Wednesday, 11 January 2017

#ResearchSpeak: who trumps who; the T-cell or the B or plasma cells?

Who is afraid of the big bad wolf? #ResearchSpeak #MSBlog

Every now an then a immunology paper grabs my attention. The paper below confirms that CSF levels of a soluble protein, sCD27, correlates with MS disease activity and immunoglobulin synthesis within the brain and spinal cord, is interesting. I predict this observation is important. 

T-cells vs. B-cells; who will be the winner?

For the immunologist reading this post you will recall that CD27 is a member of the tumour necrosis factor (TNF)-receptor superfamily and is part of an important pro-inflammatory cascade. The CD27 receptor is required for generation and long-term maintenance of T cell immunity. It binds to CD70 on B-cells, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. 

The study below observed a correlation between sCD27 and IgG index, a marker of immunoglobulin synthesis in the spinal fluid (see figure below). The author's speculate that there may be a direct role for sCD27 released by T cells on IgG production by B cells. Interestingly, the binding of sCD27 to the CD70 on memory B cells stimulates those B cells to differentiate into IgG-secreting plasma cells. Could sCD27 be the important link between T-cells and B-cells and plasma cells? It will be very interesting if sCD27 in the spinal fluid also predicts recurrence of disease activity after an induction therapy. 

The researchers' conclude that sCD27 in the CSF of pwCIS is an activation molecule directly related to the immunopathology of the disease and that is a potential clinical marker to help in treatment decisions after a first attack of suspected MS. They imply that it is marker of T-cell activation, but could it be the downstream B-cells and plasma cells that are the real players? 


van der Vuurst et al. Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome. JAMA Neurol. 2017 Jan 3. doi: 10.1001/jamaneurol.2016.4997.

IMPORTANCE: There is a growing number of therapies that could be administered after the first symptom of central nervous system demyelination. These drugs can delay multiple sclerosis (MS) diagnosis and slow down future disability. However, treatment of patients with benign course may not be needed; therefore, there is a need for biomarkers to predict long-term prognosis in patients with clinically isolated syndrome (CIS).



OBJECTIVE: To investigate whether the T-cell activation marker soluble CD27 (sCD27) measured in cerebrospinal fluid of patients at time of a first attack is associated with a subsequent diagnosis of MS and a higher relapse rate.

DESIGN, SETTING, AND PARTICIPANTS
:This prospective study included 77 patients with CIS between March 2002 and May 2015 in a tertiary referral center for multiple sclerosis, in collaboration with several regional hospitals. Patients with CIS underwent a lumbar puncture and magnetic resonance imaging scan within 6 months after first onset of symptoms.


MAIN OUTCOMES AND MEASURES: Soluble CD27 levels were determined in cerebrospinal fluid using a commercially available enzyme-linked immunosorbent assay. Cox regression analyses was used to calculate univariate and multivariate hazard ratios for MS diagnosis. Association between sCD27 levels and relapse rate was assessed using a negative binomial regression model.


RESULTS: Among 77 patients with CIS, 50 were female (79.5%), and mean (SD) age was 32.7 (7.4) years. Mean (SD) age in the control individuals was 33.4 (9.5) years, and 20 were female (66.7%).Patients with CIS had higher cerebrospinal fluid sCD27 levels than control individuals (geometric mean, 31.3 U/mL; 95% CI, 24.0-40.9 vs mean, 4.67 U/mL; 95% CI, 2.9-7.5; P < .001). During a mean (SD) follow-up of 54.8 (35.1) months, 39 of 77 patients (50.6%) were diagnosed as having MS. In a model adjusted for magnetic resonance imaging and cerebrospinal fluid measurements, sCD27 levels were associated with a diagnosis of MS (hazard ratio, 2.4 per 100 U/mL increase in sCD27 levels; 95% CI, 1.27-4.53; P = .007). Additionally, patients with MS with high sCD27 levels (median, >31.4 U/mL) at the time of CIS had a 5.5 times higher annualized relapse rate than patients with low sCD27 levels (annualized relapse rate, 0.06 vs 0.33; P = .02).

