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

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 6; pp. 1651 - 1659.e12
• Main Authors: Salzer, Elisabeth, Kansu, Aydan, Sic, Heiko, Májek, Peter, Ikincioğullari, Aydan, Dogu, Figen E., Prengemann, Nina Kathrin, Santos-Valente, Elisangela, Pickl, Winfried F., Bilic, Ivan, Ban, Sol A, Kuloğlu, Zarife, Demir, Arzu Meltem, Ensari, Arzu, Colinge, Jacques, Rizzi, Marta, Eibel, Hermann, Boztug, Kaan
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2014; Elsevier; Elsevier Limited
• Subjects: Age of Onset; Allergy and Immunology; Amino Acid Sequence; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; Biological and medical sciences; Cancer; Cell growth; Child; Child, Preschool; Cloning; common variable immunodeficiency; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Common Variable Immunodeficiency - metabolism; Consanguinity; DNA Mutational Analysis; early-onset inflammatory bowel disease; exome sequencing; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gastroenterology. Liver. Pancreas. Abdomen; Homeostasis; Humans; IL-21; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulin Class Switching; Immunoglobulin Isotypes - blood; Immunoglobulin Isotypes - immunology; Immunopathology; Immunophenotyping; Infant; Inflammatory bowel disease; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - metabolism; Interleukin-21; Interleukins - chemistry; Interleukins - deficiency; Interleukins - genetics; Life Sciences; Lymphocyte Activation; Male; Medical sciences; Methods; Models, Molecular; Molecular Sequence Data; Mutation; Other diseases. Semiology; Patients; Pedigree; Protein Conformation; Proteins; Receptors, Interleukin-21 - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Sequence Alignment; Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Austria; CD40L; TCR; IBD; common variable immunodeficiency; early-onset inflammatory bowel disease; IL-21; CVID; DMEM; exome sequencing; STAT; APC; SNP; PE; MD; SNV; IL-21R; NK; WT; Signal transducer and activator of transcription; Molecular dynamics; T-cell receptor; Dulbecco modified Eagle medium; Allophycocyanin; Single nucleotide variant; IL-21 receptor; Wild-type; Inflammatory bowel disease; Natural killer; CD40 ligand; Phycoerythrin; Single nucleotide polymorphism; Immunopathology; Common variable immunodeficiency; Deficiency; Inflammatory disease; Crohn disease; Immunology; Immunoglobulinopathy; Age of onset; Interleukin 21; Exome sequencing; Digestive diseases; Intestinal disease; Early; Ulcerative colitis; Inflammatory Bowel Diseases/genetics/immunology/metabolism; Humans; Molecular Sequence Data; Male; Infant; Molecular; Receptors; Immunoglobulin Isotypes/blood/immunology; DNA Mutational Analysis; Female; Child; Immunoglobulin Class Switching; Amino Acid Sequence; Signal Transduction; Lymphocyte Activation; Preschool; B-Lymphocyte Subsets/immunology/metabolism; Immunophenotyping; Common Variable Immunodeficiency/genetics/immunology/metabolism; Interleukin-21/metabolism; Sequence Alignment; Pedigree; Age of Onset; Protein Conformation; Models; Consanguinity; Mutation; Interleukins/chemistry/deficiency/genetics
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.02.034

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-21Leu49Pro 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.