Immune Cells and Secretory Pathways Leading to Human Systemic Autoimmunity

Abstract: As the COVID-19 pandemic was considered to have a limited impact in children, a severe multi-inflammatorysyndrome that specifically affects children (MIS-C) has recently emerged. MIS-C phenotypes include acombination of typical/atypical Kawasaki disease (KD) and toxic shock syndrome. Unlike adults with COVID-19,however, most children display gastrointestinal symptoms but fail to present significant respiratory involvement.A subset of patients develops coronary artery aneurysms, as seen in KD. Importantly, while a large body ofstudies on adult responses to SARS-CoV-2 is being reported, knowledge gaps about the immune responses toSARS-CoV-2 in children remain disproportionally large. We hypothesize that a comprehensive systems analysis approach that incorporates high-resolutionimmunologic assays is required to efficiently identify the most relevant immune factors that contributeto the pathogenesis of COVID-19 related-MIS-C and to determine its subsequent outcomes. For thesereasons, we have assembled an experienced multidisciplinary team to study COVID-19 related MIS-C. We willleverage expertise in pediatric clinical research together with application of high-resolution multi-omics andanalytical tools to characterize the immune system dysregulation underlying MIS-C. Towards this end, we willexamine longitudinal samples and will compare the results with those of matched healthy controls with andwithout previous exposure to SARS-CoV-2. This study offers a unique opportunity to carefully dissect thecontributions of the different components of the immune system to the most severe form of SARS-CoV-2 responses in children. Our specific Aims are 1) to define the clinical variables and risk factors associated with MIS-C andestablish a longitudinal sample biorepository, 2) to identify innate immunity parameters associated withSARS-CoV-2 infection-related MIS-C, and 3) to characterize specific anti-SARS-CoV2 adaptive immuneresponses in patients with MIS-C.This proposal will address major knowledge gaps in MIS-C pathogenesis in children. Completion of the projectgoals will lead to better understanding of dysregulated immune pathways and to the identification of novelbiomarkers and therapeutic targets for this new syndrome.