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Finding Therapy for Sex-Biased Autoimmune Conditions

Apr 14, 2020 10:02:00 AM / by Stacy Matthews Branch, DVM, PhD

Group Of Mature Female Friends Walking Along Path Through Yurt Campsite_AdobeStock_300323826-1By observing T cells, researchers are better identifying the connections between estrogen, testosterone, and autoimmune diseases.

The most common autoimmune diseases, such as rheumatoid arthritis, irritable bowel disease (IBD), and systemic lupus erythematous (SLE), affect women significantly more than men in terms of incidence, disease severity, progression, and response to therapy. Various studies have been conducted to explore the basis of the sexual dimorphism of autoimmune diseases. A prominent factor is the role of sex hormones in the sex-based differences associated with autoimmune diseases.

In the case of IBD (e.g., Crohn’s disease and ulcerative colitis), evidence that estrogen may play a role is seen in the results of studies that show a difference in the incidence of the disease between post-menopausal and non-menopausal women. In mouse models of colitis with a deletion of ERα in T cells, T-cell activation was reduced, and there was increased expression of a transcription factor, Foxp3, needed for the normal function of regulatory T cells. These findings suggest that ERα-targeted immunotherapy, such as downregulation of ERα in T cells, may be an effective treatment approach for autoimmune diseases. 

Men with low testosterone levels can have an increased risk of autoimmune diseases. The risk of SLE increases significantly in men with Klinefelter’s syndrome, and the SLE goes into remission after testosterone replacement therapy. Therefore, testosterone appears to have a protective role against autoimmune disease development. Testosterone regulates BAFF, a cytokine that is needed for B-cell survival, and BAFF levels increase in mice that lack androgen receptors. There is an immunotherapy, belimumab, that targets BAFF, but it is only effective in a small number of patients with autoimmune dysfunction.

The sexual dimorphism seen with autoimmune diseases may also involve factors that are not related to sex hormones. The transcription factor vestigial, like family member 3 (VGLL3), is abundant in female skin cells. Overexpression of VGLL3 in mouse skin leads to B cell expansion, autoantibody production, and systemic autoimmune dysfunction. They also develop rashes similar to those seen in lupus.

Various factors are associated with the development of an autoimmune disease, but gender factors can strongly affect the incidence and progression of autoimmune diseases. Further research can help identify additional options for effective immunotherapies that can increase patient quality of life.

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Could novel sex-linked targets provide autoimmune disease therapies?. (2020). Drug Target Review. Retrieved from

Topics: Autoimmune Disorders, T Cells

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