Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency

  • J Allergy Clin Immunol. 2014 Jun;133(6):1651-9.e12. doi: 10.1016/j.jaci.2014.02.034.
Elisabeth Salzer  1 ,  Aydan Kansu  2 ,  Heiko Sic  3 ,  Peter Májek  1 ,  Aydan Ikincioğullari  4 ,  Figen E Dogu  4 ,  Nina Kathrin Prengemann  1 ,  Elisangela Santos-Valente  1 ,  Winfried F Pickl  5 ,  Ivan Bilic  1 ,  Sol A Ban  1 ,  Zarife Kuloğlu  2 ,  Arzu Meltem Demir  2 ,  Arzu Ensari  6 ,  Jacques Colinge  1 ,  Marta Rizzi  3 ,  Hermann Eibel  3 ,  Kaan Boztug  7
Affiliations
  • 1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 2. Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey.
  • 3. Center for Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
  • 4. Department of Pediatric Immunology, Ankara University, Ankara, Turkey.
  • 5. Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
  • 6. Department of Pathology, Ankara University, Ankara, Turkey.
  • 7. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. Electronic address: [email protected].
PMID: 24746753 DOI: 10.1016/j.jaci.2014.02.034
Abstract

Background: Alterations of immune homeostasis in the gut can result in development of inflammatory bowel disease (IBD). Recently, Mendelian forms of IBD have been discovered, as exemplified by deficiency of IL-10 or its receptor subunits. In addition, Other types of primary immunodeficiency disorders might be associated with intestinal inflammation as one of their leading clinical presentations.

Objective: We investigated a large consanguineous family with 3 children who presented with early-onset IBD within the first year of life, leading to death in infancy in 2 of them.

Methods: Homozygosity mapping combined with exome Sequencing was performed to identify the molecular cause of the disorder. Functional experiments were performed to assess the effect of IL-21 on the immune system.

Results: A homozygous mutation in IL21 was discovered that showed perfect segregation with the disease. Deficiency of IL-21 resulted in reduced numbers of circulating CD19(+) B cells, including IgM(+) naive and class-switched IgG memory B cells, with a concomitant increase in transitional B-cell numbers. In vitro assays demonstrated that mutant IL-21(Leu49Pro) did not induce signal transducer and activator of transcription 3 phosphorylation and immunoglobulin class-switch recombination.

Conclusion: Our study uncovers IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development similar to those found in patients with common variable immunodeficiency. IBD might mask an underlying primary immunodeficiency, as illustrated here with IL-21 deficiency.

Keywords
IL-21; common variable immunodeficiency; early-onset inflammatory bowel disease; exome sequencing.