Early-onset inflammatory bowel disease and common variable immunodeficiency–like disease caused by IL-21 deficiency
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 a...
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| Published in | Journal of allergy and clinical immunology Vol. 133; no. 6; pp. 1651 - 1659.e12 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York, NY
Elsevier Inc
01.06.2014
Elsevier Elsevier Limited |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0091-6749 1097-6825 1097-6825 |
| DOI | 10.1016/j.jaci.2014.02.034 |
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| Abstract | 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. |
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| AbstractList | 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. 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.BACKGROUNDAlterations 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.OBJECTIVEWe 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.METHODSHomozygosity 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-21(Leu49Pro) did not induce signal transducer and activator of transcription 3 phosphorylation and immunoglobulin class-switch recombination.RESULTSA 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.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.CONCLUSIONOur 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. 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. 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 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. assays demonstrated that mutant IL-21Leu49Pro 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. 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-21Leu49Pro 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. 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 inIL21was 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 vitroassays demonstrated that mutant IL-21Leu49Prodid 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. 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-21(Leu49Pro) 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. |
| Author | Rizzi, Marta Dogu, Figen E. Demir, Arzu Meltem Májek, Peter Sic, Heiko Eibel, Hermann Kansu, Aydan Salzer, Elisabeth Boztug, Kaan Colinge, Jacques Ensari, Arzu Ikincioğullari, Aydan Kuloğlu, Zarife Pickl, Winfried F. Prengemann, Nina Kathrin Bilic, Ivan Santos-Valente, Elisangela Ban, Sol A |
| Author_xml | – sequence: 1 givenname: Elisabeth surname: Salzer fullname: Salzer, Elisabeth organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – sequence: 2 givenname: Aydan surname: Kansu fullname: Kansu, Aydan organization: Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey – sequence: 3 givenname: Heiko surname: Sic fullname: Sic, Heiko organization: Center for Chronic Immunodeficiency, University Medical Center, Freiburg, Germany – sequence: 4 givenname: Peter surname: Májek fullname: Májek, Peter organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – sequence: 5 givenname: Aydan surname: Ikincioğullari fullname: Ikincioğullari, Aydan organization: Department of Pediatric Immunology, Ankara University, Ankara, Turkey – sequence: 6 givenname: Figen E. surname: Dogu fullname: Dogu, Figen E. organization: Department of Pediatric Immunology, Ankara University, Ankara, Turkey – sequence: 7 givenname: Nina Kathrin surname: Prengemann fullname: Prengemann, Nina Kathrin organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – sequence: 8 givenname: Elisangela surname: Santos-Valente fullname: Santos-Valente, Elisangela organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – sequence: 9 givenname: Winfried F. surname: Pickl fullname: Pickl, Winfried F. organization: Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria – sequence: 10 givenname: Ivan surname: Bilic fullname: Bilic, Ivan organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – sequence: 11 givenname: Sol A surname: Ban fullname: Ban, Sol A organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – sequence: 12 givenname: Zarife surname: Kuloğlu fullname: Kuloğlu, Zarife organization: Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey – sequence: 13 givenname: Arzu Meltem surname: Demir fullname: Demir, Arzu Meltem organization: Department of Pediatric Gastroenterology, Ankara University, Ankara, Turkey – sequence: 14 givenname: Arzu surname: Ensari fullname: Ensari, Arzu organization: Department of Pathology, Ankara University, Ankara, Turkey – sequence: 15 givenname: Jacques surname: Colinge fullname: Colinge, Jacques organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria – sequence: 16 givenname: Marta surname: Rizzi fullname: Rizzi, Marta organization: Center for Chronic Immunodeficiency, University Medical Center, Freiburg, Germany – sequence: 17 givenname: Hermann surname: Eibel fullname: Eibel, Hermann organization: Center for Chronic Immunodeficiency, University Medical Center, Freiburg, Germany – sequence: 18 givenname: Kaan surname: Boztug fullname: Boztug, Kaan email: kboztug@cemm.oeaw.ac.at organization: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria |
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| ContentType | Journal Article |
| Copyright | 2014 American Academy of Allergy, Asthma & Immunology American Academy of Allergy, Asthma & Immunology 2015 INIST-CNRS Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. Copyright Elsevier Limited Jun 2014 Distributed under a Creative Commons Attribution 4.0 International License |
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| Issue | 6 |
| Keywords | 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 Immunoglobulin Class Switching Child Amino Acid Sequence Signal Transduction Lymphocyte Activation B-Lymphocyte Subsets/immunology/metabolism Preschool Common Variable Immunodeficiency/genetics/immunology/metabolism Immunophenotyping Interleukin-21/metabolism Sequence Alignment Pedigree Age of Onset Protein Conformation Models Consanguinity Mutation Interleukins/chemistry/deficiency/genetics |
| Language | English |
| License | https://www.elsevier.com/tdm/userlicense/1.0 CC BY 4.0 Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. Distributed under a Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0 |
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| Snippet | Alterations of immune homeostasis in the gut can result in development of inflammatory bowel disease (IBD). Recently, Mendelian forms of IBD have been... Background Alterations of immune homeostasis in the gut can result in development of inflammatory bowel disease (IBD). Recently, Mendelian forms of IBD have... BACKGROUND: Alterations of immune homeostasis in the gut can result in development of inflammatory bowel disease (IBD). Recently, Mendelian forms of IBD have... |
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| SubjectTerms | 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 |
| Title | Early-onset inflammatory bowel disease and common variable immunodeficiency–like disease caused by IL-21 deficiency |
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