NDLI: Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Yu, Xiaomin Almeida, Jorge R. Darko, Sam Van Der Burg, Mirjam DeRavin, Suk See Malech, Harry Gennery, Andrew Chinn, Ivan Markert, Mary Louise Douek, Daniel C. Milner, Joshua D.
Description	Country affiliation: Moldova Author Affiliation: Yu X ( Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Almeida JR ( Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Darko S ( Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); van der Burg M ( Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.); DeRavin SS ( Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Malech H ( Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Gennery A ( Department of Paediatric Immunology, Newcastle University, Newcastle upon Tyne, United Kingdom); Chinn I ( Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC.); Markert ML ( Department of Pediatrics, Division of Allergy and Immunology, Duke University Medical Center, Durham, NC); Douek DC ( Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: ddouek@mail.nih.gov.); Milner JD ( Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: jdmilner@niaid.nih.gov.)
Abstract	BACKGROUND: Human immunodeficiencies characterized by hypomorphic mutations in critical developmental and signaling pathway genes allow for the dissection of the role of these genes in the development of the T-cell receptor (TCR) repertoire and the correlation of alterations of the TCR repertoire with diverse clinical phenotypes. OBJECTIVE: The presence of T cells in patients with Omenn syndrome (OS) and patients with atypical presentations of severe combined immunodeficiency gene mutations presents an opportunity to study the effects of the causal genes on TCR repertoires and provides a window into the clinical heterogeneity observed. METHODS: We performed deep sequencing of TCRß complementarity-determining region 3 (CDR3) regions in subjects with a series of immune dysregulatory conditions caused by mutations in recombination activating gene 1/2 (RAG 1/2), IL-2 receptor Î³ (IL2RG), and Î¶ chain-associated protein kinase 70 (ZAP70); a patient with atypical DiGeorge syndrome; and healthy control subjects. RESULTS: We found that patients with OS had marked reductions in TCRß diversity compared with control subjects, as expected. Patients with atypical presentations of RAG or IL2RG mutations associated with autoimmunity and granulomatous disease did not have altered overall diversity but instead had skewed V-J pairing and skewed CDR3 amino acid use. Although germline TCRs were more abundant and clonally expanded in patients with OS, nongermline sequences were expanded as well. TCRß from patients with RAG mutations had less junctional diversity and smaller CDR3s than patients with OS caused by other gene mutations and healthy control subjects but relatively similar CDR3 amino acid use. CONCLUSIONS: High-throughput TCR sequencing of rare immune disorders has demonstrated that quantitative TCR diversity can appear normal despite qualitative changes in repertoire and strongly suggests that in human subjects RAG enzymatic function might be necessary for normal CDR3 junctional diversity.
File Format	HTM / HTML
ISSN	00916749
e-ISSN	10976825
DOI	10.1016/j.jaci.2013.11.018
Journal	Journal of Allergy and Clinical Immunology
Issue Number	4
Volume Number	133
Language	English
Publisher	Elsevier
Publisher Date	2014-04-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Immunology Immunologic Deficiency Syndromes Genetics Receptors, Antigen, T-cell Amino Acid Substitution Case-control Studies Child, Preschool Complementarity Determining Regions Dna-binding Proteins Homeodomain Proteins Immunology Infant Interleukin Receptor Common Gamma Subunit Mutation Nuclear Proteins Receptors, Antigen, T-cell, Alpha-beta Sequence Analysis, Dna Severe Combined Immunodeficiency T-lymphocyte Subsets Metabolism Zap-70 Protein-tyrosine Kinase Research Support, N.i.h., Intramural
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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