Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis

Jun Zhang, Weici Zhang, Patrick S Leung, Christopher Bowlus, Sandeep Dhaliwal, Ross L. Coppel, Aftab A. Ansari, Guo Xiang Yang, Jinjun Wang, Thomas P. Kenny, Xiaosong He, Ian R. Mackay, M. Eric Gershwin

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

UNLABELLED: The serologic hallmark of primary biliary cirrhosis (PBC), the antimitochondrial response to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), has unique features, including continuous high titers of immunoglobulin M (IgM) and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also crossreactive with chemical xenobiotics that share molecular homology with the inner lipoyl domain of PDC-E2; such chemicals have been proposed as potential etiological agents. We used flow cytometry and enzyme-linked immunospot assay (ELISPOT) to examine B-cell subsets in 59 subjects, including 28 with PBC, 13 with primary sclerosing cholangitis (PSC), and 18 healthy controls. Strikingly, in PBC, although there were no significant differences in B-cell phenotype subpopulations, 10% of the total IgG and IgA plasmablast population and 23% of the IgM plasmablast population were uniquely reactive with PDC-E2, detected in the CXCR7+ CCR10low plasmablast population. In contrast, plasmablast reactivity to a control antigen, tetanus toxoid, was minimal and similar in all groups. Additionally, we isolated plasmablast-derived polyclonal antibodies and compared reactivity with plasma-derived antibodies and noted a distinct noncirculating tissue source of xenobiotic crossreacting antibodies. The high levels of autoantigen specific peripheral plasmablasts indicate recent activation of naive or memory B cells and a continuous and robust activation. The presence of CXCR7+ CCR10low PDC-E2-specific ASCs suggests a mechanistic basis for the migration of circulating antigen specific plasmablasts to the mucosal epithelial ligands CXCL12 and CCL28.

CONCLUSION: Our findings suggest a sustained rigorous B-cell response in PBC, likely activated and perpetuated by cognate autoantigen.

Original languageEnglish (US)
Pages (from-to)1708-1716
Number of pages9
JournalHepatology (Baltimore, Md.)
Volume60
Issue number5
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Medicine(all)

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    Zhang, J., Zhang, W., Leung, P. S., Bowlus, C., Dhaliwal, S., Coppel, R. L., Ansari, A. A., Yang, G. X., Wang, J., Kenny, T. P., He, X., Mackay, I. R., & Gershwin, M. E. (2014). Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis. Hepatology (Baltimore, Md.), 60(5), 1708-1716. https://doi.org/10.1002/hep.27313