Sex chromosome aneuploidies in autoimmune disease

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DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a disease that can affect any organ. The disease has a complicated pathogenesis involving many aspects of the immune system, including acquired and innate. SLE is substantially more common among women than men such that 90% of patients are female. The sex bias of the disease is present in patients with onset before puberty as well as at older ages after menopause. Sex hormones are abnormal in both men and women with established SLE, but at the diagnosis of SLE, prior to therapy, there are no abnormalities of estrogen, androgen or prolactin. The PI has generated data showing that Klinefelter's syndrome (male 47,XXY) is 15-fold over-represented among men with SLE compared to the general population. In addition, these data indicate that Klinefelter men are at the same risk of SLE as women. Therefore, based on these data, the PI has proposed an X chromosome gene effect for SLE, which is a new hypothesis for the sex bias found in SLE. New data support this notion. We find that 47,XXX is present in 8 of 245 women with SLE, while 47,XXX is present in 1 in 1000 live female births. Women with 47,XXX are phenotypically normal in terms of sex hormones, menarche, pregnancy and menopause. Thus, these data strongly support the hypothesis that increasing number of X chromosomes imparts additional risk of SLE without regard to sex hormones. Based on these data we hypothesize a gene on the X chromosome that gives a risk of SLE to persons with two X chromosomes regardless of sex, and an even higher risk of SLE to women with three X chromosomes. In fact, based on X inactivation patterns in man and mouse as well as new preliminary data, we have identified a gene on the X chromosome, DDX3X as a possible mediator of the X chromosome dose effect. The DDX3X protein is a critical component of a cytoplasmic pathway that recognizes nucleic acids, and culminates in production of interferon. 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 lupus pathogenesis. Preliminary Data indicate the DDX3X protein is over-expressed in persons with two X chromosomes compared to those with one X. Furthermore, interferon production through the DDX3X pathway is higher in woman compared to men. DDX3X will be tested as the mediator of the X chromosome dose effect. First, we will define DDX3X levels in human immune cells and mouse tissues. In Specific Aim 2, we will determine differential interferon production as mediated by DDX3X by women versus men. In the final Specific aim, we will comprehensively study the importance of DDX3X in knock-out animals. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus, or simply lupus, is a chronic disease in which the immune system attacks various organs, including the skin, joints, muscles, lungs, kidneys, heart, and brain. More than 90% of patients are women. Our research is investigating why lupus has a predilection for women. Rare human medical conditions in which there are additional X chromosomes have been highly informative. Men should have one X and women should have 2. However, men with 2 X chromosomes are at the same lupus risk as women, and women with 3 are at an even higher risk for lupus. So, we think that the risk of lupus is related to the numbe of X chromosomes, not sex. The proposal will investigate this idea, including an attempt to identify the gene responsible for this effect. Lupus is a common illness among otherwise healthy young adults. Thus, lupus is frequently diagnosed among military personnel and leads to a medical discharge in most individuals. There are more than 10,000 patients cared for by the Department of Veterans Affairs who are diagnosed with lupus.