Disseminated autoimmunity is associated with MIS-C pathogenesis 2925

Abstract Description MIS-C is a pediatric hyperinflammatory disease characterized by inflammatory shock involving multiple organ systems. MIS-C is linked with prior SARS-CoV-2 infection, approximately 4-6 weeks before symptom onset. Acute patients display distinct circulating immune cell profiles, marked by an increase in inflammatory cytokines and chemokines. Here, we used single-cell RNA- and TCR-sequencing paired with multiplexed cytokine profiling and mass cytometry to characterize the immune signatures of PBMCs and plasma in 8 acute MIS-C patients, 15 recovered MIS-C follow-ups over a range of time points (“early”: 1-3 months, “late”: 6-18 months), and 10 healthy pediatric controls. Levels of various proinflammatory cytokines and chemokines, including IL-6, IL-15, and IL-1β, were elevated in the plasma of early follow-ups; similarly, perforin, pSTAT-3, and pSTAT-4 protein expression was higher in PBMCs within this 3-month follow-up window. Multiome analysis of 151,420 PBMCs revealed an enrichment of inflammatory pathways in genes more highly expressed in early compared to late follow-ups, specifically in monocytes. Significant expansions of various paired TCR α/β-chains were also observed in acute patients, which persisted in early follow-ups. Together, our findings establish a prolonged inflammatory phenotype up to 3 months after MIS-C resolves, suggesting that the effects of SARS-CoV-2 infection-caused MIS-C may linger well after the virus is cleared despite fast clinical resolution. Funding Sources Supported by NIH/NICHD R01HD108467-01; Helen Hay Whitney Fndn. Fellowship. Topic Categories Computational and Systems Immunology (COMP)