Forkhead Box P3+ Regulatory T Cell Underlies Male Resistance to Experimental Type 2 Autoimmune Hepatitis

Abstract

Autoimmune hepatitis (AIH), like many autoimmune diseases, is most prevalent in young women. The immunological basis of this age and sex susceptibility bias was investigated in a murine model of AIH. Xenoimmunization of 7-week-old female C57BL/6 mice resulted in more severe AIH with higher levels of liver inflammation, serum alanine aminotransferase, specific T-cell cytotoxicity, and autoantibody than younger and older females. Vaccinated males developed minimal liver inflammation and higher percentages of CD4 FoxP31 regulatory T cell in peripheral blood mononuclear cells, spleen, and liver than females. Regulatory T cells (Tregs) were virtually absent in liver-lymphocytes infiltrates of females. Castration of C57BL/6 mice, with or without 17b-estradiol supplementation, did not modify susceptibility in males, nor Treg numbers, suggesting minimal contribution of testosterone and estradiol to autoimmune hepatitis (AIH) susceptibility. Xenoimmunized Aire(1/0) mouse displayed similar AIH susceptibility, sex bias, and Tregs numbers as C57BL/6 mice, suggesting that susceptibility in females is not the result of less stringent thymic central tolerance. Autoreactive B cell response against formiminotransferase-cyclodeaminase correlated with disease activity, possibly linking B-cell autoreactivity and AIH pathogenesis. Conclusion: Peripheral tolerance and development of regulatory T cells after self-mimicking antigen exposure, and not sexual hormone nor central tolerance, are the main factors for susceptibility to AIH in females. (HEPATOLOGY 2010;51:1789-1798 P revalence of most autoimmune diseases shows a striking sex difference, with women being affected more often than men.1,2 The ratio of female patients to male ranges from 20:1 in Sjögren's syndrome, to 3:2 in multiple sclerosis.2 Less frequently, the ratio approaches 1:1, as in ulcerative colitis and diabetes.2 In autoimmune hepatitis (AIH), the female to male ratio ranges from 3:1 in type 1 AIH to 9:1 in type 2 AIH. 3Differences in the immune response have also been observed between women and men. Higher level of antibodies and stronger T cell activation are observed in women after vaccination. 4 Women also have higher absolute numbers of CD4 þ T cells and produce higher levels of Th1 cytokines than men.5 Age also affects immune responses, including incidence of several autoimmune diseases. In AIH, 40% of cases of type 1 are diagnosed before the age of 18 years, with a mean age at onset of 10 years, 6,7 and 80% of cases of type 2 are diagnosed before the age of 18 years, with a mean age at onset of 6.5 years.6,7 A second peak of incidence of AIH has also been reported in women after menopause.8 These prepubertal and postmenopausal peaks of incidence suggest that the hormonal status could influence susceptibility to AIH.Research on autoimmune diseases sex bias is scarce. Studies on AIH susceptibility factors, including its sex bias, have been severely limited by the lack of experimental models. Recently, a murine experimental model of AIH has been produced 9 in whi...

Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis

“…Our current work builds upon that observation to show that CD4 + CD25 + Tregs isolated from SAMP-F show increased functional impairment, both in vivo and in vitro , compared to Tregs from SAMP-M (Figure 3). This finding is in agreement with previous work showing phenotypic and functional defects in Tregs from female autoimmune patients 38 , as well as from female rodents in experimental models of autoimmunity 39, 40 . Of note, a strength of the CD45RB high adoptive transfer model is that it is designed to test the suppressive function of Treg cells on the same population of pathogenic Teff cells isolated from SAMP-M MLN.…”

Testosterone Suppresses Hepatic Inflammation by the Downregulation of IL-17, CXCL-9, and CXCL-10 in a Mouse Model of Experimental Acute Cholangitis

“…Differences in Treg numbers have recently been described to account for the sex bias observed in a murine model of AIH (22,32). In our model, Treg numbers were similar between female and male livers.…”

“…Differences in regulatory T cell (Treg) numbers have been described to contribute to sexual differences observed in an experimental hepatitis model (22). We therefore investigated the CD4 + CD25 + Foxp3 + Treg frequencies in the livers of male and female recipient mice on day 8 after cell transfer.…”

The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis

“…CD4+Foxp3+Treg cells play a critical role in the maintenance of self tolerance, control of autoimmune diseases, transplant rejection and have also been documented to offer a therapeutic option in severe inflammatory colitis [5,8,[17][18][19][20]. Therefore, therapeutic agents that are capable of enhancing the number and activity of this T-cell subset are highly desirable.…”