CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis

Authors

  • Lifeng Wang,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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    • These authors contributed equally to this work.

  • Ying Sun,

    1. Department for Non-infectious Diseases, Beijing, China
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    • These authors contributed equally to this work.

  • Zheng Zhang,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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    • These authors contributed equally to this work.

  • Yiqiong Jia,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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    • These authors contributed equally to this work.

  • Zhengsheng Zou,

    1. Department for Non-infectious Diseases, Beijing, China
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  • Jinbiao Ding,

    1. Medical Affairs Department, Beijing, China
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  • Yuanyuan Li,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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  • Xiangsheng Xu,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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  • Lei Jin,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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  • Tao Yang,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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  • Zhiwei Li,

    1. Department for Hepatobiliary Surgery, Beijing, China
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  • Yanling Sun,

    1. Research Center for Liver Transplantation, Beijing, China
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  • Ji-yuan Zhang,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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  • Sa Lv,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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  • Liming Chen,

    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
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  • Baosen Li,

    Corresponding author
    1. Department for Non-infectious Diseases, Beijing, China
    • Address reprint requests to: Fu-Sheng Wang, Ph.D., M.D., Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing 302 Hospital, 100039, China. E-mail: fswang302@163.com; fax: 86-010-63879735; or Baosen Li, M.D., Department of Non-infectious Liver Diseases, Beijing 302 Hospital, 100039, China. E-mail: libaosen16@sina.com; or M. Eric Gershwin, M.D., Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616. E-mail: megershwin@ucdavis.edu; fax: 530-752-4669.

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  • M. Eric Gershwin,

    Corresponding author
    1. Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA, USA
    • Address reprint requests to: Fu-Sheng Wang, Ph.D., M.D., Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing 302 Hospital, 100039, China. E-mail: fswang302@163.com; fax: 86-010-63879735; or Baosen Li, M.D., Department of Non-infectious Liver Diseases, Beijing 302 Hospital, 100039, China. E-mail: libaosen16@sina.com; or M. Eric Gershwin, M.D., Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616. E-mail: megershwin@ucdavis.edu; fax: 530-752-4669.

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  • Fu-Sheng Wang

    Corresponding author
    1. Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing, China
    2. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Hangzhou, China
    • Address reprint requests to: Fu-Sheng Wang, Ph.D., M.D., Research Center for Biological Therapy, Institute of Translational Hepatology, Beijing 302 Hospital, 100039, China. E-mail: fswang302@163.com; fax: 86-010-63879735; or Baosen Li, M.D., Department of Non-infectious Liver Diseases, Beijing 302 Hospital, 100039, China. E-mail: libaosen16@sina.com; or M. Eric Gershwin, M.D., Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616. E-mail: megershwin@ucdavis.edu; fax: 530-752-4669.

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  • Potential conflict of interest: Nothing to report.

  • Supported by the National Natural Science Foundation of China, grant 81101589; National Institutes of Health grant DK39588; National Grand Program on Key Infectious Disease grants 2012ZX10001006-003-003, 2013ZX10001002-001-002; Beijing Municipal & Technology Commission grant Z131100004013041.

  • See Editorial on Page 424

Abstract

There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5+CD4+ Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P < 0.05) and HC (P < 0.01). Second, the function of circulating Tfh cells from PBC patients, including interleukin (IL)-21 production (P < 0.05), the ability to promote B-cell maturation, and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in ursodeoxycholic acid (UDCA) responders compared to UDCA-treated nonresponders, in both cross-sectional (P = 0.023) and longitudinal studies (P = 0.036), respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. Conclusion: These results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches. (Hepatology 2015;61:627-638)

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