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).