Autoimmunity and SARS-CoV-2 infection: Unraveling the link in neurological disorders

Abstract

According to the World Health Organization, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already infected more than 400 million people and caused over 5 million deaths globally. The infection is associated with a wide spectrum of clinical manifestations, ranging from no signs of illness to severe pathological complications that go beyond the typical respiratory symptoms. On this note, new-onset neurological and neuropsychiatric syndromes have been increasingly reported in a large fraction of COVID-19 patients, thus potentially representing a significant public health threat. Although the underlying pathophysiological mechanisms remain elusive, a growing body of evidence suggests that SARS-CoV-2 infection may trigger an autoimmune response, which could potentially contribute to the establishment and/or exacerbation of neurological disorders in COVID-19 patients. Shedding light on this aspect is urgently needed for the development of effective therapeutic intervention. This review highlights the current knowledge of the immune responses occurring in Neuro-COVID patients and discusses potential immune-mediated mechanisms by which SARS-CoV-2 infection may trigger neurological complications.

Keywords: SARS-CoV-2; autoimmunity, COVID-19, neuro-COVID, neuroimmunology.

Figure 1

Mechanisms of infection‐induced autoimmunity in Neuro‐COVID. (A) Release and spreading of self‐antigens may result from tissue damage caused by direct SARS‐CoV‐2 neuronal invasion or by the indirect effect of a proinflammatory environment. Self‐antigens can be presented to T cells by activated APCs endowed with increased antigen uptake ability and costimulatory molecule expression, thus facilitating the activation and expansion of autoreactive T cells. In parallel, autoreactive antibodies can be generated in a T‐cell‐independent fashion by extrafollicular B cells that recognize self‐antigens directly on their BCR and are simultaneously activated via SARS‐CoV‐2 genome sensing through TLR engagement. (B) Recognition of a SARS‐CoV‐2 antigen that has similarity to a self‐antigen can induce activation of autoreactive T cells through a mechanism of molecular mimicry. Similarly, antibodies cross‐reactive between SARS‐CoV‐2 antigens and self‐antigens can be generated by virus‐specific B cells via a T‐cell‐dependent mechanism.

Figure 2

Model of Neuro‐COVID immunopathology. Direct SARS‐CoV‐2 neuronal invasion contributes to the induction of CNS tissue damage (A) with the consequent spread of self‐neuronal antigens (B). In parallel, increased systemic levels of proinflammatory mediators affect BBB permeability (C), thus facilitating the recruitment from the blood into the perivascular space of potentially pathogenic soluble molecules, such as autoantibodies and proinflammatory cytokines, as well as immune cells, including autoreactive T lymphocytes, plasma cells and APCs (D). Here, intrathecal clonal expansion and activation of CD4⁺ and CD8⁺ Tcell populations may occur (E), and plasma cells may release autoantibodies directly into the CSF (F). In this scenario, pathogenic T lymphocytes and antibodies infiltrate the CNS parenchyma and contribute to disease immunopathology by directly exerting cytotoxic functions and/or indirectly fueling the local inflammatory environment (G).