Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1
| Autor: | Craig D. Platt, Kasey Gauthier, Sally H. Vitali, Janet Chou, Rachael F. Grace, Raif S. Geha, Sridevi Devana, Sabrina Weeks, Douglas R. McDonald, George Maher, Adrienne G. Randolph, Pui Y. Lee |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Evans syndrome Haploinsufficiency medicine.disease_cause 0302 clinical medicine AIHA Autoimmune hemolytic anemia Immunology and Allergy SOCS1 COVID-19 Coronavirus disease 2019 Brief Report KIR Kinase inhibitory region Systemic Inflammatory Response Syndrome ITP Immune thrombocytopenia immune thrombocytopenia MIS-C Multisystem inflammatory syndrome in children 030220 oncology & carcinogenesis Child Preschool ES Evans syndrome Autoimmune hemolytic anemia JAK Janus kinase Coronavirus Infections Adolescent Immunology Pneumonia Viral SOCS Suppressor of cytokine signaling MIS-C stat 03 medical and health sciences Betacoronavirus Suppressor of Cytokine Signaling 1 Protein medicine Humans Pandemics autoimmune hemolytic anemia SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 business.industry Suppressor of cytokine signaling 1 SARS-CoV-2 STAT Signal transducer and activator of transcription COVID-19 Immune dysregulation medicine.disease Thrombocytopenia 030104 developmental biology Mutation STAT protein ISG IFN-stimulated gene Anemia Hemolytic Autoimmune business Janus kinase |
| Zdroj: | The Journal of Allergy and Clinical Immunology Journal of Allergy and Clinical Immunology |
| ISSN: | 1097-6825 0091-6749 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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