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Original Article
Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease
  1. Lowiek M Hubers1,
  2. Harmjan Vos2,
  3. Alex R Schuurman1,
  4. Robin Erken1,
  5. Ronald P Oude Elferink1,
  6. Boudewijn Burgering2,
  7. Stan F J van de Graaf1,
  8. Ulrich Beuers1
  1. 1Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research,Academic Medical Center, Amsterdam, The Netherlands
  2. 2Center for Molecular Medicine, Molecular Cancer Research Section, University Medical Center, Utrecht, The Netherlands
  1. Correspondence to Dr Ulrich Beuers, Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Phone: +31 (20) 566 2422 ; u.h.beuers{at}amc.uva.nl

Abstract

Objective Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis, IAC) and pancreas (autoimmune pancreatitis, AIP). We recently identified highly expanded IgG4+ B-cell receptor clones in blood and affected tissues of patients with IAC/AIP suggestive of specific (auto)antigenic stimuli involved in initiating and/or maintaining the inflammatory response. This study aimed to identify (auto)antigen(s) that are responsible for the clonal expansion of IgG4+ B cells in IgG4-RD.

Design We screened sera of patients with IAC/AIP (n=50), in comparison to control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies (n=47), for reactivity against human H69 cholangiocyte lysates on immunoblot. Subsequently, target antigens were immunoprecipitated and analysed by mass spectrometry.

Results Prominent reactivity against a 56 kDa protein was detected in human H69 cholangiocyte lysates exposed to sera of nine patients with IAC/AIP. Affinity purification and mass spectrometry analysis identified annexin A11, a calcium-dependent phospholipid-binding protein. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD of the biliary tract/pancreas/salivary glands and not in disease mimickers with PSC and pancreatobiliary malignancies. Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes.

Conclusion Our data suggest that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.

  • autoimmune biliary disease
  • auto-antibodies
  • pancreatitis
  • antigens
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Footnotes

  • Contributors LH: designing research studies, conducting experiments, analysing data, writing the manuscript. HV: designing research studies, conducting experiments, analysing data, providing reagents, writing the manuscript. AS: conducting experiments, analysing data, writing the manuscript. RE: conducting experiments, analysing data, writing the manuscript. RO: designing research studies, analysing data, providing reagents, writing the manuscript. BB: designing research studies, analysing data, providing reagents, writing the manuscript. SG: designing research studies, analysing data, providing reagents, writing the manuscript. UB: designing research studies, analysing data, providing reagents, writing the manuscript.

  • Competing interests None declared.

  • Ethics approval Medical ethical committee of Academic Medical Center in Amsterdam (MEC 10/007)

  • Provenance and peer review Not commissioned; externally peer reviewed.

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