Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis.
There have been several descriptions of mouse models that manifest select immunological and clinical features of autoimmune cholangitis with similarities to primary biliary cirrhosis in humans. Some of these models require immunization with complete Freund's adjuvant, whereas others suggest that a decreased frequency of T regulatory cells (Tregs) facilitates spontaneous disease. We hypothesized that antimitochondrial antibodies (AMAs) and development of autoimmune cholangitis would be found in mice genetically deficient in components essential for the development and homeostasis of forkhead box 3 (Foxp3)(+) Tregs. Therefore, we examined Scurfy (Sf) mice, animals that have a mutation in the gene encoding the Foxp3 transcription factor that results in a complete abolition of Foxp3(+) Tregs. At 3 to 4 weeks of age, 100% of animals exhibit high-titer serum AMA of all isotypes. Furthermore, mice have moderate to severe lymphocytic infiltrates surrounding portal areas with evidence of biliary duct damage, and dramatic elevation of cytokines in serum and messenger RNAs encoding cytokines in liver tissue, including tumor necrosis factor alpha, interferon-gamma, interleukin (IL)-6, IL-12, and IL-23.


CONCLUSIONS
The lack of functional Foxp3 is a major predisposing feature for loss of tolerance that leads to autoimmune cholangitis. These findings reflect on the importance of regulatory T cells in other murine models as well as in patients with primary biliary cirrhosis.
Zhang
Weici
W
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
Sharma
Rahul
R
Ju
Shyr-Te
ST
He
Xiao-Song
XS
Tao
Yanyan
Y
Tsuneyama
Koichi
K
Tian
Zhigang
Z
Lian
Zhe-Xiong
ZX
Fu
Shu Man
SM
Gershwin
M Eric
ME
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D002761:Cholangitis / Q000235:genetics / Q000276:immunology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000276:immunology*; D016133:Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D016207:Cytokines