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

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. (Hepatology 2014;)