Mechanisms Behind EBV-Induced MS and Protective Factors

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Researchers Uncover the Mechanisms Behind EBV-Induced MS and Protective Factors

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Researchers Uncover the Mechanisms Behind EBV-Induced MS and Protective Factors

While scientists had noted a correlation between Epstein-Barr virus (EBV) infection and multiple sclerosis (MS) as early as 1980, it wasn’t until 2022 that a groundbreaking study shed light on the causal relationship between the two.

Initially, the connection seemed obscure given that over 90% of the global population has been infected with EBV in their first two years of life, compared to around 2.8 million MS patients worldwide. This statistical incongruity persisted for four decades.

In January 2020, researchers from Harvard University published a seminal study in “Science,” based on a 20-year tracking investigation involving over 10 million U.S. military personnel. Their findings revealed that individuals with EBV seropositivity had a 32-fold increased risk of being diagnosed with MS compared to those with EBV seronegativity. This marked the most extensive, comprehensive, and authoritative study to date, firmly establishing EBV infection as a necessary condition for MS.

Approximately two weeks later, scientists from Stanford University School of Medicine published a significant study in “Nature,” pinpointing a molecular mimicry and cross-immune reaction between EBV nuclear antigen fragments (EBNA386-405) and myelin sheath glial cell adhesion molecule fragments (GlialCAM370-389). This clarified, for the first time, the mechanistic link between EBV and MS. However, a lingering question remained: why do some individuals with specific EBV variants not develop MS?

Now, that question finds an answer.

A research team led by Hannes Vietzen from the Medical University of Vienna, Austria, published a groundbreaking study in the prestigious journal “Cell.”

They discovered that NKG2C-positive NK cells, responsible for regulating the body’s immune response, were impaired in MS patients. These cells inhibit GlialCAM-specific immune cells through the suppressive HLA-E/NKG2A axis, preventing them from causing harm. Notably, individuals with two specific EBV variants and the HLA-E∗0101 mutation faced a staggering 261.3-fold increased risk of developing MS.

In the study’s initial phase, the Vietzen team recruited 270 EBNA-1 seropositive MS patients and matched them with EBV seropositive healthy participants, all with over five years of follow-up. Analysis revealed elevated EBNA386-405-specific IgG antibody levels in all MS patients compared to the control group. However, 40% of healthy participants exhibited similar antibody levels.

Further dividing the control group into EBNA386-405-specific IgG high (EBNA-high) and low (EBNA-low) subgroups, the researchers found that high antibody levels induced GlialCAM370-389-specific antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC). These reactions were significantly higher in both MS patients and the EBNA-high subgroup compared to the EBNA-low group.

The study delved into the protective mechanisms, discovering that NK cells played a crucial role. NKG2C-positive and NKG2D-positive NK cells were activated when exposed to stress-induced GlialCAM370-389-specific T and B cells from individuals with dual EBV and human cytomegalovirus (HCMV) seropositivity, suggesting HCMV-induced NK cells might protect EBNA-high individuals.

Subsequent investigations revealed lower levels of NKG2C-positive NK cells in MS patients compared to both EBNA-high and EBNA-low control groups. The presence of HCMV-specific IgG antibodies was higher in the EBNA-high control group than in MS patients and the EBNA-low control group.

The researchers concluded that HCMV-induced cytotoxic NKG2C-positive NK cells protected EBNA-high individuals. However, this immune regulation was overall weak or absent in MS patients. Similar observations were made for NKG2D-positive NK cells.

Considering that NKG2C-positive and NKG2D-positive NK cells can eliminate GlialCAM370-389-specific immune cells, preventing damage to the myelin sheath, the study revealed that GlialCAM370-389-specific immune cells also had the capacity to resist this destruction. The researchers found higher HLA-E expression levels in GlialCAM370-389-specific immune cells of MS patients compared to both EBNA-high and EBNA-low control groups. HLA-E, by regulating the inhibitory NKG2A receptor, prevented the killing of GlialCAM370-389-specific immune cells.

Noteworthy was the correlation between the variability in Epstein-Barr virus latent membrane protein 1 (LMP-1) and HLA-E expression. In the control groups, LMP-1 displayed higher diversity, while MS patients exhibited limited diversity, featuring higher frequencies of GGDPHLPTL and GGDPPLPTL variants. These variants further elevated HLA-E expression, intensifying the suppressive effect.

In the final phase of the study, the researchers explored the relationship between HLA-E variants and MS. They found a higher proportion of HLA-E∗0103/0103 variants in the EBNA-high control group, whereas HLA-E∗0101/0103 and HLA-E∗0101 variants predominated in MS patients and the EBNA-low control group. Specifically, HLA-E∗0103 was associated with reduced MS risk, while HLA-E∗0101 increased the risk.

Based on these findings, the Vietzen team investigated whether specific factor combinations could predict MS risk in individuals with high EBNA-1 antibody levels. The study suggested that if the individual was infected with an EBV variant of LMP-1 with GGDPHLPTL and GGDPPLPTL variants, and if the person had the HLA-E∗0101 allele, their risk of developing MS increased by 261.3 times.

In summary, the study by the Vietzen team provides a detailed exploration of the mechanisms behind EBV-induced MS from both viral infection and genetic background perspectives. It reaffirms the existence of a cross-immune reaction between EBNA and GlialCAM, with HCMV-induced NKG2C-positive NK cells potentially playing a key protective role. Additionally, EBV virus subtypes and host genetic backgrounds impact the occurrence of MS.

These findings enhance our understanding of the pathogenesis of MS and point towards directions for its prevention and treatment.

Researchers Uncover the Mechanisms Behind EBV-Induced MS and Protective Factors

References:

[1] Bjornevik K, Münz C, Cohen JI, Ascherio A. Epstein-Barr virus as a leading cause of multiple sclerosis: mechanisms and implications. Nat Rev Neurol. 2023;19(3):160-171. doi:10.1038/s41582-023-00775-5

[2] Soldan SS, Lieberman PM. Epstein-Barr virus and multiple sclerosis. Nat Rev Microbiol. 2023;21(1):51-64. doi:10.1038/s41579-022-00770-5

[3] Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222

[4] Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321-327. doi:10.1038/s41586-022-04432-7

[5] Vietzen et al., Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis. Cell. 2023. doi:10.1016/j.cell.2023.11.015

[6] Fowler K, Mucha J, Neumann M, et al. A systematic literature review of the global seroprevalence of cytomegalovirus: possible implications for treatment, screening, and vaccine development. BMC Public Health. 2022;22(1):1659. Published 2022 Sep 1. doi:10.1186/s12889-022-13971-7

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