Human interleukin-2 receptor β mutations associated with defects in immunity and peripheral tolerance.

Autor:	Zhang Z; Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK.; Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.; Harvard Medical School, Boston, MA., Gothe F; Institute of Cellular Medicine, Newcastle University, Newcastle, UK.; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany., Pennamen P; University of Bordeaux, Maladies Rares: Génétique et Métabolisme Institut National de la Santé et de la Recherche Médicale U1211, Centre Hospitalier Universitaire de Bordeaux, Service de Génétique Médicale, Bordeaux, France., James JR; Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK., McDonald D; Institute of Cellular Medicine, Newcastle University, Newcastle, UK., Mata CP; Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK.; Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK., Modis Y; Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK.; Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK., Alazami AM; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Acres M; Institute of Cellular Medicine, Newcastle University, Newcastle, UK., Haller W; Birmingham Children's Hospital, Birmingham, UK., Bowen C; Birmingham Children's Hospital, Birmingham, UK., Döffinger R; Department of Clinical Biochemistry and Immunology, Cambridge University Hospital, Cambridge, UK., Sinclair J; Starship Children's Hospital, Auckland, New Zealand., Brothers S; Starship Children's Hospital, Auckland, New Zealand., Zhang Y; Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Matthews HF; Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Naudion S; University of Bordeaux, Maladies Rares: Génétique et Métabolisme Institut National de la Santé et de la Recherche Médicale U1211, Centre Hospitalier Universitaire de Bordeaux, Service de Génétique Médicale, Bordeaux, France., Pelluard F; Department of Pathology, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France., Alajlan H; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Yamazaki Y; Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Notarangelo LD; Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD., Thaventhiran JE; Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK., Engelhardt KR; Institute of Cellular Medicine, Newcastle University, Newcastle, UK., Al-Mousa H; Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Hambleton S; Institute of Cellular Medicine, Newcastle University, Newcastle, UK sophie.hambleton@newcastle.ac.uk.; Great North Children's Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle, UK., Rooryck C; University of Bordeaux, Maladies Rares: Génétique et Métabolisme Institut National de la Santé et de la Recherche Médicale U1211, Centre Hospitalier Universitaire de Bordeaux, Service de Génétique Médicale, Bordeaux, France., Smith KGC; Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK kgcs2@cam.ac.uk., Lenardo MJ; Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD MLENARDO@niaid.nih.gov.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2019 Jun 03; Vol. 216 (6), pp. 1311-1327. Date of Electronic Publication: 2019 Apr 30.
DOI:	10.1084/jem.20182304
Abstrakt:	Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain ( IL2RB ) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer. (This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.)
Databáze:	MEDLINE
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