Sex chromosome aneuploidies in autoimmune disease

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 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) are autoimmune diseases with a complicated pathogenesis involving many aspects of the immune system. There is a strong gender bias in both SLE and SS, with 10 times more women affected than men. In both male and female patients with established SLE, sex hormones are abnormal. However, at the diagnosis of SLE, prior to therapy and regardless of age of onset, there are no abnormalities. The PI has reported that compared to the general or control population, Klinefelter's syndrome (male 47,XXY) is 15-fold and 38-fold over-represented among men with SLE and SS, respectively. These data and calculations using Bayes' theorum indicate that Klinefelter men have at least the same risk of SLE and SS as women. Therefore, based on these data, the PI has proposed an X chromosome gene effect for SLE and SS, which is a new hypothesis for the sex bias found in these disorders. Additional new data support this notion. We find 47,XXX statistically increased in female SLE (7 of 2826) and SS (3 of 1,033) patients, as compared to controls (2 of 7,074). We found no increase in 47,XXX in primary biliary cirrhosis and RA subjects, both of which have a female bias, indicating alternative mechanisms for sex bias. Women with 47,XXX are phenotypically normal in terms of sex hormones, menarche, pregnancy and menopause. Data from studies of SLE in mice with XX and XY females as well as XX and XY males also strongly support the hypothesis that increasing number of X chromosomes imparts additional risk of SLE/SS without regard to sex hormones. Based on data generated by the PI as well as these mouse data we hypothesize that X-linked genes that escape X inactivation in both man and mouse, DDX3X, CXorf38, KDM6A, KDM5C CA5B EIF2S3 may cause an increased risk of SLE or SS to persons with 2 or more X chromosomes, regardless of sex. Our proposed study will be the first to examine differential gene and protein expression of genes that escape X inactivation between normal men and women and those with extranumerary X chromosomes. New preliminary data support DDX3X and CXorf38 ( an uncharacterized gene and protein product) as possible mediators of the X chromosome dose effect as we have found correlations of expression in both proteins with X chromosome number. The DDX3X protein is a critical component of a cytoplasmic pathway recognizing nucleic acids, and culminates in interferon production. This pathway is parallel with, but independent of the toll-like receptor-dependent pathway in the endosome that also recognizes nucleic acid, produces interferon and is involved in SLE pathogenesis. Furthermore, interferon production through the DDX3X pathway is higher in woman compared to men. Preliminary Data show that CXorf38 is expressed in B cells, expression is greater in female cells compared to male cells and that this protein may be involved in B cells activation. In Specific Aim 1, DDX3X and each of the other 5 genes will be tested as possible mediator(s) of the X chromosome dose effect by defining protein levels of the six genes in human immune cells and mouse tissues. In Specific Aim 2, we will establish a functional role for differentially overexpressed X-linked genes in SLE human subjects and mouse models. In the final Specific aim, we will characterize severity and susceptibility of induced and spontaneous lupus in a chromosome aneuploidy mouse model.