Abstract
Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-β, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM , NCF1 , MCM4 , FCN3 , and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1 , NOD2 , and MEF . Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.
Keywords: MIS-C; autoimmune diseases; autoinflammatory diseases; cytokines; flow cytometry.
【저자키워드】 Cytokines, MIS-C, Autoimmune diseases, Autoinflammatory diseases, flow cytometry., 【초록키워드】 Cytokine storm, Pathogenesis, IL-17A, IL-6, knowledge, children, NGS, Genetic, Th1, variant, immunodeficiency, heterogeneity, flow cytometry, Population, lymphopenia, B cell, Autoimmune disease, lymphocyte, serum, Characteristics, management, therapeutic, Patient, pathway, NOD2, IFN, Hospital admission, Autoimmune, Genetic variant, IL-10, ATM, Admission, Critical, patients, autoinflammatory disease, Therapies, IFN-γ, TNF, cellular, Analysis, Inflammatory, cytokine response, Cytometry, Flow, immune dysregulation, IFN-α, reduction, Activation, tissue damage, acute phase, significant increase, healthy control, IFN-β, IFNγ, syndrome, help, multisystemic, serum cytokine, IL-12p70, organ, clearance, complication of COVID-19, MOST, FCN3, autoimmune pathogenesis, PRF1, immunological, event, diagnostic biomarker, develop, involved, the disease, activated, contribute, demonstrated, induce, mutated, Type, DOCK8, identified variant, inflammatory pathway, MCM4, NCF1, was increased,