Immune dysregulation and Multisystem Inflammatory Syndrome in Children (MIS-C) in individuals with haploinsufficiency of SOCS1

Lee, Pui Y.; Platt, Craig D.; Weeks, Sabrina; Grace, Rachael F.; Maher, George; Gauthier, Kasey; Devana, Sridevi; Vitali, Sally; Randolph, Adrienne G.; McDonald, Douglas R.; Geha, Raif S.; Chou, Janet

Abstract Objectives To identify the mechanisms underlying the development of infection-driven autoimmune cytopenias. Background We studied two unrelated patients with immune thrombocytopenia and autoimmune hemolytic anemia in the setting of acute infections. One patient developed Multisystem Inflammatory Syndrome in Children (MIS-C) in the setting of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods Whole exome sequencing was performed on both patients and the impact of the identified variants were validated by functional assays using the patients’ peripheral blood mononuclear cells (PBMCs). Results Each patient was found to have a unique heterozygous truncation variant in SOCS1. Suppressor of Cytokine Signaling 1 (SOCS1) is an essential negative regulator of type I and type II interferon (IFN) signaling. The patients’ PBMCs showed increased levels of STAT1 phosphorylation and a transcriptional signature characterized by increased expression of type I and type II interferon stimulated genes and pro-apoptotic genes. The enhanced IFN signature exhibited by the patients’ unstimulated PBMCs parallels the hyperinflammatory state associated with MIS-C, suggesting the contributions of SOCS1 in regulating the inflammatory response characteristic of MIS-C. Discussion Heterozygous loss-of-function SOCS1 mutations are associated with enhanced interferon signaling and increased immune cell activation, thereby predisposing to infection-associated autoimmune cytopenias.