Human endogenous retroviruses and multiple sclerosis

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Several HERVs (-W, -K, -H) and multiple pathogenic mechanisms have been described in association with MS [14]. Studies on RNA associated with viral particles in leptomeningeal, choroids plexus or B-lymphocyte cultures from patients who have multiple sclerosis have found sequences corresponding to overlapping regions of a retroviral genome that was named MSRV (multiple sclerosis-associated retrovirus virions) [36]. MSRV has genetically high homologous counterparts in normal human DNA, the HERV-W family [37]. Independent studies have confirmed an association of MSRV virion RNA with the temporal and clinical progression of MS [38], and differential MSRV/HERV-W RNA levels between MS and controls were reported in lymphoid cells [39].

Subsequent studies showed that the Env protein of HERV-K18 has superantigen activity in vitro strongly activating T cells and that this SAg activity could be reproduced with the use of a recombinant MSRV Env protein [40].

HERV-W Gag and Env proteins are induced by human herpes simplex (HSV)-1 [41,42] in neuronal and endothelial cells in vitro. The transactivation of HERV-W proteins by HSV-1 could enhance their potential oligodendro-toxic and immunopathogenic effects [42]. Epstein-Barr virus (EBV) infection of B cells also leads to transactivation of HERV-K18 env alleles that express a TCRVb13-specific SAg activity previously identified as an EBV-associated superantigen [9].

To test the pathogenicity of MSRV retroviral particles in vivo, severe combined immunodeficiency (SCID) mice grafted with human lymphocytes were injected intraperitoneally with MSRV virion. These mice developed acute neurologic symptoms and died within 5 to 10 days post injection. By RT-PCR circulating MSRV RNA was detected in serum and overexpression of proinflammatory cytokines in spleen. Necropsy revealed disseminated and major brain hemorrhages that occurred before death in multifocal areas of brain parenchyma and meninges. Interestingly, when MSRV virion was inoculated to SCID mice grafted with T lymphocyte-depleted cells a dramatic reduction in the number of affected mice was observed [43]. A different group confirmed that HERV-W Env (syncytin) is upregulated in glial cells within acute demyelinating lesions of patients who had multiple sclerosis and that conditioned medium of human fetal as-trocytes in which an HERV-W Env construct was expressed is cytotoxic to human and rat oligodendrocytes. Even more, syncytin-mediated neuroinflammation and death of oligodendrocytes were prevented by the antioxi-dant ferulic acid in a mouse model of multiple sclerosis [44].

Another recent study showed that there is a physiologic expression of an HERV-W Env in human brain that mainly is associated with infiltrating lymphoid cells or brain macrophages, whereas expression of HERV-W Gag antigens is observed in neurons (cell body, axons, dendrites). In contrast to this, an MS-specific Gag and Env pattern was described in which these antigens were detected essentially at the level of endothelial and microglial cells. Within demyelinated lesions Gag antigen accumulated in dystrophic axons [45]. Moreover, HERV-W Env can activate the innate immune system through a TLR4/CD14-dependent pathway; therefore it can induce human monocytes to produce major proinflammatory cytokines in a CD14-and TLR4-dependent fashion, induce DC maturation, and confer the capacity to support a Th1-type of T-cell differentiation [15].

In vitro, proinflammatory cytokines that are detrimental in MS, TNF-a, and IFN-g have been shown to stimulate the release of MSRV by PBMCs, whereas IFN-P blocked virus release [46]. Conversely, the surface unit of MSRV envelope protein also was shown to mediate an increase of IL-6 and IL-12p40 production by the PBMC from patients who have MS and to promote the development of naive CD4+ CD45RA T cells into IFN-g-secreting Th1-like cells. The cytokine release correlates with disease severity [47], and it has been proposed that IL-6, which in particular is produced in a TLR4-dependent manner [15], renders naive CD4+ T cells insensitive to the suppressive activity of CD4+ CD25 T reg, and therefore facilitates the priming of autoreactive T cells [48]. Taken together these data suggest a loop involving inflammation that increases MSRV, which in turn and because of their gliotoxic and superantigenic properties expands the original mechanism. The demonstration of HERV-H virions in the blood of patients who have MS and increased levels of HERV-H and HERV-K RNA levels in brain tissue and a humoral response with elevated levels of antibodies toward HERV-W in serum and HERV-H in CSF is further evidence of a role for HERV in MS [49]. Antibodies with reactivity to HERV are produced locally in MS CSF and reactivity is mainly toward gammaretroviral HERV or similar epitopes [14].

Studies comparing the proliferation of PBMCs after stimulation with MS virions or HERV-H peptides alone or in combination with HERV antigens revealed a synergistic effect on the proliferative response when both antigens were combined [14,50].

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