Beyond this fundamental research context independent studies

Beyond this fundamental research context, independent studies confirmed an association of MSRV expression with MS (Perron et al., 2012; Sotgiu et al., 2010). Its envelope protein (MSRV-Env) was shown to elicit pro-inflammatory and autoimmune responses in immune mglur antagonist (Perron et al., 2001, 2013; Rolland et al., 2006) and to impair remyelination by oligodendrocyte precursor cells (OPCs) (Kremer et al., 2013), suggesting its involvement in MS pathogenesis (Perron et al., 2012; Kremer et al., 2014; Madeira et al., 2016). Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune disease of the peripheral nervous system (PNS), with multifocal inflammatory and demyelinating lesions in nerve roots also expanding to distal regions (Vallat et al., 2010). Its clinical presentation is heterogeneous and its diagnosis is challenging without known etiology or specific biomarkers (Dalakas, 2011; Anon., 2008, 2010; Koller et al., 2005). CIDP therapies are intravenous human immunoglobulins (IVIG), corticosteroids or plasma exchange. Long-term therapy is often limited by side effects and one-third of patients are refractory to existing treatments (Latov, 2014), which illustrates the unmet need for diagnostic biomarkers and innovative treatments of CIDP. In a previous study on MS, MSRV-Env was not detected in healthy controls and in various other Neurological Diseases except for CIDP cases (5/8) (Perron et al., 2012). This observation prompted the present study to investigate a potential association of this endogenous HERV-W element with CIDP. Its results have confirmed significant MSRV expression in CIDP, have demonstrated the pathogenic effects of MSRV-Env on human Schwann cells (HSC) and their inhibition by GNbAC1, a neutralizing and highly specific humanized antibody targeting this MSRV-Env endogenous protein.
Patients and Methods
Results
Discussion After initial detection of HERV-W protein, MSRV-Env, in CIDP cases within a control group of inflammatory neurological diseases for a study on MS (Perron et al., 2012), the present study confirms an association between MSRV-Env expression and CIDP. This is now supported by significantly upregulated MSRV-env mRNA transcription in PBMC, by MSRV-Env protein detection in CIDP peripheral nerve lesions with dominant expression in Schwan cells and, with evidence of its target receptor TLR4 on HSC, by direct pro-inflammatory effects of MSRV-Env iducing IL6 and CXCL10 release from HSC. Overall, about half of the CIDP patients showed a High Expression profile for MSRV env or pol. But considering subjects presenting a HE profile for at least one MSRV transcript, up to 65% were found in CIDP population when only 12% in HBDs and 17% in ONDs. Since env- and pol-encoded proteins are expressed from different mRNAs (Blond et al., 1999), their correlated upregulation in CIDPs also indicates that MSRV genome and/or HERV-W related elements are globally upregulated but also confirm the specificity of coincident results with two different HERV-W genes. MSRV-Env has for long been shown to induce innate immune dysregulation, autoimmunity and inflammation in cellular and animal models (Perron et al., 2001, 2013; Rolland et al., 2006). TLR4 activation revealed to be a prerequisite for the activation of cytopathogenic pathways and physiopathological cascades by this endogenous protein and, as a consequence of its expression, pro-inflammatory cytokines and chemokines have regularly been evidenced (Rolland et al., 2006; Kremer et al., 2013; Madeira et al., 2016; Duperray et al., 2015). In the present study two relevant ones for CIDP and Schwann cells, IL-6 and CXCL10, were studied. Unlike available previous studies having investigated IL6 in sera of CIDP patients (Maimone et al., 1993; Sainaghi et al., 2010), we found elevated IL6 and CXCL10 levels in CIDP serum when compared to HBDs, without confounding correlation with age and gender. These diverging findings can easily be understood when considering that our study showed detectable levels of IL6 in about 30% of 47 CIDP sera, whereas these previous works having tested 7 or 8 patients only had the greatest probability not to include a single case with detectable level. CXCL10, a chemokine known as a chemoattractant for macrophages and T cells (Xuan et al., 2014) was previously detected in the CSF of CIDP patients in correlation to the degree of inflammation in proximal segments of spinal nerve roots and to blood nerve barrier damages (Kieseier et al., 2002; Mahad et al., 2002), and was also detected in CIDP lesions (Kieseier et al., 2002). Similarly, IL6 was detected in the CSF (Maimone et al., 1993) and in sural nerve biopsies of CIDP patients (Lindenlaub and Sommer, 2003; Yamamoto et al., 2002). Additionally, Schwann cells can produce CXCL10 (Medeiros et al., 2015), as well as IL6 (Lu et al., 2009), most particularly after exposure to LPS, a TLR4 agonist like MSRV-Env (de Leseleuc et al., 2013). The present study with HSC cultures shown to be TLR4-positive, exposed to or expressing MSRV-Env, demonstrated a potent induction of both IL6 and CXCL10. As in previous studies on MSRV-Env pathogenic mode of action (Rolland et al., 2006; Kremer et al., 2013; Madeira et al., 2016; Duperray et al., 2015), a specific TLR4-driven effect was also confirmed in HSC with the observed inhibition of MSRV-Env effects by LPS-RS, a competitive TLR4 antagonist. Thus, MSRV-Env can directly trigger HSC to release pro-inflammatory effectors through TLR4 activation and signaling pathways.