title: Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis.
abstract: OBJECTIVE
  Primary sclerosing cholangitis (PSC) is an autoimmune liver disease with destruction of hepatic bile ducts. A high frequency of biliary epithelial cell antibodies (BEC-Ab) is present in PSC. Here, we studied the mechanisms and signaling pathways used by these Ab in causing BEC dysfunction.
  
  
  METHODS
  Immunoassays were performed using freshly isolated BECs to study the signaling capacity of purified immunoglobulin (Ig) G and F(ab)'(2) fractions from 33 patients with PSC with anti-BEC-Ab.
  
  
  RESULTS
  We provide evidence that stimulation of BECs with PSC IgG, but not control IgG, induced expression of Toll-like receptor (TLR) 4 and TLR9 and specific phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 as well as the transcription factors ELK-1 and nuclear factor kappaB. A specific inhibitor of ERK1/2 abrogated phosphorylation of ELK-1 and protein expression of TLR4 but not TLR9 on BECs. TLR-expressing BECs, when further stimulated with lipopolysaccharide and CpG DNA, produced high levels of interleukin-1beta, interleukin-8, interferon gamma, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and transforming growth factor beta. Bile ducts stained positively for TLR4 and TLR9 in 58% of liver specimens taken from patients with PSC with BEC-Ab, as compared with 14% in those without BEC-Ab and also less frequently in diseased control livers.
  
  
  CONCLUSIONS
  Our data show that binding of PSC BEC-Ab initiates ERK1/2 signaling and up-regulation of TLR, which upon ligation induces BECs to produce cytokines/chemokines, leading to the possible recruitment of inflammatory cells. Thus, in PSC, BECs are not only targets of the immune attack but may also be active participants and mediators of their own destruction. BEC-Ab may be critical regulators of cholangitis in PSC.
authors.affiliation: Division of Transplantation Surgery, Division of Clinical Immunology, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
authors.forename: Azza
authors.initials: A
authors.lastname: Karrar
authors.forename: Ulrika
authors.initials: U
authors.lastname: Broomé
authors.forename: Towe
authors.initials: T
authors.lastname: Södergren
authors.forename: Marie
authors.initials: M
authors.lastname: Jaksch
authors.forename: Annika
authors.initials: A
authors.lastname: Bergquist
authors.forename: Mikael
authors.initials: M
authors.lastname: Björnstedt
authors.forename: Suchitra
authors.initials: S
authors.lastname: Sumitran-Holgersson
mesh_terms: D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000276:immunology*; D001653:Bile Ducts, Intrahepatic / Q000276:immunology / Q000473:pathology*; D015153:Blotting, Western; D015209:Cholangitis, Sclerosing / Q000097:blood / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000276:immunology*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: D000888:Antibodies, Anti-Idiotypic; D016207:Cytokines; D007074:Immunoglobulin G; D012333:RNA, Messenger; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9