Potential association between Epstein-Barr virus infection and myasthenia gravis

Epstein-Barr virus (EBV) has been implicated in multiple autoimmune disorders; however, its role in myasthenia gravis (MG) remains incompletely defined. We investigated EBV nuclear antigen 1 (EBNA-1)-specific humoral immunity in MG and examined whether human leukocyte antigen (HLA) genotypes modulate this association.

Serum anti-EBNA-1 IgG levels were measured in 106 treatment-naïve MG patients and 230 healthy controls (HCs). An independent MG cohort (n = 244) underwent whole-genome sequencing for HLA genotyping, with 44 treatment-naïve patients also tested for anti-EBNA-1 IgG.

MG patients showed higher proportions of anti-EBNA-1 IgG levels above the upper detection limit (>600 U/mL) compared with age- and sex-matched HCs (67% vs. 50%, p = 0.082). Among individuals with detectable antibody levels (3-600 U/mL), MG patients exhibited significantly higher titers than matched HCs (306.0 [181.5-391.0] vs. 157.0 [92.4-250.0] U/mL, p = 0.0065). No significant associations were found between anti-EBNA-1 IgG levels and MG clinical phenotypes. HLA association analyses identified the HLA-DRB4*01:03^-/DRB3*02:02⁺ genotype as a significant genetic risk factor for generalized MG versus ocular MG (OR 2.59, 95% CI 1.29-5.21, p = 0.01). Among patients who were tested for both HLA and anti-EBNA-1 IgG and had anti-EBNA-1 IgG levels >600 U/mL, ocular MG patients carried HLA DRB4*01:03 more frequently than generalized MG patients (81.8% vs. 23.5%, p = 0.006).

Our findings suggest a potential association between EBV-specific immune responses and MG. Furthermore, the HLA-DRB4*01:03-/DRB3*02:02+ genotype may confer susceptibility to generalized MG, supporting an interaction between EBV infection and host genetics in MG pathogenesis.