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J Allergy Clin Immunol. 2014 Jun;133(6):1651-9.e12. doi: 10.1016/j.jaci.2014.02.034. Epub 2014 Apr 17.

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

Author information

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey.
Center for Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
Department of Pediatric Immunology, Ankara University, Ankara, Turkey.
Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Department of Pathology, Ankara University, Ankara, Turkey.
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:



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.


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.


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.


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.


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.


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

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