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Mannan-binding lectin deficiency results in unusual antibody production and excessive experimental colitis in response to mannose-expressing mild gut pathogens
  1. Stefan Müller1,
  2. Thomas Schaffer1,
  3. Beatrice Flogerzi1,
  4. Beatrice Seibold-Schmid1,
  5. Jasmin Schnider1,
  6. Kazue Takahashi2,
  7. Arlette Darfeuille-Michaud3,
  8. Emilie Vazeille3,
  9. Alain M Schoepfer1,4,
  10. Frank Seibold1,5
  1. 1Department of Clinical Research, Division of Gastroenterology, University of Bern, Bern, Switzerland
  2. 2Programs of Developmental Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Pathogénie Bactérienne Intestinale, Centre Biomédical de Recherche et Valorisation, Université d'Auvergne, Clermont-Ferrand, France
  4. 4Farncombe Family Institute of Digestive Health Research, McMaster University, Hamilton, Ontario, Canada
  5. 5Department of Visceral Surgery and Medicine, Division of Gastroenterology, University Hospital Bern, Bern, Switzerland
  1. Correspondence to Stefan Müller, Department of Clinical Research, University of Bern, Murtenstrasse 35, CH-3010 Bern, Switzerland; stefan.mueller{at}dkf.unibe.ch

Abstract

Background In Crohn's disease (CD) the deficiency of mannan-binding lectin (MBL) is associated with an increased prevalence of anti-Saccharomyces cerevisiae antibodies (ASCA) and with complicated phenotypes of the disease. However, the role of MBL in intestinal inflammation is currently unclear. A study was undertaken to analyse local MBL expression in human intestine and the consequences of MBL deficiency in experimental colitis and yeast infection.

Methods ASCA were measured by ELISA. MBL was assessed by ELISA and quantitative PCR. Wild type and MBL-deficient mice were administered dextran sulfate sodium (DSS) in the presence or absence of viable Candida albicans or adhesive invasive Escherichia coli (AIEC). Mice were infected with C albicans to assess generation of anti-yeast mannan antibodies.

Results MBL expression was virtually undetectable in the intestinal mucosa of both healthy controls and patients with CD, irrespective of macroscopic inflammation, indicating that systemic MBL must be responsible for the reduced risk of complicated disease in MBL-competent patients with CD. MBL-deficient mice showed enhanced DSS colitis upon oral challenge with C albicans or AIEC. C albicans could be recovered from the kidneys of colitic/C albicans-fed MBL-deficient, but not wild type mice. Infection with C albicans induced high titres of anti-C albicans mannan IgM and IgG in MBL-deficient mice but only a modest and transient IgM response with no class switch to IgG in wild type mice. Cross-reactive ASCA IgM continuously increased in MBL-deficient mice but rapidly declined after transient induction in wild type mice. In MBL-deficient mice, increased C albicans dissemination correlated with reduced early retention in the circulation.

Conclusions These results suggest that systemic MBL helps to prevent excessive inflammation upon access of normally mild pathogens across the damaged intestinal epithelium. Lack of this innate defence promotes antibody responses with cross-reactive potential against common mannan epitopes. These interpretations are compatible with the increased prevalence of ASCA and complicated disease phenotypes in MBL-deficient patients with CD.

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Footnotes

  • Funding This work was supported by the Swiss National Science Foundation grant number SNSF 3200B0-107527/1 to FS.

  • Competing interests None.

  • Ethics approval Informed consent was obtained from all patients and all procedures were approved by the ethical committee of the local authorities of the Canton of Bern.

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

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