CONCLUSIONS AND RELEVANCE: Soluble CD27 in cerebrospinal fluid of patients with CIS was associated with MS diagnosis and a high relapse rate. Therefore, sCD27 is an activation molecule directly related to the immunopathology of the disease and is a potential clinical marker to help in treatment decisions after a first attack of suspected MS.

25 comments:

  1. How many scientists have religion?

    How many scientists have trouble assimilating information?

    Sorry to say the T party has blind faith:-)

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    1. I an firmly in the T-cell camp; it is not pink and fuzzy, there is no bible and the camp is not full of zealots or priests, only scientists. As you know B-cell are APCs and this explains how B-cell depletion works in MS. MS is a T-cell driven disease, show me the evidence to the contrary.

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    2. I agree this should be fun.

      Mr T show us the evidence that MS is a T-cell driven disease? In fact, show me the evidence that MS is an autoimmune disease?

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    3. I sincerely hope you not going to propose your black swan crap as an alternative explanation for the pathogenesis of MS?

      I suggest you start with the pathology of MS; the lesions are stuffed full of CD4+ and CD8+ T cells. All treatments have an impact on T-cell function. I could go on, but I have other things to do with my time.

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    4. Yep, there is a black swan flying in; I am not sure I can predict when it will arrive, but it will arrive. Can I predict that when it does arrive it will show that MS is not an autoimmune disease. The fact that immunomodulatory and immunosuppressive therapies work in MS does not necessarily mean that MS is autoimmune; there are potentially other explanations for their effects in MS.

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    5. "I could go on, but I have other things to do with my time."

      Ah, the old run away before I make a fool of myself gambit?
      Regarding the pathology of MS, this is worth a read (if you have time) and rather undermines your assertion.
      https://www.ncbi.nlm.nih.gov/pubmed/22829266

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    6. Also this.
      https://www.hindawi.com/journals/ad/2012/969657/

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    7. And this "brains of patients with MS commonly exhibit diffusely abnormal white matter in which myelin and axonal density are reduced but inflammation is not apparent18. Moreover, normal-appearing white matter from these patients exhibits myelin and axonal degeneration as well, with little evidence of an adaptive immune response."
      https://www.ncbi.nlm.nih.gov/pubmed/22714021
      "Animal models may also skew our understanding of the basis of human MS. Such models are useful, but tend to elucidate mechanisms that are deliberately selected a priori for perturbation. Experimental autoimmune encephalomyelitis (EAE), a widely used model of MS43, is a good example. In EAE, rodents are injected with myelin antigens together with immune boosters to elicit an inflammatory autoimmune reaction to CNS myelin. If we assume from the start that MS is a primary autoimmune inflammatory disease, then EAE is a very good model that recapitulates many of the inflammatory demyelinating manifestations of human relapsing–remitting MS. In light of our inside-out hypothesis, however, we suggest that EAE is instead a very good model of the inflammatory reaction that occurs in human relapsing–remitting MS, but may not reflect the underlying disease process".
      I acknowledge that we are also part of the EAE community but we have tried to spread our net a little wider than the blinkered approach of many.

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    8. Mr T, go and have a cup of tea, relax, open your mind, and do some reading. Not just the same old papers, but some new stuff, as suggested by MD2.

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    9. We can make circumstantial arguments for all sorts of stuff but what is the killer work that says definitively that MS is a T cell disease or says that MS is an autoimmune disease?...I mean a primary autoimmune disease, it is clear to me there is autoimmunity in MS, but this may be secondary to damage.

      Lesions are stuffed with T cells....actually they are not..stuffed full..however they are present as are other cells, this could occur in a viral disease.

      "All treatments have an impact on T cells"...could this argument not be made for other cellular targets?

      Rituximab depletes about 10-25% of CD4 T cells in the blood and inhibits MS, but CD4-specific antibody depletion to about 65-70% of CD4 T cells and has a marginal influence on MS...What's the explanation?

