Characterization of complement C3, C4, and factor B molecules in human bile

Sumiyoshi, Kenichi; Andoh, Akira; Fujiyama, Yoshihide; Sakumoto, Hitoshi; Bamba, Tadao

doi:10.1007/bf02936373

Cited by 10 publications

(7 citation statements)

References 20 publications

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“…However, the presence of IgG AMA, as well as functional complement, in bile could have a major effect on the inflammatory process. 7,53 The presence of disparate IgA and IgG epitopes on the same molecule FIG. 5.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous response of antimitochondrial autoantibodies and bile duct apical staining monoclonal antibodies to pyruvate dehydrogenase complex E2: The molecule versus the mimic

Migliaccio

2001

Hepatology

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The 2-oxo-acid dehydrogenase complexes and, in particular, the E2 component of the pyruvate dehydrogenase complex (PDC) are the target of antimitochondrial antibodies (AMA). More than 95% of primary biliary cirrhosis (PBC) patients have detectable levels of autoantibodies to PDC-E2 and in general these react with a region of the molecule that contains the prosthetic group lipoic acid (LA). LA is vital to the function of the enzyme, although there is conflicting evidence as to whether its presence is required for PDC-E2 recognition by AMA. Some, but not all, monoclonal antibodies (mAbs) to PDC-E2 produce an intense staining pattern at the apical surface of bile duct epithelial cells (BEC) in patients with PBC, and it has been argued that the molecule at the apical surface of PBC bile duct cells is a modified form of PDC-E2 or a cross-reactive molecule, acting as a molecular mimic. Herein, we characterize the epitopes recognized by 4 anti-PDC-E2 mAbs that give apical staining patterns (3 mouse and 1 human). In particular, by using a combination of recombinant antigens, competitive inhibition assays, and a unique peptide-on-bead assay, we determined that these apically staining mAbs recognize 3 or 4 distinct epitopes on PDC-E2. More importantly, this suggests that a portion spanning the entire inner lipoyl domain of PDC-E2 can be found at the BEC apical surface. In addition, competition assays with patient sera and a PDC-E2-specific mAb showed significant epitope overlap with only 1 of the 3 mouse mAbs and showed a differential response to the peptide bound to Primary biliary cirrhosis (PBC) is a destructive autoimmune disease of intrahepatic bile ducts characterized by inflammation of the portal triads, fibrosis, and the presence of antimitochondrial antibodies (AMA). 1,2 The major autoantigens recognized by AMA are related members of the 2-oxoacid dehydrogenase complexes including the pyruvate dehydrogenase complex (PDC-E2), the branched chain ketoacid dehydrogenase complex-E2, and the 2-oxo-glutarate dehydrogenase complex-E2. It has been hypothesized that a molecular mimic of the PDC-E2 molecule is expressed at high levels in the apical region of biliary epithelial cells (BEC) in PBC. [3][4][5] We have previously described a series of 8 monoclonal antibodies (mAbs) against the mitochondrial antigens of PBC that produce this disease-specific staining pattern. 6,7 Essentially, when probed with these disease-specific mAbs, small bile ducts in tissue from patients with PBC, but not controls, show intense staining at the apical surface of the cells lining the lumen. This pattern is in addition to the normal cytoplasmic pattern seen with mAbs against mitochondrial proteins. The fact that such apical staining is seen only with these select mAbs but not all mAbs that react with PDC-E2 has led to the hypothesis that a molecule(s) cross-reactive with PDC-E2 is located at the apical surface of PBC BEC. 3,4 Extensive efforts have been made to elucidate the AMA epitopes and link them to pathology. The consensus is that altho...

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Section: Discussionmentioning

confidence: 99%

Heterogeneous response of antimitochondrial autoantibodies and bile duct apical staining monoclonal antibodies to pyruvate dehydrogenase complex E2: The molecule versus the mimic

Migliaccio

2001

Hepatology

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“…The hepatobiliary system and the exocrine pancreas also secrete large amounts of active complement components into the gastrointestinal tract (17,18). Intestinal epithelial cells (IECs) locally synthesize and secrete complement components into the lumen (19 -22).…”

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confidence: 99%

Intestinal Trefoil Factor Induces Decay-Accelerating Factor Expression and Enhances the Protective Activities Against Complement Activation in Intestinal Epithelial Cells

