The retrovirus/superantigen hypothesis of multiple sclerosis

Abstract

The pathogenesis of multiple sclerosis (MS) is as yet unknown. Commonly, MS is assumed to be due to an autoimmune inflammation of the central nervous system (CNS). Neurodegeneration is regarded to be a secondary reaction. This concept is increasingly being challenged. Human endogenous retroviruses (HERV) that could be locally activated in the CNS have been proposed as an alternative concept. HERV-encoded envelope proteins (env) can act as strong immune stimulators (superantigens). Thus, slow disease progression following neurodegeneration might be induced by re-activation of HERV expression directly, while relapses in parallel to inflammation might be secondary to the expression of HERV-encoded superantigens. It has been shown previously that T-cell superantigens are capable to induce a cellular inflammatory reaction in the CNS of experimental animals similar to that in MS. Furthermore, B-cell superantigens have been shown to activate blood leucocytes in vitro to produce immunoglobulin in an oligoclonal manner. It remains to be established, whether the outlined hypothesis accords with all known features of MS. Furthermore, anti-HERV agents may be taken into consideration to enrich and improve MS therapy.

Fig. 1

A model for HERV/superantigen mediated neurodegeneration and neuroinflammation. HERVs constitute an integral part of our genome. Under normal conditions, expression of HERVs is switched off epigenetically (0). Triggered by diverse factors (see Table 1), reactivation of HERVs expression can be induced (1). The majority of HERV-encoded RNAs contain point mutations and deletions that hinder synthesis of HERV-encoded proteins. Such RNAs might be involved in dysregulation of RNA metabolism (2). HERV-encoded RNAs with intact open reading frames can be translated into proteins (3). In rare cases, complete virions can be formed (4) which might have direct cytopathic effect. In addition, single proteins can act as antigens or superantigens for T cell stimulation (5). Such superantigens can lead to depletion of V beta families but also to activation of proliferation of oligoclonal T cells (6). Activated T cells secrete cytokines which can lead to immune dysregulation (7). In addition, activated T cells might be able to interact and kill other cells including the superantigen expressing cells (8). However, bystander cell killing can be independent from the expression of the superantigen which was responsible for the induction of the immune response (9)