Autoantibodies to IL-1Ra and PGRN in severe COVID-19 are associated with inflammation-induced hyperphosphorylated antigen isoforms

SARS-CoV-2 infection affects multiple immune mechanisms and leads to severe COVID-19 and death, in part related to infection-induced or pre-existing autoantibodies. Here, we describe severe COVID-19 to associate with autoantibodies against interleukin-1 receptor antagonist (IL-1Ra) and progranulin (PGRN), endogenous antagonists of IL-1 and TNF signaling, respectively. These autoantibodies coincide with hyperphosphorylation of IL-1Ra (Thr111) or PGRN (Ser81), form immune complexes independent of phosphorylation, reduce antigen plasma levels, and permit enhanced IL-1 and TNF signaling. Using phage-display selected Fabs specific for hyperphosphorylated isoforms, we track phospho-antigens and autoantibodies in a German national pandemic network cohort. Most seropositive patients show both autoantibodies. Levels peak at baseline and decline over 12 months, with phospho-antigens decreasing before autoantibodies. Seropositivity associates with hyperinflammation and cytokine profiles. Importantly, signaling by key inflammatory cytokines induce IL-1Ra and PGRN hyperphosphorylation in healthy monocytes, but require up to 1000-fold higher doses than in monocytes from previously seropositive severe COVID-19 survivors.

• Thurner, L.
• Fadle, N.
• Thurner, B.
• Kos, I. A.
• Bewarder, M.
• Regitz, E.
• Bette, B.
• Fischer, Y.
• Lesan, V.
• Rixecker, T.
• Hoffmann, M. C.
• Preuss, K. D.
• Schormann, C.
• Kaddu-Mulindwa, D.
• Roemer, K.
• Cetin, O.
• Mang, S.
• Becker, A.
• Seiler, F.
• Herr, C.
• Lensch, C.
• Lehmann, J.
• Thiel-Bodenstaff, A.
• Link, A.
• Werner, C.
• Wuchter, P.
• Korper, S.
• Pfuhl, T.
• Lohse, S.
• Rissland, J.
• Thieser, K.
• Pilch, J.
• Papan, C.
• Roth, S.
• Vehreschild, J. J.
• Scherer, M.
• Brohl, I.
• Wagner, P.
• Witzenrath, M.
• Thibeault, C.
• Haack, I. A.
• Mitrov, L.
• Putz, S. M.
• Reese, J. P.
• Krawczak, M.
• Hamelmann, E.
• Kopfnagel, V.
• Fiedler, K.
• Geisler, R.
• Valentin, H.
• Stahl, D.
• Hanss, S.
• Ameling, S.
• Volker, U.
• Hansch, S.
• Dorr, M.
• Blaschke, S.
• Braunsteiner, J.
• Dahl, E.
• Pape, D.
• Petersmann, A.
• Stilgenbauer, S.
• Bloos, F.
• Schrezenmeier, H.
• Langer, F.
• Gabelein, G.
• Friesenhahn-Ochs, B.
• Pfeifer, J.
• Bauer, M.
• Becker, S. L.
• Neumann, F.
• Bohm, M.
• Anton, G.
• Kuenne, C.
• Pullamsetti, S. S.
• Looso, M.
• Bals, R.
• Smola, S.
• Meybohm, P.
• Krawczyk, M.
• Lepper, P. M.
• Kessel, C.