Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-18925-4
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Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Agence National de la Recherche as part of the Investment for the Future program [ANR-10-IAHU-01, ANR-18-RHUS-0010]
- Ligue Contre le Cancer-Comite de Paris
- Fondation ARC pour la recherche sur le CANCER
- Centre de Reference Deficits Immunitaires Hereditaires (CEREDIH)
- Agence National de la Recherche [ANR-14-CE14-0026-01, ANR18-CE17-0001]
- German Reseach Foundation (DFG) under German's Excellence strategy [CIBBS-EXC-2189, 390939984]
- German Ministry for Education and Research (BMBF grant) [GAIN FSE2018-041]
- UCB Pharma
- INSERM poste d'acceuil program
- Institut Imagine MD-PhD fellowship program - Fondation Bettencourt Schueller
- Berta-Ottenstein clinician scientist program of the Faculty of Medicine, University of Freiburg
- Agence Nationale de la Recherche (ANR) [ANR-14-CE14-0026, ANR-18-RHUS-0010] Funding Source: Agence Nationale de la Recherche (ANR)
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Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-gamma, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells. SOCS1 is a potent suppressor of JAK-STAT signalling responses to IFN gamma and gamma-chain cytokines and thereby limits inflammation. Here the authors identify and characterize heterozygous SOCS1 mutations in 10 patients from 5 unrelated families with autoimmune diseases.
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