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

Abstract

SARS-CoV-2 infection affects multiple immune mechanisms and leads to severe COVID-19 anddeath,inpartrelatedtoinfection-inducedorpre-existing autoantibodies. Here, we describe severe COVID-19 to associate with auto antibodies against interleukin-1 receptor antagonist (IL-1Ra) and progranulin (PGRN), endogenousantagonistsofIL-1 andTNFsignaling,respectively. These autoantibodies coincide with hyperphosphorylationof IL-1Ra(Thr111)orPGRN (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 hyperin flammation and cytokine profiles. Importantly, signaling by key inflammatory cytokines induce IL-1Ra and PGRN hyperphosphorylation in healthy mono cytes, but require up to 1000-fold higher doses than in monocytes from pre viously seropositive severe COVID-19 survivors.