COVID-19 as an Immune Complex Hypersensitivity in Antigen Excess Conditions: Theoretical Pathogenetic Process and Suggestions for Potential Therapeutic Interventions

Abstract

Because of particular properties of SARS-Cov-2, such as an high infection speed, its antigenic nature, evolutionarily unknown to the human immune system, and/or a viral interference on the immune response mechanisms, this virus would determine in the subjects a delayed anomalous (slow and/or low) immune response, ineffective and, finally, self-damaging. The hypothetical pathogenetic process for covid-19 could occur in three phases: a) Viral phase, asymptomatic or weakly symptomatic, with an a-specific innate immune response; b) Immunological phase, intermediately symptomatic, with an anomalous specific immune response (delayed, slow and/or low synthesis of IgM and IgG) in antigen excess conditions, immune complex formation and complement activation with tissue damages; c) Hemo-vascular phase, severely symptomatic, where complement-mediated tissue damages would induce vascular inflammation and systemic alteration of the coagulation homeostasis. This hypothesis is well supported by the immune-histochemical and microscopic demonstration in severe patient lungs of co-localized spike viral proteins, terminal components of the activated complement system (C5b-9 membrane attack complex) and microvascular deposits of small fibrin thrombi. This picture could be aggravated by the involvement of neutrophils and macrophages, releasing additional lytic and inflammatory factors. Thus, covid-19 would arise as a simple viral infection, develop as a diffuse immune complex hypersensitivity and explode as a systemic hemo-vascular pathology. If this hypothesized process would be real, suitable therapeutic interventions might be carried out, able to interfere with or block the critical factors in the various phases.

Circulating multimeric immune complexes drive immunopathology in COVID-19

“…Using an adapted reporter cell activation assay optimized to detect sICs (25, 44) we provide first evidence of circulating sICs in the serum of COVID-19 patients and experimentally confirm previous hypotheses suggesting immune complexes as potential drivers of disease progression in COVID-19 (34-36, 38). In fundamental contrast to opsonized antigens decorating virus-infected cells in tissues, sICs become distributed systemically.…”

“…Next to afucosylation, it has been proposed that uncleared antigen-antibody immune complexes (ICs) might be involved in the pathogenesis of severe COVID-19. (34-36, 38). However, the actual presence of circulating, multimeric soluble ICs (sICs) in critically or severely diseased patients has not been shown yet.…”

First description of immune complex vasculitis after COVID-19 vaccination with BNT162b2: a case report

“…Until now, data on pathogenesis and clinical manifestations of COVID-19 support the hypothesis of three distinct phases of the disease: viral phase, immunological phase and haemo-vascular phase [ 9 , 10 ]. In October 2020 Manzo discussed COVID-19 as a trigger for an immune complex hypersensitivity reaction [ 11 ]. He highlighted the significant antigen excess in the second phase of COVID-19 disease that may lead to the formation of soluble antigen-antibody immune complexes, which cannot be removed by phagocytes anymore.…”

Immunometabolic bases of type 2 diabetes in the severity of COVID-19

“…AGEs produced in diabetic patients are also known to activate the classical complement pathway by recognizing C1q, which in turn inactivates CD59 and increases vascular injury in blood vessels of T2D patients[ 108 ]. In agreement with this concept, membrane attack complex deposits present in lung tissue from patients with severe COVID-19 has revealed complement-mediated damage which in turn induces vascular inflammation and results in extended lung damage[ 109 ].…”