Wednesday, 4 June 2014

Deficiency in CD8 T cells in MS....a reason why EBV is a problem?

Can the Pender Hypothesis explain the mode of action of the emerging DMTs? #MSResearch #MSBlog

"The following paper from Professor Pender's group supports his theory that MS is due to a deficiency of CD8+ effector cells; these are the cells that kill virally infected cells and are responsible for tumour surveillance. His hypothesis is that a deficiency of these cells against EBV-infected B cells within the brain lets the EBV cells survive long-term and drive autoimmunity. If we can boost these cells to kill EBV infected cells then we can down regulate one arm of the autoimmune loop and switch off inflammation in the CNS."

"Against the Pender theory is the recent observation that MSers have a lower incidence of cancer than the  general population; if MSers had a long-standing deficiency of these CD8+ effector cells we would expect more tumours, not less. Another observation that goes against this theory would be the effectiveness of some of the newer DMTs that target the immune system; in particular natalizumab, fingolimod, alemtuzumab, anti-CD20 and daclizumab (anti-CD25) therapies. How do these treatments improve the deficiency of CD8+ effector cells in MSers? Natalizumab blocks their entry of CD8+ cells into the brain; we know this because of PML. CD8+ effector cells are needed to fight the JC-virus. Fingolimod, drastically reduces circulating numbers of lymphocytes; although has a greater effect on naive rather than memory cells. According the Pender theory would expect fingolimod to make MS worse. However, it may depend on  the balance between CD8+ and CD4+ cells entering the brain and spinal cord. Alemtuzumab depletes all cells and they reconstitute slowly over the next 12 months; T cells, which include the CD8+ population, take the longest to reconstitute and they never come back to normal. Anti-CD20 ablates peripheral B-cells and does not target CD8+ cells. In rheumatoid arthritis patients rituximab treatment does not alter CD4+, CD8+ or T-regulatory cells numbers. Some would argue that the response of MS to anti-CD20 would support the Pender hypothesis as it is working via EBV infected B-cells. This is a possibility, but we have no clear evidence that rituximab works on B cells within the central nervous system. Daclizumab increases natural killer cells (NK cells) and reduce T-regulatory and CD8+ cells; the effectiveness of daclizumab in MS would argue against the Pender hypothesis unless the NK cells are substituting for the CD8+ effector cells and killing the EBV-infected B cells within the central nervous system."

"As you can see immunology is very complex and can be very confusing; it is not helped by the difficult reproducing results across labs. What is evident that if you do come up with a causation hypothesis it needs to explain everything and I mean everything, the epidemiology, the clinical phenotypes, pathology and responses to treatment to mention a few. There can be no facts, little of big, left untouched. To quote Thomas Huxley 'the great tragedy of Science: the slaying of a beautiful hypothesis by an ugly fact.'"

CD8+ T cells

BACKGROUND: MSers have a deficiency of circulating CD8+ T cells, which might impair control of Epstein-Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells.

OBJECTIVE: Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course.

METHODS: We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MSers and 112 healthy subjects.

RESULTS: MSers had a decreased frequency of EM (CD45RA-CD62L-) and EMRA (CD45RA+CD62L-) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal.

CONCLUSION: Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.


  1. "In rheumatoid arthritis patients rituximab treatment does not alter CD4+, CD8+ or T-regulatory cells numbers or function."

    Rituximab definetley effects T-regulatory function. You may want to start citing sources that support your statements because they are increasingly becomming untrustworthy.

    1. Apologies corrected. Not really relevant here as I was referring to the the Pender CD8 hypothesis.

    2. Why do we need to cite references when you are there to cite contrdictory references:-).
      We have stated non B cell effects of rituxan numerous times be before as it gives card carrying immunologists like myself a cop out.

    3. Mouse Doc - a question not related to CD8 but important.

      Do you have people in the clinic who take DMTs and statins at the same time?

      Will simva (10mg) lower the DMTs (Aubagio or Tecfidera) effect?

      My GPs prescribed the statins but are not able to tell me anything about the interactions between the drugs- he's my heart doc (the neuro had no clue either) so I am left to my own devices.

    4. The problem with immunology is that for every claim there is a paper that makes a counter claim. In general the immunology field is all over the place.

    5. I am surprised "you" have let ProfG get away saying that alemtuzumab is a B cell depleter. Maybe in the blood, but in the lymphoid organs what happens? In humans we don't know as we do not make a habit of chopping-out their spleens, but in humanised CD52 transgenic mice, not a lot of long term depletion...Point is you can find references on both sides of the equation, generally evidence builds up on one side.

