## 6 Discussion  
Multiple sclerosis is an inflammatory, immune-mediated, demyelinazing, and neurodegenerative disease of the central nervous system. The disease's onset results from a combination of genetic and environmental factors, especially infections. Currently, many theories accept that immune system activation may be triggered by multiple mechanisms associated with some viral agents. For some time, the candidate role of the human herpes virus (HHV) group as a main trigger has been accepted. The blood-brain barrier may become permeable to T cells as a consequence of an infection, and T cells remain trapped and activated in situ even after the infection has been solved. The neuroinvasive potential of SARS-CoV-2 has been already described. SARS-CoV-2 may cross the blood-brain barrier through particular cell types: pericytes or astrocytes. The virus stimulates the local activation of the immune system, and therefore, consequent production of locally recruited IL-1 beta and IL6 by T cells may occur. Another theory identifies the role of IFN-I response. Its deficiency in some individuals promotes the development of severe COVID-19. The corresponding clinical lapel shows that MS patients lacking IFN-I may exhibit decreased COVID-19 risk after IFN-I administration. Similarly, Th-17 axis is also highly involved in MS pathogenesis. TH-17 axis is highly expressed in individuals with aggressive MS, and it is further stimulated by SARS-CoV-2, suggesting a synergy between these two diseases. Ultimately, SARS-CoV-2 may activate inflammasome complexes, which represent a molecular drivers of the innate immune system's inflammatory response. These cellular complexes are highly expressed in people with MS and play a significant role in supporting MS inflammation. [13; 14]  
Since the outbreak of the COVID-19 pandemic, the number of cases reporting a temporal association between the infection and the onset of demyelinating diseases is increasing [5]. Either the central nervous system and/or the peripheral nervous system seem to be involved, as the manifestation of COVID-19-related demyelinating diseases included inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and acute disseminated encephalopathyitis (ADEM) [5]. A relationship between COVID-19 and onset of multiple sclerosis (MS) are reported in just six case reports [6; 7; 8; 9; 10; 11]. The question arises as to whether COVID-19 infection may trigger an immunogenic central nervous system (CNS) inflammatory response in genetically predisposed individuals, acting as a precipitating event rather than as a direct cause [7]. Despite the complete aetiology of MS still being unknown, the importance of viral infections as a possible trigger factor is widely suspected [15; 16]. This idea has been supported by a recent observational study on the role of EBV in the pathogenesis of multiple sclerosis points towards the likelihood of a viral trigger whether by stimulation of the immune responses in genetically predisposed individuals or as a result of molecular mimicry between viral antigens and CNS cell structures [17]. Other findings are that that in up to 90% of MS cases, patients manifest oligoclonal bands in the CSF, and that chronic inflammatory disorders of CNS are especially infectious. Amongst the viruses, Epstein-Barr (EBV) infection may be a risk factor for the development of the disease [18], while human herpesvirus 6 (HHV-6) may be a risk factor for its exacerbation [19]. Indeed, influenza virus, adenovirususes, and herpes simplex virus have been associated with more frequent and severe relapses of MS [16]. Considering instead the relationship between coronaviruses (CoV) and MS, it has been experimentally proved that some strains of CoV have neuroinvasive and neurotrophic potentials. The virus may enter through hematogenous spread or intranasal inoculation, and from there trans-synaptically transfer across infected neurons [2].