Evidence of molecular mimicry in multisystem inflammatory syndrome in children (MIS-C)

Multisystem inflammatory syndrome in children (MIS-C) is a severe,
post-infectious sequela of SARS-CoV-2 infection, yet the
pathophysiological mechanism connecting the infection to the broad
inflammatory syndrome remains unknown. Here we leveraged a large set of
MIS-C patient samples (n=199) to identify a distinct set of host proteins
that are differentially targeted by patient autoantibodies relative to
matched controls. We identified an autoreactive epitope within SNX8, a
protein expressed primarily in immune cells that regulates an antiviral
pathway associated with MIS-C pathogenesis. In parallel, we also probed
the SARS-CoV-2 proteome-wide MIS-C patient antibody response and found it
to be differentially reactive to a distinct domain of the SARS-CoV-2
nucleocapsid (N) protein relative to controls. This viral N region and the
mapped SNX8 epitope bear remarkable biochemical similarity. 
Furthermore, we find that many children with anti-SNX8 autoantibodies also
have T cells cross-reactive to both SNX8 and this distinct region of the
SARS-CoV-2 N protein. Together, these findings suggest that MIS-C patients
develop a characteristic immune response against the SARS-CoV-2 N protein
that is associated with cross-reactivity to the self-protein SNX8,
demonstrating a mechanistic link from the infection to the inflammatory
syndrome with implications for better understanding a range of
post-infectious autoinflammatory diseases.