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

Zhang, Zinan; Gothe, Florian; Pennamen, Perrine; James, John R.; McDonald, David; Mata, Carlos P.; Modis, Yorgo; Alazami, Anas M.; Acres, Meghan; Haller, Wolfram; Bowen, Claire; Doffinger, Rainer; Sinclair, Jan; Brothers, Shannon; Zhang, Yu; Matthews, Helen F.; Naudion, Sophie; Pelluard, Fanny; Alajlan, Huda; Yamazaki, Yasuhiro; Notarangelo, Luigi D.; Thaventhiran, James E.; Engelhardt, Karin R.; Al-Mousa, Hamoud; Hambleton, Sophie; Rooryck, Caroline; Smith, Kenneth G. C. und Lenardo, Michael J. (2019): Human interleukin-2 receptor beta mutations associated with defects in immunity and peripheral tolerance. In: Journal of Experimental Medicine, Bd. 216, Nr. 6: S. 1311-1327

Abstract

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) beta 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-2R beta and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2R beta expression and function. IL-2R beta 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-2R beta 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0022-1007
• Sprache: Englisch