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p-ANCA in Autoimmune Liver Disorders Recognize Human Beta-Tubulin Isotype 5 and Cross-react with Microbial Protein FtsZ
  1. Birgit Terjung1,*,
  2. Jennifer Soehne1,
  3. Berthold Lechtenberg1,
  4. Judith Gottwein1,
  5. Marit Muennich1,
  6. Volker Herzog2,
  7. Michael Maehler3,
  8. Tilman Sauerbruch1,
  9. Ulrich Spengler1
  1. 1 Department of Internal Medicine, University of Bonn, Germany;
  2. 2 Institute of Cell Biology, University of Bonn, Germany;
  3. 3 Biomedical Diagnostics, Hannover, Germany
  1. Correspondence to: Birgit Terjung, Department of Internal Medicine, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, 53105, Germany; birgit.terjung{at}ukb.uni-bonn.de

Abstract

Objective: Autoimmune hepatitis and primary sclerosing cholangitis are chronic inflammatory disorders of unknown aetiology, frequently associated with the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) directed against an unknown antigen of myeloid cells.

Methods & Results: Here, we report that p-ANCA in autoimmune liver disorders react with beta-tubulin isotype 5 (TBB-5) as autoantigen as well as with its evolutionary bacterial precursor protein FtsZ. Both proteins were confirmed as antigens of p-ANCA in autoimmune liver disorders by demonstrating reactivity of ANCA-positive sera with recombinant TBB-5 (72-88%) and FtsZ (64-82%) on immunoblots and antigen-specific abrogation of ANCA immunofluorescence when sera had been pre-absorbed with tubulin and FtsZ. Using sera from interleukin-10 deficient mice (Il10-/-), an animal model of inflammatory bowel disease, we also demonstrated that antibodies against TBB-5 are generated in response to intestinal microorganisms. However, unlike autoimmune liver disorders, human antibodies to FtsZ in the absence of TBB-5 antibodies were also a frequent finding in non-autoimmune liver diseases (up to 95%). Reactivity to TBB-5 without presence of FtsZ antibodies was found in very few cases (< 1%) in autoimmune liver disorders.

Conclusions: Thus, p-ANCA in autoimmune liver diseases are directed against human TBB-5 cross-reacting with the bacterial protein FtsZ, probably reflecting an abnormal immune response to intestinal microorganisms in susceptible, possibly genetically pre-disposed individuals.

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