Early-onset autoimmunity associated with SOCS1 haploinsufficiency

被引：103

作者：

Hadjadj, Jerome ^{[1
,2
]}

Castro, Carla Noemi ^{[3
]}

Tusseau, Maud ^{[4
]}

Stolzenberg, Marie-Claude ^{[1
,2
]}

Mazerolles, Fabienne ^{[1
,2
]}

Aladjidi, Nathalie ^{[5
,6
]}

Armstrong, Martin ^{[7
]}

Ashrafian, Houman ^{[8
]}

Cutcutache, Ioana ^{[9
]}

Ebetsberger-Dachs, Georg ^{[10
,11
]}

Elliott, Katherine S. ^{[12
]}

Durieu, Isabelle ^{[13
,14
]}

Fabien, Nicole ^{[15
]}

Fusaro, Mathieu ^{[16
]}

Heeg, Maximilian ^{[3
]}

Schmitt, Yohan ^{[17
]}

Bras, Marc ^{[2
]}

Knight, Julian C. ^{[12
]}

Lega, Jean-Christophe ^{[18
,19
,20
]}

Lesca, Gaetan ^{[21
,22
]}

Mathieu, Anne-Laure ^{[4
]}

Moreews, Marion ^{[4
]}

Moreira, Baptiste ^{[23
]}

Nosbaum, Audrey ^{[4
,24
]}

Page, Matthew ^{[7
]}

Picard, Cecile ^{[25
]}

Leahy, T. Ronan ^{[26
]}

Rouvet, Isabelle ^{[27
]}

Ryan, Ethel ^{[28
]}

Sanlaville, Damien ^{[21
,22
]}

Schwarz, Klaus ^{[29
,30
]}

Skelton, Andrew ^{[9
]}

Viallard, Jean-Francois ^{[31
]}

Viel, Sebastien ^{[32
]}

Villard, Marine ^{[4
]}

Callebaut, Isabelle ^{[33
]}

Picard, Capucine ^{[16
,34
]}

Walzer, Thierry ^{[4
]}

Ehl, Stephan ^{[3
,35
]}

Fischer, Alain ^{[2
,36
,37
]}

Neven, Benedicte ^{[1
,2
,36
]}

Belot, Alexandre ^{[4
,19
,38
]}

Rieux-Laucat, Frederic ^{[1
,2
]}

机构：

[1] Univ Paris, Imagine Inst, Lab Immunogenet Pediat Autoimmune Dis, INSERM,UMR 1163, 24 Blvd Montparnasse, F-75015 Paris, France

[2] Univ Paris, IHU Imagine, 24 Blvd Montparnasse, F-75015 Paris, France

[3] Univ Freiburg, Inst Immunodeficiency, Ctr Chron Immunodeficiency, Fac Med,Med Ctr, Freiburg, Germany

[4] Univ Lyon, Univ Claude Bernard Lyon 1, Ecole Normale Super Lyon,CNRS, Ctr Int Rech Infectiol,INSER,CIRI,UMR5308,U111, Lyon, France

[5] INSERM, Ctr Reference Natl Cytopenies Autoimmunes Enfant, CICP, CIC 1401, Bordeaux, France

[6] Univ Hosp, Pediat Oncol Hematol Unit, INSERM, CICP,CIC 1401, Pl Amelie Raba Leon, Bordeaux, France

[7] UCB Pharma, Translat Med, Braine Lalleud, Belgium

[8] Univ Oxford, Radcliffe Dept Med, Expt Therapeut, Oxford, England

[9] UCB Pharma, Translat Med, Slough, Berks, England

[10] Johannes Kepler Univ Linz, Dept Pediat, Kepler Univ Hosp, Linz, Austria

[11] Johannes Kepler Univ Linz, Sch Med, Linz, Austria

[12] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England

[13] Hosp Civils Lyon, Grp Hosp Lyon Sud, Internal Med & Vasc Pathol Dept, Adult Cyst Fibrosis Ctr, Pierre Benite, France

[14] Univ Lyon, HESPER, EA 7425, Lyon, France

[15] Hosp Civils Lyon, Immunol Lab, Ctr Hosp Lyon Sud, Lyon, France

[16] Necker Hosp Sick Children, AP HP, Study Ctr Primary Immunodeficiencies, Paris, France

[17] INSERM, Imagine Inst, Genom Core Facil, UMR1163, Paris, France

[18] Hosp Civils Lyon, Ctr Hosp Lyon Sud, Dept Internal & Vasc Med, Lyon, France

[19] Natl Referee Ctr Pediat Onset Rheumatism & Autoim, Lyon, France

[20] Claude Bernard Univ Lyon 1, Equipe Evaluat & Modelisat Effets Therapeut, Lab Biometrie & Biol Evolut, CNRS,UMR 5558, Lyon, France

[21] Univ Claude Bernard Lyon 1, Univ Lyon, Hosp Civils Lyon GHE, Serv Genet, Lyon, France

[22] Univ Claude Bernard Lyon 1, Univ Lyon, Inst Neuromyogene, CNRS,INSERM,UMR 5310,U1217, Lyon, France

[23] Necker Childrens Hosp, AP HP, Immunol Lab, Paris, France

[24] Hosp Civils Lyon, Grp Hosp Lyon Sud, Allergy & Clin Immunol Dept, Pierre Benite, France

[25] UCBL Lyon 1 Univ, Grp Hosp Est, Hosp Civils Lyon, Inst Pathol Multisite, Lyon, France

[26] Childrens Hlth Ireland Crumlin, Dept Paediat Immunol & Infect Dis, Dublin, Ireland

[27] Hosp Civils Lyon, Grp Hosp Est, Ctr Biotechnol Cellulaire & Biotheque, F-69677 Bron, France

[28] Univ Hosp Galway, Dept Paediat, Galway, Ireland

[29] Univ Ulm, Inst Transfus Med, D-89081 Ulm, Germany

[30] German Red Cross Blood Serv Baden Wurttemberg Hes, Inst Clin Transfus Med & Immunogenet Ulm, D-89081 Ulm, Germany

[31] Univ Bordeaux, CHU Haut Leveque, Dept Med Interne & Malad Infect, Pessac, France

[32] Hosp Civils Lyon, Grp Hosp Lyon Sud, Serv Immunol Biol, Pierre Benite, France

[33] Sorbonne Univ, Inst Mineral Phys Mat & Cosmochim, CNRS, Museum Natl Hist Nat,Unite Mixte Rech 7590, Paris, France

[34] Univ Paris, Imagine Inst, Lab Lymphocyte Activat & Susceptibil EBV, INSERM,UMR 1163, 24 Blvd Montparnasse, F-75015 Paris, France

[35] Univ Freiburg, CIBSS Ctr Integrat Biol Signalling Studies, Freiburg, Germany

[36] Necker Enfants Malades Univ Hosp, AP HP, Paediat Immunohaematol & Rheumatol Dept, F-75015 Paris, France

[37] Coll France, Paris, France

[38] Mother & Children Univ Hosp, Dermatol Unit, Hosp Civils Lyon, Paediat Nephrol,Rheumatol, Bron, France

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

CYTOKINE SIGNALING-1; LYMPHOPROLIFERATIVE SYNDROME; GERMLINE MUTATIONS; STAT1; MUTATIONS; T-CELLS; SUPPRESSOR; EXPRESSION; LYMPHOMA; ACTIVATION; PREVENTS;

D O I：

10.1038/s41467-020-18925-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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