Sex Chromosome Effects in Lupus

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DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) affects females much more frequently than males with a ratio of 9:1. Many murine models of lupus also demonstrate a greater incidence in females as compared to males. Sex hormones, sex chromosomes or both may contribute to this female bias. Since, it has been much easier to study the effect of gonadal hormones, than the effects of X and Y genes, the role of sex chromosomes in lupus remain poorly understood. Mice which differ in the complement of sex chromosomes (XX vs. XY), while having the same gonadal type, have been created to determine the effect of sex chromosomes in the absence of confounding effects of exposure to different types of sex hormones. Originally on outbred MF1 mice, the mice with an informative complement of sex chromosomes have recently been backcrossed by our laboratory onto the SJL strain, a strain with a female preponderance for pristane induced lupus. In aim #1 of this proposal, we will induce lupus with pristane in SJL mice with the informative complement of sex chromosomes to determine whether clinical disease course, proteinuria, BUN levels, kidney pathology and immune measures are influenced by sex chromosome genotype in this model of lupus. In aim #2, we will cross SJL XY- Sry male mice with female NZB mice to create (NZBxSJL)F1 mice having the informative sex chromosome complement. Then, the effect of sex chromosome complement on the known female preponderance of this spontaneous model of lupus will be ascertained using the same measures of disease and immune responses as in aim #1. Together this exploratory (R21) application will or will not support a role for sex chromosomes in the female preponderance in experimental and spontaneous models of lupus. This is an exploratory (R21) application to determine the effect of sex chromosomes on two murine models of lupus (one chemically induced and one spontaneous). This disease was chosen in light of the 9:1 female preponderance of the human disease system lupus erythematosus.