Cooperative molecular mimicry drives prolonged autoinflammation in multisystem inflammatory syndrome in children 2308508

Abstract Introduction Multisystem inflammatory syndrome in children (MIS-C) is a pediatric hyperinflammatory disease manifesting 4-6 weeks after SARS-CoV-2 infection. While the immunological hallmarks of MIS-C have been defined, few details regarding the underlying disease pathology have been resolved. Methods To address this, we used a multiomics approach to profile the plasma and peripheral immune cells of 13 acute MIS-C patients, 18 recovered MIS-C follow-ups resampled over multiple time points (1-18 months), and 15 healthy pediatric controls. Results Despite rapid clinical disease resolution, circulating pro-inflammatory (IL-8, IL-6, IL-1α, IL-1β, TNF-β) and TH2-type cytokines (IL-4, IL-5, IL-13) remained elevated up to three months post-MIS-C onset, revealing a subclinical inflammatory state that endures in recovered children. Surprisingly, the majority of patient-expanded TCRs recognizing SARS-CoV-2 epitopes (84.2%, 16/19 expanded TCRs) were cross-reactive for autoantigen epitopes targeting prostaglandin biology (PTGS2, SLCO2A1) and insulin metabolism (SLC30A8), suggesting the breakdown of self-tolerance via SARS-CoV-2 molecular mimicry. Indeed, autoantibody screening confirmed that 13 candidates exhibited elevated autoantibodies in MIS-C patients. Further, autoreactive TCR expansions lasted over time and correlated with cytokines involved in allergic inflammation. Conclusion Together, our findings point to a mechanism of sustained autoimmunity wherein promiscuous TCRs recognize both viral and self-antigens that are activated during primary SARS-CoV-2 infection in children who will develop MIS-C. Upon onset, these circulating cross-reactive T cells drive clinically apparent sterile autoinflammation that persists subclinically into convalescence. Funding Source Helen Hay Whitney Postdoctoral Research Fellowship Topic Categories Immune Mechanisms of Human Disease (HUM)