Abstract
Human endogenous retroviruses (HERVs) arise from ancient infections of the host germline cells by exogenous retroviruses, constituting 8% of the human genome. Elevated level of envelope transcripts from HERVs-W has been detected in CSF, plasma and brain tissues from patients with Multiple Sclerosis (MS), most of them from Xq22.3, 15q21.3, and 6q21 chromosomes. However, since the locus Xq22.3 (ERVWE2) lack the 5′ LTR promoter and the putative protein should be truncated due to a stop codon, we investigated the ERVWE2 genomic loci from 84 individuals, including MS patients with active HERV-W expression detected in PBMC. In addition, an automated search for promoter sequences in 20 kb nearby region of ERVWE2 reference sequence was performed. Several putative binding sites for cellular cofactors and enhancers were found, suggesting that transcription may occur via alternative promoters. However, ERVWE2 DNA sequencing of MS and healthy individuals revealed that all of them harbor a stop codon at site 39, undermining the expression of a full-length protein. Finally, since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we also investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG). Comparison of the MOG to the envelope identified five retroviral regions similar to the Ig-like domain of MOG. Interestingly, one of them includes T and B cell epitopes, capable to induce T effector functions and circulating Abs in rats. In sum, although no DNA substitutions that would link ERVWE2 to the MS pathogeny was found, the similarity between the envelope protein to MOG extends the idea that ERVEW2 may be involved on the immunopathogenesis of MS, maybe facilitating the MOG recognizing by the immune system. Although awaiting experimental evidences, the data presented here may expand the scope of the endogenous retroviruses involvement on MS pathogenesis.
Highlights
Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), but precise immunologic mechanisms involved in the induction and chronic course of MS are still poorly understood
Since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG)
Since the Human endogenous retroviruses (HERVs)-W envelope can work as autoantigen and hypothetically, serve as trigger for autoimmune disease, we evaluated the level of similarity between HERV-W envelope protein and the different isoforms of myelin basic protein (MBP) and MOG using Blastp tool
Summary
Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS), but precise immunologic mechanisms involved in the induction and chronic course of MS are still poorly understood. Epidemiological studies have shown both environmental and genetic factors to display an association with this disease. Genetic predisposition includes some familiar inherited risk, the association to the HLA class II DRB1∗1501 and DRB5∗0101 alleles in Caucasians (Gregersen et al, 2006) and an abnormal autoimmune reaction against the prominent CNS myelin antigens such as the myelin oligodendrocyte glycoprotein (MOG). Despite evidence of humoral and T cell-mediated responses to myelin basic protein (MBP) and MOG (Bernard and de Rosbo, 1991), unambiguous relationship between myelin reactivity and disease has yet to be demonstrated. Www.frontiersin.org do Olival et al. Endogenous retroviruses and multiple sclerosis
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