Andoh

Kinoshita

Rosenberg

et al. 2001

The Journal of Immunology

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Mucosal damage induces a massive influx of serum complement components into the lumen. The epithelium produces a number of factors that can potentially ameliorate injury including intestinal trefoil factor (ITF), a small protease-resistant peptide produced and secreted onto the mucosal surface by goblet cells, and decay-accelerating factor (DAF), a protein produced by columnar epithelium which protects the host tissue from autologous complement injury. However, coordination of these intrinsic defensive products has not been delineated. DAF protein and mRNA expression were evaluated by immunoblotting and Northern blotting, respectively. NF-κB-DNA binding activity and DAF promoter activity were assessed by an electrophoretic gel mobility shift assay and a reporter gene luciferase assay, respectively. ITF induced a dose- and time-dependent increase in DAF protein and mRNA expression in human (HT-29 and T84) and rat (IEC-6) intestinal epithelial cells. In differentiated T84 cells grown on cell culture inserts, basolateral stimulation with ITF strongly enhanced DAF expression, but apical stimulation had no effects. The C3 deposition induced by complement activation was significantly blocked by the treatment with ITF. In HT-29 cells, ITF increased the stability of DAF mRNA. ITF also enhanced the promoter activity of the DAF gene via NF-κB motif and induced activation of NF-κB-DNA binding activity. ITF promotes protection of epithelial cells from complement activation via up-regulation of DAF expression, contributing to a robust mucosal defense.

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“…Previous studies have reported that intestinal epithelial cells are the local source of complement components (4,5) and that these complement components are also supplied into the gut lumen from the exocrine pancreas and bile system. (6,7) Therefore, blockade of the complement cascade at the C5 step may modulate the composition of the gut microbiota. The gut microbiota are an important factor which can affect colitis development.…”

Section: Discussionmentioning

confidence: 99%

“…(4,5) Complement components are also supplied into the gut lumen from the exocrine pancreas and bile system. (6,7) Furthermore, previous studies have reported the deposition of complement components at the inflamed mucosa of inflammatory bowel disease (IBD) patients, suggesting that complement-mediated tissue injury is involved in the pathophysiology of IBD. (8,9) The regulatory mechanisms of complement activation are finely balanced, since overactivation of the complement system leads to tissue injury.…”

Section: Introductionmentioning

confidence: 99%

Neutralization of complement component C5 ameliorates the development of dextran sulfate sodium (DSS)-colitis in mice

Aomatsu

Imaeda

Takahashi

et al. 2013

J. Clin. Biochem. Nutr.

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The complement system is a potent effector of innate immunity. To elucidate the pathophysiological role of the complement system in inflammatory bowel disease, we evaluated the effects of anti-C5 antibodies on the development of dextran sulfate sodium-induced colitis in mice. Dextran sulfate sodium-colitis was induced in BALB/c mice with intraperitoneal administrations of anti-C5 antibodies (1 µg/body) every 48 h. Tissue samples were evaluated by standard histological procedures. The mucosal mRNA expression of the inflammatory cytokines was analyzed by real-time PCR. Body weight loss in the mice was completely blocked by the administration of anti-C5 antibody. The disease activity index was significantly lower in the anti-C5 antibody-treated mice than the dextran sulfate sodium mice. The colonic weight/length ratio, histological colitis score and mucosal myeloperoxidase activity were significantly lower in the anti-C5 antibody-treated mice than the dextran sodium sulfate mice. The administration of the anti-C5 antibody significantly reduced the mucosal expression of mRNAs for tumor necrosis factor-α, interleukin-1β and interleukin-6. In conclusion, the complement system plays a role in the development of dextran sodium sulfate-induced experimental colitis.

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Characterization of complement C3, C4, and factor B molecules in human bile

Cited by 10 publications

References 20 publications

Heterogeneous response of antimitochondrial autoantibodies and bile duct apical staining monoclonal antibodies to pyruvate dehydrogenase complex E2: The molecule versus the mimic

Heterogeneous response of antimitochondrial autoantibodies and bile duct apical staining monoclonal antibodies to pyruvate dehydrogenase complex E2: The molecule versus the mimic

Intestinal Trefoil Factor Induces Decay-Accelerating Factor Expression and Enhances the Protective Activities Against Complement Activation in Intestinal Epithelial Cells

Neutralization of complement component C5 ameliorates the development of dextran sulfate sodium (DSS)-colitis in mice

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