Forkhead box p3+ regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis
✍ Scribed by Pascal Lapierre; Kathie Béland; Caroline Martin; Fernando Alvarez Jr.; Fernando Alvarez
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 535 KB
- Volume
- 51
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
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(+)CD25(+)FoxP3(+) 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 17beta-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(+/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.