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

Abstract

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 IgM and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also cross-reactive 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 have used flow cytometry and ELISPOT to examine B cell subsets in 59 subjects, including 28 with PBC, 13 with 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 non-circulating tissue source of xenobiotic cross-reacting 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. In conclusion, our findings suggest a sustained rigorous B cell response in PBC, likely activated and perpetuated by cognate autoantigen.

Incidence and Risk Factors for Hepatocellular Carcinoma in Primary Biliary Cirrhosis

“…There have been significant advances in our understanding of primary biliary cirrhosis (PBC) including dissection of molecular and immunological mechanisms that lead to biliary cell destruction, development of animal models, and further details on geoepidemiology [1][2][3][4][5][6][7][8]. These advances, notwithstanding, and because of the potential presence of cirrhosis, there remain the critical questions regarding the relative frequency and risk factors for developing hepatocellular carcinoma (HCC) in PBC [9].…”

The Natural History and Prognosis of Primary Biliary Cirrhosis with Clinical Features of Autoimmune Hepatitis

“…There have been extraordinary and extensive studies of the genetic basis, the immunological features, and the molecular characteristics of not only human PBC but also of several mouse models [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”

Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice

“…These data take on significance in PBC in which, thus far, there has not been a successful translation of the critical immunological and molecular data in both human and murine models towards new therapy [38][39][40][41][42][43][44][45][46]. In addition, we should note that further attention should be placed not only on the local tissue microenvironment, but also on innate immunity, not only in PBC but also in other autoimmune diseases [35,[47][48][49].…”