus exists amo ng studies mapping the New Zealand Black (NZB) and New Zealand White ( NZW) loci that contribute to lupus-like disease, considerable variabil ity is also apparent. A variable in these studies is (he genetic backg round of the nonautoimmune strain, which could influence genetic contr ibutions from the affected strain, A direct examination of this questi on was undertaken in the present study by mapping NZB nephritis-linked loci in backcrosses involving different non-autoimmune backgrounds, I n a backcross with MHC-congenic C57BL/6J mice, H2(z) appeared to be th e strongest genetic determinant of severe lupus nephritis, whereas in a backcross with congenic BALB/cJ mice, H2(z) showed no influence on d isease expression, NZB loci on chromosomes 1, 4, 11, and 14 appeared t o segregate with disease in the BALB/cJ cross, but only the influence of the chromosome 1 locus spanned both crosses and showed linkage with disease when all mice were considered, Thus, the results indicate tha t contributions from disease-susceptibility Loci, including MHC, may v ary markedly depending on the non-autoimmune strain used in a backcros s analysis, These studies provide insight into variables that affect g enetic heterogeneity and add an important dimension of complexity for linkage analyses of human autoimmune disease.