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

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• 作者：Elisabeth Salzer ; MD^a ; Aydan Kansu ; MD^b ; Heiko Sic ; PhD^c ; Peter Má ; jek ; PhD^a ; Aydan Ikincio臒ullari ; MD^d ; Figen E. Dogu ; MD^d ; Nina Kathrin Prengemann ; MSc^a ; Elisangela Santos-Valente ; MD ; MSc^a ; Winfried F. Pickl ; PhD^e ; Ivan Bilic ; PhD^a ; Sol A Ban^a ; Zarife Kulo臒lu ; MD^b ; Arzu Meltem Demir ; MD^b ; Arzu Ensari ; MD^f ; Jacques Colinge ; PhD^a ; Marta Rizzi ; PhD^c ; Hermann Eibel ; PhD^c ; Kaan Boztug ; MD^a ; ^g ; ^{kboztug@cemm.oeaw.ac.at" class="auth_mail}
• 关键词：IL-21 ; early-onset inflammatory bowel disease ; common variable immunodeficiency ; exome sequencing
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：June 2014
• 年：2014
• 卷：133
• 期：6
• 页码：1651-1659.e12
• 全文大小：2652 K

文摘

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.