**3.2 Superantigen theory**

The virus binds to the immune cell *via* toll-like receptor (TLR) and is endocytosed. A fragment of SARS-CoV-2 spike glycoprotein 1 (S1) is similar to staphylococcal enterotoxin B [39]. This viral structure interacts with a high affinity between the major histocompatibility complex II (MHC II) and CD4+ T cell receptors (TCR). This interaction between MHCII and TCR would be the same that occurs with enterotoxin B of staphylococcus, acting as a superantigen in the pathophysiology of toxic shock syndrome (TSS) [39]. An expansion of TCR β variable gene 11–2 (TRBV11–2) has been found. This TCR correlates with MIS-C severity and serum cytokine levels and it has been associated with HLA class I alleles [40]. Proteins would act as superantigen interacting not only with TCR, but also at the endothelial level between Major Histocompatibility Complex I (MHC I) and CD28+ T cells [41]. The cytokine storm that occurs in TSS occurs during acute staphylococcal infection, whereas in MIS-C SARS-CoV-2 is usually no longer detected, so the superantigen properties of SARS-CoV-2 and its role in the pathophysiology of MIS-C have yet to be confirmed.

### **3.3 Genetic susceptibility**

All pediatric patients infected with SARS-CoV-2 have a similar antibody response, independent of whether they develop MIS-C. The fact that MIS-C only occurs in a small group of children suggests that the immune response is associated with a genetic predisposition. It is thought that there are mutations or polymorphisms of genes that encode molecules that trigger immune cascades, among other TLRs and Fcγ receptors [42]. It has been described that there could be an alteration in genes that regulate the suppression of cytokine signals (SOCS1). An alteration in these genes would mean an impossibility of stopping the inflammatory cascade in these children. Despite all the descriptions seen above, there is no specific genetic alteration that can explain why some children develop MIS-C and other does not.
