Hypothesis Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis, 2023, Vietzen et al.

[Midnattsol]

I wasn't sure what prefix to use given that the paper has been accepted in Cell but not published. I read about it in a paywalled news article as the abstract was presented at the ECTRIMS 2023.

Ineffective Immune Control of Epstein-Barr Virus-Induced Autoreactive Responses is an Important Cause of Multiple Sclerosis

The news article says the following of their work:

- Claim to be able to predict people with 260x the risk of developing MS
- They've used blood samples from people who have developed MS following EBV infections, and controls who have not developed MS following EBV infection
- Most of those who developed MS had high expression levels of EBNA1, this was also seen in some of the participants that did not develop MS
- They compared genetic markers, immune cells and the reaction towards cytomegalovirus

The hypothesis is presented thus by Andreas Lossius, one of the Norwegian participants at ECTRIMS (translation by me):
"The hypothesis, without getting a good insight of the study through the abstract or presentation, is that the imagine that autoimmune B-cells that produce antibodies towards the glial adhesion molecule are killed by other immune cells in persons that do not develop MS, but in those that do develop MS this does not happen"

Paywalled article (in Norwegian): https://www.dagensmedisin.no/ebv-ec...heten-av-funnene-sier-norske-eksperter/592562

Edit: The article is now published, see post #5

 

[Arvo]

I wasn't sure what prefix to use given that the paper has been accepted in Cell but not published.

That would be "in print"
(if I understand correctly that you mean that the paper has been accepted but not yet published by Cell)

And what an interesting study!

 

[Amw66]

I think the long term mono study could throw up potentially interesting correlations if it could be funded for intermittent followups over a long time.

 

[EndME]

Sounds interesting, thanks for sharing. Let’s see what the paper will really entail (scientific news reports are of course highly unreliable and very clickbaity).

I couldn’t find a google scholar account, but Thomas Berger has a ResearchGate account https://www.researchgate.net/profile/Thomas-Berger-19/research.

Whilst I can’t read the news article, this was the programme of the conference https://apps.congrex.com/ectrims2023/en-GB/pag. There are quite a few names even familar to me in the EBV-MS field (Alberto Ascherio, William Robinson), so I guess it has to be quite a big conference. Thomas Berger gave a very short talk titled “Ineffective Immune Control of Epstein-Barr Virus-Induced Autoreactive Responses is an Important Cause of Multiple Sclerosis” in the session “Late Breaking Abstracts”.

 

[SNT Gatchaman]

Merged thread

Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis
Hannes Vietzen; Sarah M. Berger; Laura M. Kühner; Philippe L. Furlano; Gabriel Bsteh; Thomas Berger; Paulus Rommer; Elisabeth Puchhammer-Stöckl

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.

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

Link | PDF (Cell)

 

[SNT Gatchaman]

There is a substantially higher risk to develop MS after primary EBV infection, and this is especially linked to the development of high-level EBV-EBNA-1-specific antibody titers in individual hosts. Mechanistically, this is probably due to the molecular mimicry between an EBNA-1-derived antigen (EBNA386–405) and the CNS glial cell adhesion molecule (GlialCAM370–389) that results in cross-reactive EBNA386–405-specific immune responses against the GlialCAM 370–389 peptide.

However, because MS occurs only in a small fraction of EBV infected individuals and EBNA386–405-specific immune responses are also observed in healthy individuals, there must be additional factors that protect from the development of MS. Observational studies indicated that infections with human cytomegalovirus (HCMV) may moderately protect against MS

Here, we report that MS pathogenesis is based on an ineffective control of EBNA-1-mediated autoimmune response. The development of MS was earlier associated with high cross-reactive EBNA-1 specific antibody levels in humans, albeit the majority of EBNA high individuals do not develop MS. Our study demonstrates that the main protective factors against MS are distinct cytotoxic NK cell responses. [...] Here, we demonstrate that only specific cytotoxic NK cell responses, in particular the well-characterized NKG2C+ and NKG2D+ NK cell subsets are correlated with the control of GlialCAM370–389-specific autoreactive cells.

We found that the efficacy of the NKG2C+ NK cell responses was significantly associated with previous infection with HCMV, which leads to high NKG2C+ NK cell levels, similar to the previously reported result of an HCMV-specific imprint in the NK cell repertoire. [...] earlier observational studies demonstrated a somewhat lower MS prevalence in HCMV-seropositive individuals

Here, we show that the protection against MS was not only associated with previous HCMV infections but was highly dependent on the UL40 peptide variant encoded by the respective infecting HCMV isolates. VMAPRTLVL, VMAPRTLIL, VMAPRTLLL, and VMAPRTLFL UL40 peptides elicited a more potent NKG2C+ NK cell response, which was further associated with protection from MS in our study cohort. Protection was, however, only achieved in persons who did not display a homozygous deletion of the KLRC2 receptor and were thus able to confer an NKG2C+ NK cell response.

Our data are of special interest because recently published studies correlated high NKG2C+ NK cell levels in MS patients with a low disability score and a decreased risk of disability progression.[...] Furthermore, our data also suggest that therapeutic vaccination with the specific highly potent UL40 peptides could be an additional option to limit the progression of MS, by leading to high-level NKG2C+ NK cell responses.

 

[Jonathan Edwards]

I suspect this is wishful thinking. Not long ago the antigen in MS was supposed to be something else. I doubt it has anything to do with cross reactivity.