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    10. "black swan crap"
      By "crap" I'm assuming you're using the well-known acronym, Considered Response Against Preconception? ;-)

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    11. What about Team G doing research which answers questions? We have been round the same buoys for too long: inflammation or neurodegeneration; T cells v B cells; autoimmune v virus. That Black Swan must be tired out as it never lands. Please, let's stop theorising, hypothesising, pontificating... and come up with some fax / answers. Until EAE is scrapped we will never understand human MS.

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    12. Blaming EAE for insufficient answers from MS is a cop-out. But agree that the answer to MS lies in MS.

      Answers on the way...depends on reviewers how quick

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  2. Please note that T-cells are a very big bucket. Are we talking Th1, Th2, Th17, Treg, CTLs, etc.?

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  3. Sorry for my ignorance, but if sCD27 is a soluble protein that is part of the TNF-alpha family, would it be linked to TNFR1 or TNFR2?

    MD these days said in a publication that there appears to be a dichotomy of function for TNFR2 in myeloid cells with TNF2 microglial providing protective signals to contain monocyte/macrophagic disease and TNFR2 boosting immune activation and initiation EAE.
    We know that certain viruses can inhibit antiviral effects of TNF-α during lithic reactivation or primary infection, as in the case of EBV.

    So where does all this fit?

    http://multiple-sclerosis-research.blogspot.com/2017/01/stay-clear-of-tnf-therapy.html?m=1

    ReplyDelete
    Replies
    1. CD27 is a member of the tumor necrosis factor receptor superfamily. The s means it is soluble so sCD27 is cleaved from the cell surface.

      The TNF receptor superfamily
      https://en.wikipedia.org/wiki/TNF_receptor_superfamily as you can see there are 27 members of the family but it is not linked to TNFR1 or TNFR2 and the binding molecule for CD27 is CD70 not TNF.

      I selected the paper on the TNFR because i wanted to highlight the problem with TNF as a target, we we will see why soon.

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  4. I want more & would love to see debates like this on this site. Throw up more papers, convince us. It always provides focus when trying to teach difficult topics.

    Unfortunately, Mr. T left too soon. Also, I'm not crazy about the rancor popping up in the debate. We get enough of that elsewhere.

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    1. Barts-MS run the 'Burning Debate' session at ECTRIMS. I think a 'Rumble in the Jungle: with T-cells vs. B-cells' would draw in the punters. What we would need, however, was to make sure we get the best debaters on the podium and a very good chairperson. We need the debaters to be passionate, adversarial and willing to knock their opponent(s) out.

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    2. I was looking forward to a "lively" debate on this too but sadly my suspicions about Mr T appear to have been confirmed.
      Shame, though we've put our side of things in his absence.

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  5. So given the option of Lemtrada or Ocrelizumab what would you suggest ?

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    1. Re: "Lemtrada or Ocrelizumab"

      It is about choice. Lemtrada is a PIRT (pulsed immune reconstitution therapy) and ocrelizumab is a maintenance therapy. If for example you wanted to start or extend a family you may be more inclined to go with Lemtrada. A lot of commentators on this blog are worried about the potential cancer, in particular breast cancer risk. This may sway them towards Lemtrada. In fact, I saw a patient this week with active MS on DMF; I offered her the choice of Lemtrada or Ocrelizumab in a phase 4 trial. When she heard about the potential cancer risk she opted for alemtuzumab. If the regulators take a dim view of the potential cancer risk with ocrelizumab they may not give it a broad or first-line license. If this is the case then alemtuzumab may continue to mop-up all the pwMS who want a highly-effective DMT first-line.

      What I should be asking is what would you choose? In addition, there are other options, including emerging ones, for example cladribine.

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    2. Lemtrada takes out both T and B cells. Ocrelizumab takes out mainly B-cells and a very small population of CD20 expressing T-cells. If you want to hedge your bets with a foot in the both the T-cell and B-cell camp then you would go with Lemtrada.

      I am personally a B-cell man, so either would be fine.

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    3. Thanks Dr.G , your opinion is appreciated . Do you think lemtrada's cancer risk is less than Ocrelizumab? Not to mention serious infusion reaction, thyroid problems etc with lemtrada! Both have there serious side effects , it's a toss of the coin I guess !! It's a hard decision! What are the cancer statistics of both ? Thanks

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