Fig. 5.

Mechanisms of immune-mediated manifestations. Circulating T cells and macrophages release pro-inflammatory cytokines, such as Interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα) and interferons (IFNs) in response to SARS-CoV-2 infection [20]. In severely ill patients, the immune cells and cytokines may cross the blood brain barrier (BBB), further activating microglia and astrocytes [25]. This causes inflammation within the CNS, resulting in a spectrum of neuroinflammatory diseases [29]. In addition, circulating B cells may produce autoantibodies to either surface or intracellular neuronal antigens, which cross the BBB into the CNS, binding to neurons and leading to cell dysfunction and death [66,82]. There is additional evidence that, in some cases, the virus directly gains access to the CNS via the ACE2 receptor to infect CNS immune cells and neurons, subsequently causing cell damage, death and CNS inflammation [11].