Table 1.
Selection of studies investigating the role of infectious factors in MS.
| MS | ||
|---|---|---|
| Infectious Agent | Evidence | References |
| EBV | Definitively established association between EBV infection and MS onset in a wide cohort study | [21] |
| High titers of anti-EBNA and VCA antibodies are observed in patients with MS | [25,26,27] | |
| EBV is a necessary causative agent in the pathogenesis of MS | [28] | |
| Serum titers of pre-onset anti-EBNA antibodies are strong markers of MS | [29] | |
| EBNA-1 recognized by MS patient sera induces signs of EAE in a murine model | [30] | |
| EBNA-1 peptides are cross recognized by anti-MBP antibodies | [31] | |
| Immunoreactivity against EBV proteins BRRF2 and EBNA-1 is higher in MS; OCBs belonging to MS patients bound both EBV proteins | [32] | |
| OCBs in CSF belonging to MS patients are able to bind EBNA-1 and EBNA-2 epitopes | [33] | |
| There is high-affinity molecular mimicry between EBNA-1 and GlialCAM in MS | [34] | |
| High titers of anti-EBNA increase the risk of MS and are observed between 15 and 20 years before the onset of the disease | [35] | |
| The risk of MS is notably increased after infectious mononucleosis | [36] | |
| There is evidence of EBV infection in brain-infiltrating B cells and plasma cells in MS | [37] | |
| Mutations in EBNA-2 could influence the host response to EBV | [38] | |
| HLA-DRB1*15:01 acts as coreceptor for EBV infection of B cells | [39] | |
| Specific EBNA-1 antibodies and HLA-DRB1*1501 interact in the MS risk | [40] | |
| EBNA-3 blocks the activation of vitamin D receptor-dependent genes | [41] | |
| EBNA-1 antibodies correlate with radiological disease activity | [42,43] | |
| The cellular immune response to EBV decreases during ocrelizumab treatment | [44] | |
| Teriflunomide inhibits cellular proliferation in EBV-transformed B cells | [45] | |
| HERV | The envelope protein of HERV-W has been detected in serum, brain, perivascular infiltrates and macrophages of patients with MS | [46,47,48] |
| HERV mRNA has been found in the brain lesions, CSF and blood cells of individuals with MS | [49,50] | |
| The expression of HERV is increased in patients with active MS | [51,52] | |
| There is evidence of molecular mimicry between HERV-W envelope protein and myelin proteins | [53] | |
| HERV may activate the host immune response by acting as an agonist of human toll-like receptor 4 | [54] | |
| The HERV-H envelope and gag proteins have been reported to be present in the serum of MS patients | [55] | |
| HERV-W could act as effector in MS pathogenesis through its activation during EBV infection | [56] | |
| EBV transactivates the HERV-K18 that encodes a superantigen | [57] | |
| HERV-W DNA copy number was found to be higher in MS patients and was inversely correlated with vitamin D level | [58] | |
| Interferon beta may decrease the expression of HERV-W | [59] | |
| Natalizumab inhibits the expression of HERV-W | [60] | |
| A new drug tested in a phase II clinical trial for MS, known as GNbAC1, is able to block the HERV-W-dependent inflammatory cascade | [61,62] | |
| HHV-6 | OCBs specific against HHV-6 have been identified in patients with MS | [63] |
| Pro-inflammatory cytokines are higher in HHV-6 infected patients and HHV-6 positivity is associated with higher disability | [64] | |
| Anti-HHV-6 IgG titers significantly predict subsequent relapse risk in MS | [65] | |
| The lymphoproliferative response to HHV-6A is increased in MS | [66] | |
| There is an increased prevalence of HHV-6A in MS | [67] | |
| MBP cross-reacts with HHV-6 antigens; thus, there is evidence of a molecular mimicry | [68] | |
| Increased serological response against HHV-6A is associated with the risk of MS | [69] | |
| There is an interaction between environmental factors and high titers of anti-HHV-6A antibodies in the risk of MS | [70] | |
| HHV-6A is a risk factor for MS | [71] | |
| Gut Microbiota | Gut bacteria from patients with MS have pro-inflammatory properties | [72] |
| Disease-modifying therapies alter gut microbial composition in MS | [73] | |
| Interferon beta can cause an increase in Prevotella | [74] | |
| Gut microbiota differs from MS and controls. Enterobacteriaceae and several Clostridium species are associated with progressive course and disability | [75] | |
| There is an alteration of gut microbiota in MS patients, with an over-representation of Saccharomyces and Aspergillus | [76] | |
| Fungi | First evidence of fungal infection in CNS tissue of MS patients, with detection of fungal DNA | [77] |
| The specific enzyme activity of Candida albicans is greater in MS patients and correlates with disease severity | [78] | |
| Fungal antigens and antibodies against several Candida species have been detected in CSF of MS patients | [79] | |
| Calprotectin levels in the CSF reflect disease activity | [80] | |
| Some improvement in MS symptoms was observed in MS patients after treatment with antifungal drugs | [81] | |
| MAP | MAP peptides are cross-recognized by anti-MBP antibodies | [31] |
| MAP is associated with MS in Sardinian population | [82,83] | |
| MAP is associated with MS in Japanese population | [84] | |
| Epitopes of MAP2694 homologous to TCR are highly recognized in MS | [85] | |
| Human IRF 5 homologous epitopes of MAP induce a specific immune response | [86] | |
| There is no association between the haplotypes predisposing to MS and MAP positivity | [87] | |
| CMV | CMV can intensify the symptoms in MS patients | [88] |
| CMV seropositivity is negatively associated with MS | [89,90] | |
MS: multiple sclerosis; EBV: Epstein–Barr virus; EBNA: Epstein–Barr nuclear antigen; VCA: viral capsid antigen; EAE: experimental autoimmune encephalomyelitis; OCBs: oligoclonal bands; MBP: myelin basic protein; CSF: cerebrospinal fluid; HERV: human endogenous retrovirus; HHV: herpes human virus; CNS: central nervous system; MAP: mycobacterium avium paratuberculosis; IRF: interferon regulatory factor; CMV: cytomegalovirus.