MS is a chronic immune-mediated disease of the CNS whose pathological hallmark is focal demyelination associated with various degrees of neurodegeneration [
37]. Complex immunological dysfunction—involving peripheral T and B lymphocytes and resident CNS immune cells—represents the immunological substrate for MS development and progression [
38]. The intermittent aberrant activation of self-reacting immune cell subsets results in their transmigration across the BBB into the CNS, where they induce demyelinating and, ultimately, neuronal damage manifesting as clinical relapse and disability accumulation. The aetiology of the disease, as well as its periodic relapses, is not established yet, but environmental triggers acting on susceptible individuals are implicated. For over a century, since Pierre Marie initial intuition in 1884, MS was believed to be caused by infectious agents and many viruses, including coronavirus, have been proposed as potential candidates [
39]. Viral infection contributes to demyelination through several mechanisms such as molecular mimicry, bystander inflammatory damage or direct oligodendrocyte infection [
39]. MS onset may occur long after acute infection as consistently demonstrated for by Epstein–Barr virus (EBV) [
40]. Infectious mononucleosis by EBV supervening during the early adulthood, in fact, is an established risk factor for further MS development [
41‐
45]; moreover, compelling evidence shows that almost all subjects with MS have positive serology for EBV. The “prime/challenging” theory has been proposed to explain the delay between early infection and MS onset; according to this assumption, the initial infection, such as by EBV, would prime autoreactive cells in susceptible individuals via molecular mimicry and bystander activation, setting up a fertile-field. Further infection by other microorganism, or even reactivation of EBV under favouring circumstances, will activate the preexisting autoreactive cells leading to inflammatory demyelination [
40,
46]. Studies in MS patients infected by SARS-CoV2 are ongoing aiming at identifying the effects of iatrogenic immune modulation/suppression on the severity of infection [
47,
48]. Nevertheless, the effect of the virus on MS-related inflammatory activity has not been investigated yet, but few cases of acute inflammatory demyelinating disorder have been already described. It would not be surprising that SARS-CoV2 might act as “priming” or “challenging” infectious agent in “primed” individuals. Moreover, in individuals with MS, autoreactive T cells able to recognize both viral and myelin antigens have been found [
49]. Additionally, SARS-CoV2 infection is associated with peripheral lymphopenia in more than 80% of patients with COVID-19. Lymphopenia is sustained by a predominant decrease of CD3 + , CD8 + , and CD4 + T cell counts, while B cells and NK are only mildly affected [
50]. Patients infected by SARS-CoV during the 2002–04 outbreak recovered normal T lymphocytes count in about 2 months in the majority of case, and more rarely the recovery took more than 12 months [
51]. Sequestration in the lung, intestine and other tissues, and senescence and exhaustion of the anti-viral CD8 response [
50,
52], explain this selective immunodepletion. We can speculate that defective anti-viral CD8 immunological response may reduce immunosurveillance on other latent pathogens potentially able to trigger MS or other post-infectious demyelinating disorders, such as Guillain–Barrè syndrome or its variants [
53]. Co-infection with EBV, in fact, has been observed in patients affected by COVID-19, mainly in those with lower CD4/CD8 ratio [
54]. Nevertheless, unbalance of peripheral lymphocyte subsets induced by COVID-19, and in particular B cell overshooting, may hypothetically represent an additional risk for MS relapses in patients with pre-existing diagnosis, as observed in similar immunological framework [
55]. The “cytokine storm” in response to the SARS-CoV2 infection may promote a switch toward a pro-inflammatory status of T cell subsets, such as Th17, which are implicated in MS pathogenesis [
56]
Building on these evidences, MS may result from previous SARS-CoV2 infection due several mechanisms: (1) a “challenging” effect of the virus in susceptible subjects previously exposed to priming pathogens; (2) unbalance of peripheral lymphocyte subsets and massive cytokine release producing a pro-inflammatory environment and triggering autoimmune reactions; (3) induction of post-infectious demyelinating events associated with direct CNS invasion and microglial reaction.