Multiple sclerosis: an example of pathogenic viral interaction?
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REVIEW
Open Access
Multiple sclerosis: an example of pathogenic viral interaction? Walter Fierz
Abstract A hypothesis is formulated on viral interaction between HHV-6A and EBV as a pathogenic mechanism in Multiple Sclerosis (MS). Evidence of molecular and genetic mechanisms suggests a link between HHV-6A infection and EBV activation in the brain of MS patients leading to intrathecal B-cell transformation. Consequent T-cell immune response against the EBV-infected cells is postulated as a pathogenic basis for inflammatory lesion formation in the brain of susceptible individuals. A further link between HHV-6A and EBV involves their induction of expression of the human endogenous retrovirus HERV-K18-encoded superantigen. Such virally induced T-cell responses might secondarily also lead to local autoimmune phenomena. Finally, research recommendations are formulated for substantiating the hypothesis on several levels: epidemiologically, genetically, and viral expression in the brain. Keywords: Multiple Sclerosis, HHV-6A, EBV, EBNA-2, LMP1, MHC2TA, RBPJ-kappa, Syncytin-1, HERV-K18
Background The role of viral interactions in pathogenesis has been reported for several human diseases. Examples are coinfection with HCV and HIV [1] or other hepatitis viruses [2] as well as with HIV and HHV-6 [3] or HHV-7 [4]. For a long time a viral aetiology of Multiple Sclerosis (MS) has been suspected und discussed. Evidence for it has often been circumstantial and sometimes not reproducible. However, in the past 20 to 30 years the importance of two viruses for MS has stood the test of time and recent reviews have summarized the evidence for their aetiological role in MS – Human Herpes Virus 6A (HHV6A) [5] and Epstein Barr Virus (EBV) [6, 7]. The hypothesis on a viral interaction between HHV-6A and EBV as a pathogenic mechanism in multiple sclerosis (MS) has first been formulated by the author in 2004 [8]. However, a possible connection between the two herpes viruses has not been further studied in detail so far. Here, it will be argued that that the involvement of two different herpes viruses in MS is not circumstantial but fundamental to the aetio-pathogenetic processes in MS. This view could partly explain why two highly prevalent viruses are causing a relatively rare disease. First, some of the pertinent evidence for the involvement of the two viruses in MS will Correspondence: [email protected] labormedizinisches zentrum Dr Risch, Landstr. 157, 9494 Schaan, Fürstentum, Liechtenstein
be summarized, and then the pieces of the puzzles will be put together in sight of new evidence supporting the picture.
HHV-6A An important fact is that all evidence relating MS to HHV-6 involves HHV-6A but not HHV-6B, two quite different herpes viruses [9]. Leibovitch & Jacobson (2014) have recently reviewed the role of HHV-6A in MS [5]. The basic concept is that HHV-6A is a neurotropic virus infecting the astrocytes of MS-patients [10]. The active replication of HHV-6A in MS patients correlates with a polymorphism of MHC2TA (rs4774C) [11], a g
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