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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.

Recently, we identified LDL receptor related protein associated protein 1 (LRPAP1) as frequent autoantigen of recombinant B-cell receptors (BCRs) of mantle cell lymphoma (MCL). This autoantigen induced proliferation in two cell lines with BCR-reactivity against LRPAP1. Of interest, high-titered and light-chain-restricted LRPAP1-autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1-autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics and prognostic impact. LRPAP1-autoantibodies were detected in 41 (13 %) of 312 evaluable patients with MCL. These LRPAP1-autoantibodies belonged predominantly to the IgG class (IgG: 37; IgM: 4, IgG-subclasses: IgG1: 25, IgG2: 7, IgG3: 4 and IgG4: 1) and were clonally light-chain-restricted (27 with kappa light-chains, 14 patients with lambda light-chains). Titers ranged between 1:400 up to 1:3200. The presence of LRPAP1-autoantibodies was not significantly associated with any baseline clinical characteristic. However, the presence of LRPAP1-autoantibodies was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% CI: 57%-87%) vs. 51% (95% CI: 44%-58%) p:0.0052; and for overall survival (OS) of 93% (95% CI: 85%-100%) vs. 68% (95% CI 62%-74%), p=0.0142. LRPAP1-seronegative patients had a MIPI-adjusted HR for FFS of 2.1 (95% CI 1.2-3.6, p=0.0083) and for OS of 2.1 (95% CI 1.07-4.2, p=0.032). LRPAP1-autoantibodies were frequently detected in serum samples of a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients.

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