A distinct cross-reactive autoimmune response in multisystem inflammatory syndrome in children (MIS-C)
Author:
Bodansky AaronORCID, Sabatino Joseph J.ORCID, Vazquez Sara E., Chou Janet, Novak TanyaORCID, Moffitt Kristin L.ORCID, Miller Haleigh S.ORCID, Kung Andrew F., Rackaityte Elze, Zamecnik Colin R.ORCID, Rajan Jayant V., Kortbawi Hannah, Mandel-Brehm Caleigh, Mitchell Anthea, Wang Chung-YuORCID, Saxena AditiORCID, Zorn KelseyORCID, Yu David J.L., Asaki JamesORCID, Pluvinage John V., Wilson Michael R., Loftis Laura L., Hobbs Charlotte V.ORCID, Tarquinio Keiko M.ORCID, Kong Michele, Fitzgerald Julie C., Espinal Paula S., Walker Tracie C., Schwartz Stephanie P., Crandall Hillary, Irby Katherine, Staat Mary Allen, Rowan Courtney M., Schuster Jennifer E., Halasa Natasha B., Gertz Shira J.ORCID, Mack Elizabeth H., Maddux Aline B.ORCID, Cvijanovich Natalie Z.ORCID, Zinter Matt S., Zambrano Laura D., Campbell Angela P., Randolph Adrienne G.ORCID, Anderson Mark S., DeRisi Joseph L.ORCID,
Abstract
AbstractMultisystem 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 which 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 domain of the SARS-CoV-2 N protein. Together, these findings suggest that MIS-C patients develop a distinct immune response against the SARS-CoV-2 N protein that is associated with cross reactivity to the self-protein SNX8, demonstrating a link from the infection to the inflammatory syndrome.
Publisher
Cold Spring Harbor Laboratory
Cited by
4 articles.
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