title: Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Salzer
authors.affiliation: Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: Kansu
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Sic
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Májek
authors.affiliation: Department of Pediatric Immunology, Ankara University, Ankara, Turkey.
authors.forename: Aydan
authors.initials: A
authors.lastname: Ikincioğullari
authors.affiliation: Department of Pediatric Immunology, Ankara University, Ankara, Turkey.
authors.forename: Figen E
authors.initials: FE
authors.lastname: Dogu
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Nina Kathrin
authors.initials: NK
authors.lastname: Prengemann
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Elisangela
authors.initials: E
authors.lastname: Santos-Valente
authors.affiliation: Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bilic
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Sol A
authors.initials: SA
authors.lastname: Ban
authors.affiliation: Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey.
authors.forename: Zarife
authors.initials: Z
authors.lastname: Kuloğlu
authors.affiliation: Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey.
authors.forename: Arzu Meltem
authors.initials: AM
authors.lastname: Demir
authors.affiliation: Department of Pathology, Ankara University, Ankara, Turkey.
authors.forename: Arzu
authors.initials: A
authors.lastname: Ensari
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center, Freiburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.affiliation: 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.
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000276:immunology; D016130:Immunophenotyping; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D008213:Lymphocyte Activation; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D053655:Receptors, Interleukin-21 / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D000098546:Interleukin-21
chemical_list: D007132:Immunoglobulin Isotypes; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21
keywords: IL-21; common variable immunodeficiency; early-onset inflammatory bowel disease; exome sequencing