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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

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: kboztug@cemm.oeaw.ac.at.

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

PMID:
24746753
DOI:
10.1016/j.jaci.2014.02.034
[Indexed for MEDLINE]

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