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. Epub 2014 Apr 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Amino Acid Sequence
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • Child
  • Child, Preschool
  • Common Variable Immunodeficiency / genetics*
  • Common Variable Immunodeficiency / immunology
  • Common Variable Immunodeficiency / metabolism
  • Consanguinity
  • DNA Mutational Analysis
  • Female
  • Humans
  • Immunoglobulin Class Switching
  • Immunoglobulin Isotypes / blood
  • Immunoglobulin Isotypes / immunology
  • Immunophenotyping
  • Infant
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / metabolism
  • Interleukins / chemistry
  • Interleukins / deficiency*
  • Interleukins / genetics*
  • Lymphocyte Activation
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Protein Conformation
  • Receptors, Interleukin-21 / metabolism
  • Sequence Alignment
  • Signal Transduction


  • Immunoglobulin Isotypes
  • Interleukins
  • Receptors, Interleukin-21
  • interleukin-21