Trends Mol Med. 2016 Nov 8. pii: S1471-4914(16)30149-6. doi: 10.1016/j.molmed.2016.10.007. [Epub ahead of print]
EBV Infection and Multiple Sclerosis: Lessons from a Marmoset Model.
Multiple sclerosis (MS) is thought to be initiated by the interaction of genetic and environmental factors, eliciting an autoimmune attack on the central nervous system. Epstein-Barr virus (EBV) is the strongest infectious risk factor, but an explanation for the paradox between high infection prevalence and low MS incidence remains elusive. We discuss new data using marmosets with experimental autoimmune encephalomyelitis (EAE) – a valid primate model of MS. The findings may help to explain how a common infection can contribute to the pathogenesis of MS. We propose that EBV infection induces citrullination of peptides in conjunction with autophagy during antigen processing, endowing B cells with the capacity to cross-present autoantigen to CD8+CD56+ T cells, thereby leading to MS progression.
Our biggest pathogenic contender to date for causing MS is EBV (Epstein-Barr virus), closely followed by endogenous retroviruses and HHV-6 (Human herpes virus-6). But trying to prove this has been no mean feat, as MS-EBV association studies in people are hampered by the fact that difference between the prevalence of EBV in MS (100%) and the healthy (>90%) population is small. Therefore, scientists need to come up with more inventive ways of studying disease associations, which is where animal models come in.
Marmosets evolutionarily are ~ 50 million years in proximity to humans, sharing both genetic and immunological similarities. Like us they’re exposed from birth to pathogens, creating a similar pathogen-educated immune system that may present us with the answer that we’re seeking.
To date, the autoimmune hypothesis around MS is basically attributed to T cells; for instance, crossreactive CD4+ Tcells recognising EBV and myelin epitopes as one and the same (resulting in the proinflammtory targeting of myelin and demyelination). What about B cells? ‘tHart et al. argue using evidence from the marmoset model, that B cells infected with the virus may endow them with the capacity to activate self aggressive CD8+ T cells already present in our immune repertoires (normal B cells are less capable of doing this). Moreover, they state that the frequency of human B cells that actually contain the virus is small (<0.01%) , which may explain the low frequency of MS in the population despite the high prevalence of EBV! And, that is how a new hypothesis is born.