SARS-CoV-2 infection in most cases is characterised by mild symptoms of fever, tiredness and dry cough. Coronaviruses can also induce cognitive, emotional, neurovegetative and behavioral dysregulation due to direct neurological injury through hypoxic damage and neuroinvasion. Most SARS-CoV-2 infections resolve within two weeks. However, the infection, which is characterized by neurological and neuropsychiatric symptoms, may last longer than 12 weeks. This phenomenon has been termed as Long COVID (LC) – a multisystemic condition, associated with acute phase disease severities. Several hypotheses for its pathogenesis have been suggested, including immune dysregulation with or without reactivation of herpesviruses. The inflammation is central to pathogenesis of psychiatric symptoms in COVID-19 patients, which is often associated with presence of neural autoantibodies.
 The following changes are established of innate immunity in patients with SARS-CoV-2 infection and long COVID: 1) cytokine storm, which manifests itself in high concentration of proinflammatory cytokines and chemokines (IFN-β, IFN-λ1, IFN-γ, CXCL9, CXCL10, IL-8, IL-1α/β, IP-10, MCP-1); 2) elevated level C-reactive protein; 3) decreased number of NK, NKT cells and its exhaustion; 4) lower expression of NKG2C, upregulation of checkpoint receptors (LAG3, TIGIT and TIM3) on NK cells; 5) poor interacting between monocytes, infectious agents and Tolllike receptor (TLR) ligands; 6) reinforced products of thromboxane-A2, resulting in increased platelet aggregation, which mediate thrombus formation. It was also found in such patients the changes of adaptive immunity: 1) T cell alterations, including exhausted T cells; 2) reduced CD4+ and CD8+ effector memory cell numbers, which mainly express PD-1, CTLA-4, TIGIT and Tim-3; 3) a lack of naive T and B cells; 4) increases in the numbers of IL-4- and IL-6-secreting CD4+ T cells; 5) higher expression of cytotoxic granules (GrA, GrB, perforin) on CD8+ T cells.
 The exact mechanisms underlying the immune response after SARS-CoV-2 infection remain unclear. The count of helper T cells, regulatory T cells and memory T cells are all diminished in severe COVID- 19 cases, though Th1 and Th2 cytokine levels remain high. T cell activation (indicated by CD38 and HLA-DR) occur during severe COVID-19. Besides, T cells are overactivated in COVID-19 patients, leading to cytokine storm, and decreased Treg cells are a reason for severe disease. A subset of T cell expressed at the same time both: T cell immunoglobulin and mucin domain-3 (Tim-3) and programmed death-1 (PD-1).
 The overproduction of several inflammatory cytokines, overactivated and exhausted T cells, overstimulation of immune system and loss of self-tolerance alone can cause the production of autoantibodies. In addition, are activated the extrafollicular B cells in conjunction with autoantibody-secreting B cells. As seen in COVID-19 patients with autoantibodies and autoreactive CD4+ and CD8+ cells, probably promotes the development of neural autoantibody-associated psychiatric disease. The neural autoantibodies probably promote the development of psychiatric disease according to such pathomechanisms: 1) molecular mimicry: 2) NETs; 3) altered blood-brain barrier permeability; 4) coagulopathy and endothelial dysfunction (brain microhaemorrhages); 5) neuronal injury and apoptosis; 6) chronic hypoxia; 7) oxidative stress.
 Some features of COVID-19 resemble clinical diseases that accompany certain acute and chronic viral diseases, including diseases caused by HHV-6. Virus HHV-6 act in the following ways: 1) downregulation of CD3; 2) induction of IL-10-producing T-regulatory type 1 cells; 3) inhibition of IFN-β, IL-2, IL-12, and molecules MHC class I production; 4) immunomodulation – alterations in cell surface receptor expression and cytokine/chemokine production. Infection with SARS-CoV-2 causes overproduction of inflammatory cytokines that activate the inflammatory cascade. The hyperinflammatory processes in COVID-19 patients reactivate latent HHV-6, and that this is related to the inflammatory status of the patient. HHV-6 infects a broad array of immune and non-immune cell types and may introduce changes in T cell expression profiles and differential proliferation rates. The subclinical reactivation HHV-6 may affect the degree or severity of the SARS-CoV-2 infection. The severity of the course of the SARS-CoV-2 infection against the background of reactivation of HHV-6 threatens the formation of immunopathological syndromes, first of all is autoimmune syndrome. Long COVID could be induced by different mechanisms, including viral persistence that leads to disorders of immune response regulation, the release of superantigens that overactivate the immune system, destroys the blood-brain barriers which collectively may result in autoimmunity and polyautoimmunity, including neuroautoimmunity. This process was accompanied by the production of autoantibodies against thyroglobulin, thyroid peroxidase, insulin, double-stranded DNA, topoisomerase 1, glomerular basement membrane, and myoloperoxidase, which are detected in many autoimmune diseases. The production of antibodies against autoantigens that are detected mainly in polyautoimmunity through a completely new mechanism which involves the disruption of central tolerance Therefore, neuropsychiatric disorders in patients who have experienced moderate and severe forms of the course of COVID-19 are in the vast majority caused by deep immune changes and concominant lymphotropic/ neurotropic infection (HHV-6). The depth of disorders is often associated with autoimmunity to neuronal and other autoantigens.
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Feb 8, 2024
Cecilia Serena Pace + 3
