Immune response profiling of HERV-W envelope proteins in multiple sclerosis: potential biomarkers for disease progression

Introduction: The envelope proteins syncytin-1 and pHERV-W from the Human Endogenous Retroviral family ‘W’ (HERV-W) have been identified as potential risk factors in multiple sclerosis (MS). This study aims to evaluate both humoral and cell-mediated immune response to antigenic peptides derived from these proteins across different clinical forms and inflammatory phases of MS. Methods: Indirect enzyme-linked immunosorbent assay (ELISA) was employed to measure immunoglobulin G (IgG) responses to syncytin-1env 486-500 and pHERV-Wenv 486-504 peptides in MS patients. Discriminant analysis was used to assess whether clinical course prediction could be enhanced by integrating clinical variables with humoral response data against other MS-associated viral factors. Additionally, peripheral blood mononuclear cells from MS patients and healthy controls (HC) were analyzed for inflammatory responses following stimulation with these peptides. Results: MS patients exhibited significantly elevated antibody titers against -pHERV-Wenv 486-504 and syncytin-1env 486-500 compared to HCs, with the highest levels observed in progressive MS forms. Discriminant analysis accurately predicted the clinical course in 75.3% of the cases, with an 85% accuracy rate for progressive MS. In vitro, stimulation with pHERV-Wenv 486-504 led to a notable increase in pro-inflammatory cytokine production by CD4, CD8, and CD19 cells compared to syncytin-1env 486-500. A strong correlation was found between pHERV- Wenv 486-504 induced cytokine production and EBV and CMV titers in MS patients. Discussion: These findings suggest that the pHERV-W envelope protein could be a valuable biomarker for monitoring peripheral inflammation in MS.