Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19

Abstract

Immune perturbation is a hallmark of Coronavirus Disease 2019 (COVID-19) with ambiguous roles of various immune cell compartments. Plasma cells, responsible for antibody production, have a two-pronged response while mounting an immune defence with 1) physiological immune response producing neutralizing antibodies against protein structures of SARS-CoV-2 and 2) potentially deleterious autoantibody generation. Growing evidence hints towards broad activation of plasma cells and the presence of pathologic autoantibodies (abs) that mediate immune perturbation in acute COVID-19 [1]. Recently, a systematic screening for abs confirmed induction of diverse functional abs in SARS-CoV-2 infection, targeting several immunomodulatory proteins, including cytokines/chemokines and their respective G-protein coupled receptors (GPCR) [1]. Abs against GPCR act as agonistic and allosteric receptor modulators and are linked to chronic inflammatory diseases [2] and, as we recently demonstrated, disease severity in acute COVID-19 [3].

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…Interestingly, patients with severe forms of COVID-19 also have high titers of anti-PAR1 autoantibodies that stimulate PAR1 in endothelial cells and platelets, and thus contribute to the pathogenesis of microthrombosis. A positive correlation was shown between the level of autoantibodies to PAR1 and the content of the thrombosis marker D-dimer [294].…”

“…Endogenous allosteric regulators of PAR1 are autoantibodies produced against its extracellular domains [237,[292][293][294]. A significant proportion of patients with systemic sclerosis have autoantibodies to extracellular regions of PAR1, which are able to activate the receptor, like thrombin, thus acting as allosteric agonists [293].…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…Endogenous allosteric regulators of PAR1 are autoantibodies produced against its extracellular domains [ 295 , 296 , 297 ]. A significant proportion of patients with systemic sclerosis have autoantibodies to extracellular regions of PAR1, which are able to activate the receptor, such as thrombin, thus acting as allosteric agonists [ 296 ].…”

“…Interestingly, patients with severe forms of COVID-19 also have high titers of anti-PAR1 autoantibodies that stimulate PAR1 in endothelial cells and platelets, and thus contribute to the pathogenesis of microthrombosis. A positive correlation was shown between the level of autoantibodies to PAR1 and the content of D-dimer, a marker of thrombosis [ 297 ].…”

Protease-Activated Receptor-1 IgG Autoantibodies in Patients with COVID-19

“…Recently, increased levels of protease-activated receptor-1 (PAR-1) AAbs were linked to severe COVID-19. 2 Here, we investigated the plasma levels of PAR-1 AAb using solid-phase sandwich ELISA Kits detecting only AAbs of the immunoglobulin G (IgG) isotype (CellTrend GmbH, Lucken-walde, Germany) 3 in healthy control subjects (n ¼ 10), hospitalized COVID-19 patients with mild-to-moderate symptoms (n ¼ 35), 4 and COVID-19 patients with a severe course who developed clinical deterioration with respiratory failure and acute respiratory distress syndrome requiring mechanical ventilation (n ¼ 47) (►Fig. 1A, B) (local ethics committee approval identifier EA2/066/20, EA4/147/15).…”