Unique relationship identified between SLE, estrogen, and toll-like receptors Estrogen plays a major role in the female predominance of autoimmune disease, particularly systemic lupus erythematosus (SLE), a researcher stated here. Among the current hypotheses attempting to explain the greater prevalence of autoimmunity among women are that these diseases are X-chromosome linked, and because women have two X chromosomes their risk is greater, or that autoimmunity is related to the activation of certain genes on the X chromosome, said Wael N. Jarjour, MD, director of rheumatology and immunology at The Ohio State University College of Medicine in Columbus, at the Ohio Association of Rheumatology annual meeting. Another theory has suggested the possibility of an X chromosome "dose effect," because no one has ever seen a patient with lupus who had Turner's syndrome, where one of the X chromosomes is completely or partially missing, he said. A further potential explanation involves microchimerism, where genes embedded from the mother in the genome of the offspring can influence disease many years later. However, Jarjour's research into the effects of estrogen on the immune system has led him to favor a direct role for the hormone. He noted that SLE typically develops in young women of childbearing age, when the female to male ratio is 9:1, compared to a ratio of 2:1 during childhood and after menopause. "What changes at age 12 or 13 in females and at menopause? It's not the number of X chromosomes -- that doesn't change. What changes is sex hormones. I consider that irrefutable evidence that sex hormones play a role in lupus, even though in the last 20 years sex hormones [as being involved in SLE pathogenesis and disease course] have been under assault." I strongly disagree," Jarjour argued. Among the supporting evidence implicating estrogen in SLE are findings regarding the use of oral contraceptives, infections, and toll-like receptors, he said. Many studies have looked at the effects of oral contraceptives containing estrogen or estrogen/progesterone on lupus disease flares, with older studies showing significant effects but more recent studies showing no increased risk. Potential reasons for this difference are the reduced doses of hormones in recent years and the likelihood of referral bias, as patients with severe disease have been excluded from studies, he said. A role for sex hormones on lupus and disease flares is further supported by the observation that many women with active disease experience significant disease flares during pregnancy. Moreover, women with lupus who have developed ovarian failure after cyclophosphamide treatment tend to do better than those with comparable disease severity but without ovarian failure, he noted. It's also been observed that females fare better than males with infections, including tuberculosis, raising the question why. One explanation is that females of species ranging from small organisms such as nematodes to mammals have longer life spans, suggesting that they are more resistant to pathogens. "The idea is that estrogen can heighten the immune response, which works well when fighting infection but causes trouble when it comes to overstimulating the immune system resulting in autoimmunity," he said. He and his colleagues wrote in Clinical Immunology, "Data on global infection rates of Mycobacterium tuberculosis show similar incidence in pre-adolescent males and females, but are markedly higher in adult males despite lower healthcare standards for many women in underdeveloped nations. Sex differences in immune function making males less resilient to infection are well established and thought to account for this propensity." They proposed that estrogen increases activation of the immune system through upregulation of various genes and cytokines, including to toll-like receptor (TLR) 8, which is X-linked, involved in innate immunity, and has a known association with SLE. In experiments using peripheral blood mononuclear cells from lupus patients and healthy volunteers, his group found that TLR8 expression was significantly upregulated in cells from both males and females when stimulated with a synthetic TLR8 agonist, but that the effect was stronger in females and further enhanced with exposure to 17β-estradiol. They also observed that estrogen exposure led to an upregulation of other members of the endosomal subset of TLRs, including TLR3, 7, and 9. "This is particularly intriguing since endosomal TLR signaling is required for the production of anti-nucleic autoantibodies in mice, which is a clinical hallmark of systemic lupus erythematosus," they explained. "In conclusion," he said, "we have identified a novel relationship between SLE, estrogen, and TLR expression. Future work will focus on TLR signaling and estrogen responses to identify additional viable therapeutic targets in the treatment of SLE." Source
