**3.1 Immune dysregulation**

SARS-CoV-2 infection in pediatric population would produce a functional activation of phagocytes and complement mediated by immunoglobulin G (IGG), similar to the response of adults with moderate COVID-19, and different to severe adult COVID-19 infection that is primarily mediated by IGA and neutrophils [26]. Once the acute infection has passed, often asymptomatic, the child persists with high levels of IGG similar to acute infection levels and with the ability to activate the immune system later. In addition, the prolonged permanence of the virus in the intestine of children is described. If intestinal inflammation is persistent, the possibility of increased permeability is real, with consequent leakage of viruses into circulation [27]. Single-cell RNA sequencing of peripheral blood mononuclear cells from children with acute MIS-C has been studied, showing low viral and bacterial

signatures, suggesting that there are no viral or bacterial infections as triggers of MIS-C [28]. The response of children to the Spike glycoprotein (S) is strong in IGG but weak in immunoglobulin M (IGM). They also have a poor immune response to the nucleocapsid protein (N) [29–31]. Adults on the other hand have a better response to protein S in any types of immunoglobulin, as well as better neutralizing capacity [32]. The asymptomatic nature of the disease in children could be related to this type of immune response. The immunoglobulin response in children with MIS-C is shown in **Figure 1**. Between 20 and 50% of people without exposure to SARS-CoV-2 have T cell reactivity against the virus. This may be due to some cross-reaction between CD4+ T cells and the seasonal coronavirus before the pandemic [33, 34]. Seasonal coronavirus antibodies do not vary between children with MIS-C and children hospitalized for other reasons so the role played by these previously activated T cells in the pathophysiology of MIS-C is not yet clarified [35]. High IFNy levels correlate with high levels of plasma-soluble markers from natural killer (NK) cells and T cells, suggesting that there is an increase in cytotoxic gene expression, which could contribute to tissue damage [28]. There is activation of CD8+ T cells that express inflammatory molecules of the vascular endothelium that could be related to cardiovascular alterations, D-dimer production, thrombocytopenia, and vasoactive drug requirement. This activation would be only in pediatric patients infected with SARS-CoV-2 who develop MIS-C and is related to cytotoxicity although to a less than NK. The proportion of CD8+ T cells decreases as the child's clinical condition improves [28, 36]. Non-specific B cell activation and elevation of plasmablast can be observed [37]. Complement activation is part of the inflammatory process in MIS-C. The elevation of C5b-9 in sick patients is related to endothelial dysfunction. There is an associated within complement activation and thrombotic microangiopathy. Patients with MIS-C have a higher incidence of thrombotic events compared to healthy children or patient COVID-19 without MIS-C [38].

#### **Figure 1.** *The immunoglobulin response in children with MIS-C.*