    6. Mouse Doc - Do you have people in the clinic who take DMTs and statins at the same time?

      Simple Cop out answer is "No I don't" however that is because I don't do clinics :-).

      ProfG will need to answer this but I suspect there will be many MSers on DMT and simvastatin/or other statin, because people are taking statins to control cholesterol levels and the DMT for their MS

      Am J Health Syst Pharm. 2012 Sep 1;69(17):1494-9. doi: 10.2146/ajhp110675.
      Efficacy of statins in combination with interferon therapy in multiple sclerosis: a meta-analysis.Bhardwaj S, Coleman CI, Sobieraj DM.

      PURPOSE:The efficacy of statins in combination with interferon therapy in patients with multiple sclerosis (MS) is reviewed.
      METHODS:A systematic literature search was conducted through September 2011 to identify randomized controlled trials that evaluated the effect of combination statin-interferon therapy compared with interferon therapy alone in patients with MS. Trials had to report at least one of the following outcomes of interest: clinical relapse rate, disease progression, or Expanded Disability Status Scale (EDSS) score.
      RESULTS: Four unique trials were included in the analysis (n = 463 subjects; range of follow-up, 9-24 months) All trials evaluated patients with relapsing-remitting MS (RRMS). Most trials enrolled patients taking interferon beta therapy either twice or three times weekly. The mean baseline EDSS scores ranged from 1.2 to 3.4. Evaluated statins included simvastatin and atorvastatin. No significant difference was found between the statin and control groups in the incident rate ratio for clinical relapse (0.72; 95% confidence interval [CI], 0.17 to 3.11), risk of relapse (relative risk [RR], 0.99; 95% CI, 0.53 to 1.85], disease progression (RR, 1.31; 95% CI, 0.73 to 2.36), or difference in the change in the EDSS score from baseline (weighted mean difference, -0.06; 95% CI, -0.30 to 0.19).
      CONCLUSION: A meta-analysis revealed that the addition of statins to interferon therapy did not significantly influence the relapse risk, disease progression, or EDSS scores in patients with RRMS.

      Simvastatin as add-on therapy to interferon β-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial.
      Sorensen PS, Lycke J, Erälinna JP, Edland A, Wu X, Frederiksen JL, Oturai A, Malmeström C, Stenager E, Sellebjerg F, Sondergaard HB; SIMCOMBIN study investigators. Lancet Neurol. 2011 Aug;10(8):691-701 "We found no beneficial effect of simvastatin as add-on therapy to interferon beta-1a. Although unlikely, we can not exclude that combination of other statins with other disease-modifying drugs still could be beneficial".

      As you mention drugs can have interactions with other drugs and so it is best if your treating physician is aware of the drugs you are taking. There does not yet appear to be a litterature on the combination of statins with aubagio and tecfidera. Maybe others know

  2. Anon: do you have any more evidence re rituximab and T-reg cells. The paper you are referring to relates to patients with ITP, and not RA. In addition, all the patients in the study had already received corticosteroids and intravenous immunoglobulin therapy, and the majority had also received other treatments as well. Talk about comparing apples and oranges.

    Prof G is suspect this a malicious comment from a troll.

    1. You probably should start doing your own research:

      "B cell depletion enhances T regulatory cell activity essential in the suppression of arthritis."

  3. " This is a possibility, but we have no clear evidence that rituximab works on B cells within the central nervous system." Is there any data on reduction of B-cells in CNS on intrathecal administration of rituximab? Would the use of rituximab play the same role as CD8+ effector cells in controlling EBV infected B-cells?

  4. Prof G,

    Are you backing away from the idea that EBV is th cause of MS? I thought this was the point of the Charcot Project. Your comments above appear to question Prof P's hypothesis.

    1. That's because Professor G and Professor P do not agree on the role of EBV in MS. Prof P believes EBV is a catalyst such that people with defective immune systems react innapropriately to it. Prof G believes EBV is directly causing the damage in MS.

    2. I think the epidemiology is clear that EBV is in the causal pathway. At present I have no idea how EBV causes MS. Prof Pender's hypothesis is reasonable and needs to be disproved. Yes, you are correct in that I don't buy into it as it does not explain how all of the MS DMTs work. At present the most congruent hyppothesis in relation to the DMTs is that MS is an autoimmune disease with the B cell being a central player.

    3. Prof G,

      Any comments?

      Incomplete B-Cell Depletion Linked to Fewer MRI Lesions

  5. Does someone with a low CD4 (T-Helper Cell) count to high CD8 (T-Supressor Cell) count have a lower or higher chance of devloping or having MS? I also like to add EBV titers are already elevated

    1. The CD4+ to CD8+ ratio is low, 0.82 to be exact.


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