Abstract
BackgroundMultiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested.ResultsMSRV transcription levels were higher in MS patients than in controls (U-Mann–Whitney; p = 0.004). Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [χ2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann–Whitney; p = 0.039) or TT patients (U-Mann–Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann–Whitney; p = 0.003).ConclusionsOur present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS.
Highlights
Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men
MS patients presented higher Multiple Sclerosis Associated Retrovirus (MSRV) RNA levels compared to controls (U-Mann– Whitney; p = 0.004) (Figure 1A)
We found a correlation with the clinical forms (Spearman’s rho = 0.28; p = 0.0003) and lower levels of MSRV expression were found in blood donors (BD) than in relapsing-remitting (RR) MS patients (U-Mann–Whitney; p = 0.005) or secondary-progressive (SP) patients (U-Mann–Whitney; p = 0.005) (Figure 1B)
Summary
Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Human endogenous retroviruses (HERVs) are believed to be remnants of ancient exogenous infections. They entered the germ line during primate evolution and as retroviruses were able to replicate and retrotranspose, increasing their copy number and spreading all over the genome. Most of the HERV proviruses have undergone extensive mutations and are unable to replicate Nowadays, they reside in the genome of all human cells and are transmitted in Mendelian fashion. Some HERVs have retained open reading frames (ORFs) putatively encoding functional proteins. These proteins can display a physiological role, as Syncytin-1 which is involved in the formation of the syncytiotrophoblast during pregnancy [2]; but as viral products, they might show antigenic properties involving the immune system. HERVs RNAs, proteins or virions have been found in different tumor tissues [3,4,5,6,7], in schizophrenia [8,9,10], rheumatoid arthritis [11] and especially in multiple sclerosis (MS) [12,13]
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