Autoantibodies against IL-1-receptor-antagonist in multisystem inflammatory syndrome in children

Pfeifer, J.; Thurner, B.; Kessel, C.; Fadle, N.; Regitz, E.; Hoffmann, M.-C.; Kos, I.; Preuss, K.-D.; Fischer, Y.; Roemer, K.; Lohse, S.; Heyne, K.; Detemple, M.-C.; Fedlmeier, M.; Juenger, H.; Sauer, H.; Meyer, S.; Rohrer, T.; Wittkowski, H.; Masjosthusmann, K.; Becker, S. L.; Smola, S.; Bewarder, M.; Boehm, M.; Anton, J.; Pino-Ramirez, R. M.; Abdul-Khaliq, H.; Foell, D.; Thurner, L.

Multisystem inflammatory syndrome in children (MIS-C or PIMS) is a rare but serious complication after an infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently neutralizing autoantibodies against anti-inflammatory receptor antagonists progranulin (PGRN) and IL-1-receptor antagonist (IL-1-Ra) were discovered in adult patients with critical COVID-19. Plasma of an index case with severe PIMS/MIS-C was analyzed for autoantibodies against IL-1-Ra and PGRN. The study was extended by a case series of 12 additional patients. In addition to ELISA for of antibodies, IL-1-Ra plasma levels were determined and IL-1-Ra was analyzed by Western-blot and isoelectric focusing. Functional activity of the autoantibodies was examined in vitro with IL-1beta reporter assays. Antibodies against IL-1-Ra could be detected in 10 of 13 (76.9%) patients with PIMS/MIS-C, but not in controls. In contrast to critical COVID-19 in adults, no IL-1-Ra antibodies of the IgM class were detected in PIMS/MIS-C. IL-1-Ra-antibodies exclusively belonged to IgG1. No antibodies directed against PGRN were detected. Western blots and ELISA showed a concomitant reduction of free IL-1-Ra plasma levels in the presence of IL-1-Ra-antibodies. The antibodies inhibited IL-1-Ra function in IL-1beta reporter cell assays. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1-Ra was observed in all IL-1-Ra autoantibody-positive patients. To conclude, IL-1-Ra autoantibodies were observed in high frequency in children with PIMS/MIS-C. They may represent a diagnostic and pathophysiologically relevant marker for PIMS/MIS-C. Their generation is likely to be triggered by an atypical, hyperphosphorylated isoform of IL-1-Ra.