EBV Increases MS Risk

[NHE]

Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis
Cell. 2023 Dec 21;186(26):5705-5718.

Highlights:

• Control of autoimmunity by NKG2C+ NK cell responses is severely impaired in MS patients

• MS-patient-derived GlialCAM-specific cells evade control via inhibitory HLA-E/NKG2A axis

• MS patients are predominantly infected with EBV variants that highly upregulate HLA-E

• Specific cytotoxic T cell responses can control EBV-infected GlialCAM-specific B cells

Abstract:

Multiple sclerosis (MS) is a demyelinating disease of the CNS. Epstein-Barr virus (EBV) contributes to the MS pathogenesis because high levels of EBV EBNA386-405-specific antibodies cross react with the CNS-derived GlialCAM370-389. However, it is unclear why only some individuals with such high autoreactive antibody titers develop MS. Here, we show that autoreactive cells are eliminated by distinct immune responses, which are determined by genetic variations of the host, as well as of the infecting EBV and human cytomegalovirus (HCMV). We demonstrate that potent cytotoxic NKG2C+ and NKG2D+ natural killer (NK) cells and distinct EBV-specific T cell responses kill autoreactive GlialCAM370-389-specific cells. Furthermore, immune evasion of these autoreactive cells was induced by EBV-variant-specific upregulation of the immunomodulatory HLA-E. These defined virus and host genetic pre-dispositions are associated with an up to 260-fold increased risk of MS. Our findings thus allow the early identification of patients at risk for MS and suggest additional therapeutic options against MS.

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