EBV: 35 years later scientists confirm a seminal observation

EBV & MS: association or causation? That is the question. #MSBlog #MSRsearch

"It is always reassuring when science is able to reproduce itself. The paper below has confirmed that when you take blood cells from MSers and put them into culture fluid the B cells transform themselves into more immature cells, call lymphoblastoid cells, and become immortal, i.e. they continue to divide and live. In comparison this rarely happens to cells from normal controls. We now know that this occurs due to the presence of the Epstein Barr virus that provides the necessary survival signals to the B cell that keeps it alive. The first observation of this phenomenon in MSers was published on 1979, 35 before this latest paper."

"What does this observation tell us about EBV and MS? Not much, except it supports the hypothesis that MSers have a problem with the component of their immune system that keeps EBV in check. The cells that do this are called cytotoxic T lymphocytes or CTLs. The CTLs are the population of cells that Michael Pender is using as a therapy to treat MS. His hypothesis is that EBV infected B cells in the brain and spinal cord of MSers are driving local autoimmune responses and that MSers don't have the ability to kill these cells. This is why he is taking CTLs from MSers and expanding and priming them in the laboratory before infusing them back into the blood stream of MSers. These CTLs will then home to the brains of MSers and kill these EBV infected B cells and switch off the local autoimmune reactions. Another way of addressing this problem is to give drugs that kill the B cells directly, for example anti-CD20 therapies, are with antivirals that target EBV-infected cells. All these strategies should work. The deficient or poor anti-EBV CTL response is a hypothesis and needs to be falsified. Which is why clinical trials are ongoing."

"I am not sure if I agree with the CTL hypothesis. The efficacy of several drugs in MS that reduce CTL responses within the brain and spinal cord should make MS worse according to this hypothesis, when in fact they improve MS, for example natalizumab and fingolimod. You could argue these drugs also reduce the CD4+ autoimmune cells hence they switch off the autoimmunity as well. This may be the case, but the evidence that CD4+ cells are involved in the pathogenesis of MS is also poor; anti-CD4 was tried and failed in MS in the mid 1990's. When you look at the pathology of MS lesions, the CD8+ cells predominate in the tissue with the CD4+ cells mainly located in the inflammatory cuff around veins. This tells me the CD8+ cells that include CTLs are the most important cells; interestingly this population of lymphocytes is traditionally the population that fights viruses."

"Yes, I am still making the claim that EBV causes MS and we need to do the studies to prove this. This claim is based on epidemiological observations and not biological mechanisms. If you don't get infected with EBV your chances of developing MS is close to zero. The ultimate experiment is a vaccination study to see if preventing a population from being infected with EBV protects them from getting MS when they are older. This experiment is easier said than done; firstly we don't have an effective vaccine and if we did the study it would require over 10,000 children to participate and it will take 20-30 years to complete." 

"Why do I think the correlation between EBV and MS is causation rather than association? Please read my previous post on this topic."

Epub: Tørring et al. Higher incidence of Epstein-Barr virus-induced lymphocyte transformation in multiple sclerosis. Acta Neurol Scand. 2014 Mar 31.

OBJECTIVES: Epstein-Barr virus (EBV) infection is associated with MS, and EBV may transform lymphoblastoid cell lines more frequently in MSers than controls, but it is not clear whether this reflects a higher viral load or an enhanced ability to reactivate EBV.

MATERIAL AND METHODS: MSers and controls were examined for their B-cell subsets and during 16 weeks for spontaneous lymphocyte transforming events.

RESULTS: MSers had normal distribution of B-cell subsets, but a significantly higher incidence of B-cell transforming events, which occurred with kinetics similar to controls.

CONCLUSIONS: The higher incidence suggests an increased frequency of latent EBV-infected B cells in MS.

Classic paper: Fraser et al. Increased tendency to spontaneous in-vitro lymphocyte transformation in clinically activemultiple sclerosis. Lancet. 1979 Oct 6;2(8145):175-6.

Lymphocytes from 8 of 10 MSers with clinically active MS but from only 3 of 18 patients with quiescent MS and 4 of 20 healthy donors transformed spontaneously on in-vitro culture. The transformed cells from all donors had the characteristics of B lymphocytes (surface and intracytoplasmic immunoglobulin and complement receptors) and carried antigens of Epstein-Barr virus. It is suggested that these results are further evidence that immunoregulation in active MS is abnormal.

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