Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1 - 04/11/20
Abstract |
Background |
We studied 2 unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed multisystem inflammatory syndrome in children in the setting of a severe acute respiratory syndrome coronavirus 2 infection.
Objectives |
We sought to identify the mechanisms underlying the development of infection-driven autoimmune cytopenias.
Methods |
Whole-exome sequencing was performed on both patients, and the impact of the identified variants was validated by functional assays using the patients’ PBMCs.
Results |
Each patient was found to have a unique heterozygous truncation variant in suppressor of cytokine signaling 1 (SOCS1). SOCS1 is an essential negative regulator of type I and type II IFN signaling. The patients’ PBMCs showed increased levels of signal transducer and activator of transcription 1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II IFN-stimulated genes and proapoptotic genes. The enhanced IFN signature exhibited by the patients’ unstimulated PBMCs parallels the hyperinflammatory state associated with multisystem inflammatory syndrome in children, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of multisystem inflammatory syndrome in children.
Conclusions |
Heterozygous loss-of-function SOCS1 mutations are associated with enhanced IFN signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias.
Le texte complet de cet article est disponible en PDF.Key words : SOCS1, Evans syndrome, autoimmune hemolytic anemia, immune thrombocytopenia, COVID-19, MIS-C, SARS-CoV-2
Abbreviations used : AIHA, COVID-19, ES, ISG, ITP, JAK, KIR, MIS-C, SARS-CoV-2, SOCS, STAT
Plan
| This work was supported by the National Institutes of Health: National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant no. K08-AR074562 to P.Y.L.), Centers for Disease Control and Prevention (to A.G.R.), Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant no. R21HD095228 to A.G.R.), National Institute of Allergy and Infectious Diseases (grant no. 5K08AI116979 to J.C. and grant no. R01-AI139633 to R.S.G.), the Perkin Fund (to R.S.G.), and the Samara Jan Turkel Center for Autoimmune Diseases (to J.C.). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 146 - N° 5
P. 1194 - novembre 2020 Retour au numéro
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