Human Endogenous Retrovirus and Neuroinflammation in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

• A protein from endogenous retroviruses (8% of human genome) is found in chronic inflammatory demyelinating polyradiculoneuropathies (CIDP).
• Identified in multiple sclerosis, MSRV-Env induces inflammation and autoimmunity.
• It is now shown in peripheral nerve lesions, serum and blood cells of CIDP patients.
• In Schwann cells, it induces pro-inflammatory factors; the same is detected in serum.
• Antibody neutralization of MSRV-Env effects raises therapeutic perspectives in CIDP.Since the 1980's, a new horizon in the search for pathogenic players in complex human disease arose from studies in which human endogenous retrovirus families (HERV) were identified. HERVs represent 8% of the human genome and may express pathogenic proteins as shown here in a chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). The present study shows that MSRV-Env, an HERV protein, is detected in CIDP lesions and blood. It triggers inflammation in immune and nervous cells. A specific antibody revealed efficient in experimental conditions. This offers new therapeutic and diagnostic perspectives for this disabling disease without curative treatment.

BackgroundHuman endogenous retroviruses HERV-W encode a pro-inflammatory protein, named MSRV-Env from its original identification in Multiple Sclerosis. Though not detected in various neurological controls, MSRV-Env was found in patients with chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). This study investigated the expression of MSRV in CIDP and evaluated relevant MSRV-Env pathogenic effects.Methods50 CIDP patients, 19 other neurological controls (ONDs) and 65 healthy blood donors (HBDs) were recruited from two different countries. MSRV-env and -pol transcripts, IL6 and CXCL10 levels were quantified from blood samples. MSRV-Env immunohistology was performed in distal sensory nerves from CIDP and neurological controls biopsies. MSRV-Env pathogenic effects and mode of action were assayed in cultured primary human Schwann cells (HSCs).FindingsIn both cohorts, MSRV-env and -pol transcripts, IL6 positivity prevalence and CXCL10 levels were significantly elevated in CIDP patients when compared to HBDs and ONDs (statistically significant in all comparisons). MSRV-Env protein was detected in Schwann cells in 5/7 CIDP biopsies. HSC exposed to or transfected with MSRV-env presented a strong increase of IL6 and CXCL10 transcripts and protein secretion. These pathogenic effects on HSC were inhibited by GNbAC1, a highly specific and neutralizing humanized monoclonal antibody targeting MSRV-Env.InterpretationThe present study showed that MSRV-Env may trigger the release of critical immune mediators proposed as instrumental factors involved in the pathophysiology of CIDP. Significant MSRV-Env expression was detected in a significant proportion of patients with CIDP, in which it may play a role according to its presently observed effects on Schwann cells along with previously known effects on immune cells.Experimental results also suggest that a biomarker-driven therapeutic strategy targeting this protein with a neutralizing antibody such as GNbAC1 may offer new perspectives for treating CIDP patients with positive detection of MSRV-Env expression.FundingGeneuro-Innovation, France.