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Original article
Early-onset Crohn’s disease and autoimmunity associated with a variant in CTLA-4
  1. Sebastian Zeissig1,2,
  2. Britt-Sabina Petersen3,
  3. Michal Tomczak2,
  4. Espen Melum2,4,5,
  5. Emilie Huc-Claustre1,
  6. Stephanie K Dougan2,
  7. Jon K Laerdahl6,7,
  8. Björn Stade3,
  9. Michael Forster3,
  10. Stefan Schreiber1,3,
  11. Dascha Weir8,
  12. Alan M Leichtner8,
  13. Andre Franke3,
  14. Richard S Blumberg2
  1. 1Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Kiel, Germany
  2. 2Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  4. 4Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  5. 5K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  6. 6Department of Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  7. 7Bioinformatics Core Facility, Department of Informatics, University of Oslo, Oslo, Norway
  8. 8Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA
  1. Correspondence to Professor Richard S Blumberg, Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA; rblumberg{at}partners.org Andre Franke, Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12 24105 Kiel, Germany; a.franke{at}mucosa.de Sebastian Zeissig, Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Schittenhelmstr. 12 24105 Kiel, Germany; szeissig{at}1med.uni-kiel.de

Abstract

Objective IBD is a group of complex, systemic disorders associated with intestinal inflammation and extraintestinal manifestations. Recent studies revealed Mendelian forms of IBD, which contributed significantly to our understanding of disease pathogenesis and the heritability of IBD.

Design We performed exome sequencing in a family with Crohn’s disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed in silico and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function.

Results A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in vitro and associated with an increased ratio of memory to naive T cells in vivo, consistent with impaired regulation of T cell activation.

Conclusions Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.

  • CROHN'S DISEASE
  • GENE MUTATION
  • IMMUNOLOGY
  • IMMUNOREGULATION

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