Autoantibodies against Progranulin and IL-1 receptor antagonist due to immunogenic posttranslational isoforms contribute to hyperinflammation in critically ill COVID-19

Abstract

STRUCTURED ABSTRACTINTRODUCTIONHyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, caused by autoantibodies in a proportion of patients, lead to severe courses. In addition, hyperactive responses of the humoral immune system have been described so far.RATIONALEIn the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-10, IL-18BP, IL-22BP and IL-1-RA. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations.RESULTSPGRN-autoantibodies were detected with high titers in 11 of 30 (36.7%), and IL-1-RA-autoantibodies in 14 of 30 (46.7%) patients of a discovery cohort with severe to critical COVID-19. In a validation cohort of 41 patients with critical COVID-19 high-titered PGRN-Abs were detected in 12 (29.3%) and IL-1-RA-Abs in 19 of 41 patients (46.2%). PGRN-Abs and IL-1-RA-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-RA-Abs were detected significantly less frequently and at low titers. Neither PGRN-nor IL-1-RA-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins or against IL-1-RA. Plasma levels of both free PGRN and IL-1-RA were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID controls. Functionally, PGRN-Abs from patients reduced PGRN-dependent inhibition of TNF-α signaling in vitro. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a yet unidentified hyperphosphorylated IL-1-RA isoform was only found in patients with high-titer IL-1-RA-Abs. No autoantibodies against IL-10, IL-18BP or IL-22BP were found.CONCLUSIONTo conclude, neutralizing autoantibodies to IL-1-RA and PGRN occur in a significant proportion of patients with critical COVID-19, with a concomitant decrease in circulating PGRN and IL-1-RA, which is indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical isoforms of both antigens due to hyperphosphorylation. It remains to be determined whether these secondary modifications are induced by the SARS-CoV-2-infection itself, or are preexisting and predispose for a critical course.

Elevated Serum Levels of Progranulin and Soluble Vascular Cell Adhesion Molecule-1 in Patients with COVID-19

“…10,13 The significant increase in levels of PGRN in COVID-19 patients may therefore suggest that the PGRN-mediated antiviral strategy is also functional in SARS-CoV-2 infection. Nevertheless, Thurner et al 21 have recently reported the presence of autoantibodies against PGRN in patients with critical COVID-19 and showed that plasma from PGRN-Autoantibodies-negative patients was more effective than plasma from PGRN-Autoantibodies-positive patients to neutralize the TNF-α-induced cytotoxicity. It was therefore proposed that the significantly decreased levels of PGRN are responsible for the critical COVID-19.…”

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

“…Here we report on the high prevalence of neutralizing autoantibodies against the anti-inflammatory molecule IL-1-Ra in a case-series of patients with PIMS/MIS-C. Autoantibodies against IL-1-Ra were just recently described by our group in adults with critical COVID-19 ( 14 ); their occurrence was also reported in IgG4 associated diseases ( 21 ). In adults with critical COVID-19, IL-1-Ra-Abs were detected at a frequency of about 50%, along with autoantibodies against PGRN (in about 40% of patients).…”

“…Notably, the plasma levels of free IL-1-Ra were strongly reduced in all patients with autoantibodies and simultaneously antibody-bound IL-1-Ra was detected. IL-1-Ra-Abs in PIMS/MIS-C belonged exclusively to IgG1 subclass, no antibodies of IgM class as in adults with critical COVID-19 were detected ( 14 ). The titers of IL-1-Ra-abs were lower compared to the adults with critical COVID-19 (1:200-1:800 in PIMS/MIS-C vs. 1:800-1:1600 in critical COVID-19 of adults).…”

“…Longitudinal samples of adult patients with severe or critical COVID-19 had revealed that hyperphosphorylation of IL-1-Ra preceded the formation of autoantibodies. The data of COVID-19 of adults suggested that the immunogenic secondary modifications were induced by the SARS-CoV-2-infection itself or the inflammatory environment evoked by the infection ( 14 ), and that these modifications are immunogenic.…”

“…In addition, we found evidence that the autoantibodies probably have been evoked by a preceding and transient hyperphosphorylation of the antigens. The antibodies belonged to a broad range of Ig classes including IgM and several IgG subclasses, indicating recent immune responses ( 14 ). PGRN-antibodies (Abs) and the immunogenic pSer81 PGRN isoform have been initially described in systemic primary vasculitides ( 15 )( 16 ).…”