Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis

Weici Zhang, Rahul Sharma, Shyr Te Ju, Xiaosong He, Yanyan Tao, Koichi Tsuneyama, Zhigang Tian, Zhe Xiong Lian, Shu Man Fu, M. Eric Gershwin

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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 α, interferon-γ, interleukin (IL)-6, IL-12, and IL-23. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)545-552
Number of pages8
JournalHepatology
Volume49
Issue number2
DOIs
StatePublished - 2009

Fingerprint

Cholangitis
Regulatory T-Lymphocytes
Biliary Liver Cirrhosis
Antibodies
Cytokines
Interleukin-23
Freund's Adjuvant
Interleukin-12
Serum
Interferons
Immunization
Interleukin-6
Homeostasis
Transcription Factors
Tumor Necrosis Factor-alpha
Messenger RNA
Mutation
Liver
Genes

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. / Zhang, Weici; Sharma, Rahul; Ju, Shyr Te; He, Xiaosong; Tao, Yanyan; Tsuneyama, Koichi; Tian, Zhigang; Lian, Zhe Xiong; Fu, Shu Man; Gershwin, M. Eric.

In: Hepatology, Vol. 49, No. 2, 2009, p. 545-552.

Research output: Contribution to journalArticle

Zhang, Weici ; Sharma, Rahul ; Ju, Shyr Te ; He, Xiaosong ; Tao, Yanyan ; Tsuneyama, Koichi ; Tian, Zhigang ; Lian, Zhe Xiong ; Fu, Shu Man ; Gershwin, M. Eric. / Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. In: Hepatology. 2009 ; Vol. 49, No. 2. pp. 545-552.
@article{e45c599788014bf78d2e82d056d15d72,
title = "Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis",
abstract = "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 α, interferon-γ, interleukin (IL)-6, IL-12, and IL-23. Conclusion: 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.",
author = "Weici Zhang and Rahul Sharma and Ju, {Shyr Te} and Xiaosong He and Yanyan Tao and Koichi Tsuneyama and Zhigang Tian and Lian, {Zhe Xiong} and Fu, {Shu Man} and Gershwin, {M. Eric}",
year = "2009",
doi = "10.1002/hep.22651",
language = "English (US)",
volume = "49",
pages = "545--552",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "2",

}

TY - JOUR

T1 - Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis

AU - Zhang, Weici

AU - Sharma, Rahul

AU - Ju, Shyr Te

AU - He, Xiaosong

AU - Tao, Yanyan

AU - Tsuneyama, Koichi

AU - Tian, Zhigang

AU - Lian, Zhe Xiong

AU - Fu, Shu Man

AU - Gershwin, M. Eric

PY - 2009

Y1 - 2009

N2 - 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 α, interferon-γ, interleukin (IL)-6, IL-12, and IL-23. Conclusion: 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.

AB - 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 α, interferon-γ, interleukin (IL)-6, IL-12, and IL-23. Conclusion: 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.

UR - http://www.scopus.com/inward/record.url?scp=61949143670&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=61949143670&partnerID=8YFLogxK

U2 - 10.1002/hep.22651

DO - 10.1002/hep.22651

M3 - Article

C2 - 19065675

AN - SCOPUS:61949143670

VL - 49

SP - 545

EP - 552

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 2

ER -