Abstract
Multiple sclerosis (MS) is a complex multifactorial disease of the central nervous system (CNS) for which animal models have mainly addressed downstream immunopathology but not potential inducers of autoimmunity. In the absence of a pathogen known to cause neuroinflammation in MS, Mycobacterial lysate is commonly used in the form of complete Freund's adjuvant to induce autoimmunity to myelin proteins in Experimental Allergic Encephalomyelitis (EAE), an animal model for MS. The present study demonstrates that a protein from the human endogenous retrovirus HERV-W family (MSRV-Env) can be used instead of mycobacterial lysate to induce autoimmunity and EAE in mice injected with MOG, with typical anti-myelin response and CNS lesions normally seen in this model. MSRV-Env was shown to induce proinflammatory response in human macrophage cells through TLR4 activation pathway. The present results demonstrate a similar activation of murine dendritic cells and show the ability of MSRV-Env to trigger EAE in mice. In previous studies, MSRV-Env protein was reproducibly detected in MS brain lesions within microglia and perivascular macrophages. The present results are therefore likely to provide a model for MS, in which the upstream adjuvant triggering neuroinflammation is the one detected in MS active lesions. This model now allows pre-clinical studies with therapeutic agents targeting this endogenous retroviral protein in MS.
Highlights
Multiple sclerosis is a complex multifactorial disease of the central nervous system, which involves environmental factors and genetic susceptibility as upstream factors [1]
The present study demonstrates that Multiple Sclerosis associated RetroViral element (MSRV)-envelope protein (Env) protein from the human endogenous retroviruses (HERV)-W family is efficient in inducing EAE in C57/BL6 mice when administered in emulsion together with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55
To determine whether MSRV-Env-surface domain (SU) stimulated phenotypic changes associated with dendritic cell (DC) maturation, flow cytometry analyses were performed for the expression of CD11c and MHC class II (MHCII) by primary DC derived from bone marrow of mice
Summary
Multiple sclerosis is a complex multifactorial disease of the central nervous system, which involves environmental factors and genetic susceptibility as upstream factors [1]. As no ‘‘upstream’’ pathogen responsible for the induction of demyelinating neuroinflammatory lesions of MS had been identified, a ‘‘heterologous’’ pathogen extract, i.e. mycobacterial lysate with peculiar immunoadjuvant properties capable of promoting auto-immunity against artificially presented myelin antigens, has been used in the form of mineral oil suspension designated as ‘complete Freund’s adjuvant’ -CFA[7,8]. This has permitted the elucidation of many immunological functions that could lead to immune-mediated demyelination and, has delineated the therapeutic scope for MS within the boundaries of immunological effectors [9,10,11]. The great majority of them are inactivated by genetic alterations and the few potentially active elements with open reading frames (orf) are usually epigenetically silenced, non-physiological expression of retroviral genes and particles have been reported in several human diseases [19]
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