Forkhead box p3+ regulatory T cell underlies male resistance to experimental type 2 autoimmune hepatitis.
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.


CONCLUSIONS
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.
Division of Gastroenterology, Hepatology and NutritionUniversité de Montréal, Canada.
Pascal
P
Lapierre
Kathie
K
Béland
Caroline
C
Martin
Fernando
F
Alvarez
Fernando
F
Alvarez
D000375:Aging; D000642:Ammonia-Lyases; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000502:physiology*; D051042:Glutamate Formimidoyltransferase; D019693:Hepatitis, Autoimmune / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology; D008099:Liver / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000276:immunology*; D064251:Multifunctional Enzymes; D012737:Sex Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; C494850:Ftcd protein, mouse; D051042:Glutamate Formimidoyltransferase; D000642:Ammonia-Lyases