Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs more in females than males at a ratio of 9:1. The female bias for the development of lupus is also seen in most genetically lupus-susceptible Vertebrate Animals: We have found that even chemically induced lupus in an otherwise healthy mouse strain (SJL) displays a female bias. The fundamental basis for such gender bias remains unclear. Sex hormones, sex chromosomes or both may contribute to such sex difference. Extensive human and animal studies have investigated the role of gonadal hormones on the development of SLE. It has been difficult to dissect the role of contribution of sex chromosome X and Y genes, independent of sex hormones. We have made use of mice that differ in the complement of sex chromosomes (XX vs. XY), while having the same gonadal type, to determine the effect of sex chromosome complements. In preliminary work, we have introgressed the informative complement of sex chromosomes from the stock MF1 background onto the SJL background to generate XX females, testes determining factor gene Sry-deficient XY (XY-) females, and Sry transgenic XX (XX.Sry) males, and XY-.Sry males. We have found that mice of the XX sex chromosome complement (XX and XX.Sry), as compared to XY (female XY- and male XY-.Sry), experience more severe autoimmune disease, namely autoimmune encephalomyelitis and pristane-induced lupus. Guided by these novel data, we hypothesize that XX sex chromosome complement, as compared to XY, confers greater susceptibility to lupus. In this proposal, we will test this hypothesis and begin to dissect the mechanisms.
In Aim 1, we will investigate mechanisms that confer greater susceptibility to pristane-induced lupus in SJL mice with the informative complement of sex chromosomes.
In Aim 2, we will introgress the Y- chromosome (deleted for Sry) and the Sry transgene onto the genetically lupus-prone NZM.2328 strain to the N10 generation. Then, the effect of sex chromosome complement on this spontaneous model of lupus will be ascertained using disease measures (proteinuria, creatinine, blood urea nitrogen and renal pathology), autoantibodies and immune responses. Finally, in Aim 3, we will generate mice of the XO genotype to determine if the sex chromosome effect on disease outcomes and immune measures in Aims 1 and 2 is attributable to a gene unique to the Y chromosome versus the dosage of X genes. Together these proposed studies will greatly advance the understanding of the role of sex chromosomes in lupus.
The goal of the current proposal is to investigate the contribution of sex chromosomes in the gender bias in autoimmune diseases such as systemic lupus erythematosus, which affect women much more frequently than men with a ratio of 9:1. The results of the proposed study will not only aid our understanding of lupus, but will also potentially lead to identification of newer targets of treatment.
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