title: 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 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.
  
  
  CONCLUSIONS
  Our findings suggest a sustained rigorous B-cell response in PBC, likely activated and perpetuated by cognate autoantigen.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Bowlus
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhaliwal
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Jinjun
authors.initials: J
authors.lastname: Wang
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Kenny
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackay
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000918:Antibody Specificity; D000921:Antibody-Producing Cells / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000276:immunology*; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D054447:Receptors, CCR10 / Q000378:metabolism; D054387:Receptors, CXCR / Q000378:metabolism; D055815:Young Adult
chemical_list: C501896:ACKR3 protein, human; D001324:Autoantigens; C515706:CCR10 protein, human; D054447:Receptors, CCR10; D054387:Receptors, CXCR; D051047:Dihydrolipoyllysine-Residue Acetyltransferase