Risk surveillance and mitigation: autoantibodies as triggers and inhibitors of severe reactions to SARS-CoV-2 infection

Abstract

COVID-19 clinical presentation differs considerably between individuals, ranging from asymptomatic, mild/moderate and severe disease which in some cases are fatal or result in long-term effects. Identifying immune mechanisms behind severe disease development informs screening strategies to predict who are at greater risk of developing life-threatening complications. However, to date clear prognostic indicators of individual risk of severe or long COVID remain elusive. Autoantibodies recognize a range of self-antigens and upon antigen recognition and binding, important processes involved in inflammation, pathogen defence and coagulation are modified. Recent studies report a significantly higher prevalence of autoantibodies that target immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins in COVID-19 patients experiencing severe disease compared to those who experience mild or asymptomatic infections. Here we discuss the diverse impacts of autoantibodies on immune processes and associations with severe COVID-19 disease.

Keywords: Autoantibodies; Autoimmunity; COVID-19; SARS-CoV-2.

Fig. 1

Potential processes affected by presence of autoantibodies in COVID-19. Left panel: pathogen uptake results in release of inflammatory markers and complement proteins which lead to neutrophil recruitment, activation and translocation of autoantigens. Anti-neutrophil cytoplasmic antibodies (ANCA) (anti-MPO, anti-PR3, anti-ELANE, and anti-aPL autoantibodies and anti-H3/H4), bind autoantigens and promote NETosis which induces a thrombotic response. NET contents can be recognised by anti-MPO, anti-H3/H4 and anti-ELANE autoantibodies. Autoantibodies to complement proteins (anti-MASP2, anti-C1q) interfere with complement activation. Right panel: autoantibodies bind to the B cell activating factor (BAFF) which enables production of more autoantibodies by pre-existing autoantibody producing B cells. Autoantibodies which interfere with pathogen defence include antibodies to complement, tissue antigens and cytokines which can disrupt cytokine communication (anti-GM-CSF) and cytokine clearance (anti-IFNs). SARS-CoV-2 bound to soluble ACE2 complex can be phagocytosed by macrophages and presented on the surface, inducing anti-ACE2 antibodies. Anti-ACE2 can bind soluble ACE2, reducing its capacity to act as a decoy for SARS-CoV-2, as well as have cross-reactivity with surface attached ACE, triggering further detrimental inflammation. Created with BioRender.com

Fig. 2

Incomplete NET degradation leads to hypercoagulation. (1) Incomplete NET degradation causes macrophage and dendritic cells (DCs) to present NET components to CD4 + T cells. (2) The T cells release IL-21 inducing differentiation of B cells into plasma cells to induce autoantibody production. (3) Anti-neutrophil cytoplasmic antibodies (ANCAs) can form circulating immune complex (CIC). (4) ANCAs and CIC activate neutrophils through FcɣR and complement receptor binding. Hyperactivation of neutrophils by autoantibodies produces Reactive Oxygen Species (ROS), cytokines storms, lytic enzymes, and NET. (5) NETosis releases decondensation of chromatin constructed from unwound neutrophil DNA and histones coated with neutrophil enzymes such as neutrophil elastase (NE), myeloperoxidase (MPO), and proteinase 3 (PR3). (6) Von Willebrand Factor (vWF) attracts platelets and histones activate them leading to the intrinsic pathway of coagulation. (7) NE cleaves anticoagulant which contributes to more coagulation. (8) CIC can trigger a fibrotic response from DCs and macrophages. (9) Macrophages carry inactive tissue factors which will be activated by pyroptosis, specifically by protein disulfide isomerase. Pyroptosis results in microvesicles that contain active tissue factors that lead to the extrinsic pathway of coagulation. (10) The vicious cycle of uncontrolled neutrophils activation and incomplete net degradation causes hypercoagulation through intrinsic and extrinsic pathways. Created with BioRender.com and adapted from Bautista-Becerril et al. (2021) and Jayarangaiah et al. 2020)