The possible triggering of MIS-C via antibody-dependent enhancement
A number of reports documented the finding that most of the individuals presenting with MIS-C have significant levels of SARS-COV-2 antibodies in their sera but they are negative for SARS-COV-2 by RT-PCR. We reasoned that to a potential role of the antibody-dependent enhancement (ADE) that is well described in dengue and Zika virus infections[15]. ADE could trigger the MIS-C syndromes whereby the pathogen-specific antibodies can promote pathology.
It has been observed that the severe disease caused by SARS-CoV-1 infection is associated with the peak of neutralizing antibody response, suggesting that antibody responses that potentially contain ADE antibodies may also be related to disease outcome in SARS-CoV-1 infection [16]. The spike protein of SARS-CoV-2 contains various epitopes that could induce neutralizing and non-neutralizing antibody production. The neutralizing antibodies afford a protective effect against virus entry into the host cells. On the other hand, the antibodies generated against the non-neutralizing epitopes could enhance virus entry leading to severe disease outcomes.
We hypothesize that the initial exposure of children to the SARS-COV-2 induces both neutralizing and non-neutralizing antibodies production by immune cells. However, over time, it is possible that those children with predominantly virus neutralizing antibodies progress to asymptomatic COVID-19 illness. However, a select number of those that shift to producing predominantly non-neutralizing antibodies progress to severe disease due to ADE. This is exemplified by the finding that at low dilutions anti-sera against SARS-CoV neutralized SARS-CoV infection, while highly diluted anti-sera significantly increased SARS-CoV infection and induced higher levels of apoptosis [17]. Thus, the low levels of neutralizing antibodies could be insufficient to inhibit virus entry, while the low levels of non-neutralizing antibodies could enhance virus entry and worsen the disease outcome. It is important to note the delay between the recognized beginning of the SARS-COV-2 pandemic in the population and the recent emergence of MIS-C illness in children. It is possible that COVID-19 induced pathology changed since the beginning of the pandemic, after the virus began circulating within the general population due to varied levels of generational immunity background of hosts. The severe or mild and symptomatic or asymptomatic infections produce a different ratio of neutralizing and non-neutralizing antibodies that will affect the pathology of the second infection with SARS-COV-2 (Figure 1).