Friday, 20 April 2018

Is the B cell idea broken?....Sort of Th17 and Th1 are the problem.

The B cell hypothesis gains momentum with the Pharma Industry, but do our academic colleagues know better and it really is the TH17 cell at the top of the pyramid.
Both Th1 and Th17 cells use distinct transmigration routes to enter the CNS. In experimental autoimmune encephalomyelitis, Th1 cells preferentially migrate into the spinal cord, while Th17 cells mainly infiltrate the brain. This is facilitated by their differential expression of pro-inflammatory cytokines, chemokine receptors and integrins 

Interleukin-17 (IL-17) and C-C chemokine receptor 6 (CCR6) are key determinants for Th17 transmigration across the blood–brain barrier

The surface expression of another chemokine receptor, CXCR3, defines Th17 cells with Th1-like which are called Th17.1

In people with CIS that convert to MS there are less TH17.1 cells in the blood.  "The, Th1-like Th17 effector memory cells to non-effector memory ratios in CIS blood inversely correlated to anti-EBNA1 IgG titres (P = 0.013; Fig. 1C). So more link with EBV. Great I say but I must admit this a "neurology correlation" a P value as long as your arm but something that would mean nothing in predicting the influence on an individual. It fails the "smack you in the eye test" and you can draw a line of correlation where ever you like as there is nothing obvious:-(.

Reduction of Th1-like Th17 effector cells in the blood of CIS patients with short time to CDMS. CIS patients were selected based on blood sampling within 4 months after diagnosis and time between CIS and CDMS. ‘CIS-CDMS’ patients were diagnosed with CDMS within 1 year (n = 16; filled bars), while ‘CIS-CIS’ patients were not diagnosed with CDMS for at least 5 years (n = 16; shaded bars). CD4+ T cells in the blood were compared for (A) Th1 (CCR6−CXCR3+), Th17 (CCR6+CXCR3−) and Th1-like Th17 (CCR6+CXCR3+) cell distribution, as well as (B) effector memory (EM; CCR7−CD45RA−) to central memory (CM; CCR7+CD45RA−) cell ratios within each of these subsets, as determined by flow cytometry. Th1-like Th17 effector to central memory cell ratios were correlated to reported predictors of early CIS to CDMS transition, anti-EBNA1 IgG blood titre (C) and fatigue severity scale (FSS; D). *P < 0.05; **P < 0.01.

The cells are gone from the blood because they are in the brain.

These TH17.1 cells however produce interferon gamma and granulocycte macrophage colony stimulating factor but not much IL-17. Is this why anti-IL17A dind't do much in MS?

However, why didn't anti-IL-12/IL-23 as these cells have receptor for IL-23R? This issue was not addressed, yet response to therapy is important is determining what is important and what is not.

Actually, inhibition of IL-12/IL-23 is great at eliminating the induction of disease in mice but to be honest this activity didn't inhibit relapse in mice, so why would you expect it to work in relapsing MS?

The use of both CCR6 and CXCR3 as discriminating markers for Th17 cells does not only reflect their pro-inflammatory state, but also their capability to migrate into local inflammatory sites. 

So should we consider chemokine therapy to get rid of these cells?

In this study theeveal that IFN-γ-/GM-CSF-producing (CCR6+,CXCR3+), but not IL-17-producing (CCR6+CXCR3-) Th17 effector cells are key regulators of multiple sclerosis onset. A Th1-like Th17 subpopulation termed Th17.1  (CCR6+CXCR3+,CCR4-) is selectively targeted by natalizumab in patients with multiple sclerosis who remained free of clinical relapses.

The paper ends " The prominent association of Th1-like Th17 cells, in particular Th17.1, with multiple sclerosis activity suggests the possibility for more specific T cell-targeted therapies, and pleads for further assessment of the use of natalizumab earlier in the disease course of multiple sclerosis"

If DrK got his wish and everyone at diagnosis/presentation was put on natalizumab to stop disease activity whilst time is taken to do clinical work-up and drug selection, this would happen.

So is the B cell idea dead and this is proof that the B cell hypothesis is incorrect. We don't know, as they did not report on what happened with memory B cells so maybe an oppertunity lost. Maybe they measured memory B cells and this failed to show anything interesting maybe they are reporting fantastic results as we read.

van Langelaar J, van der Vuurst de Vries RM, Janssen M, Wierenga-Wolf AF, Spilt IM, Siepman TA, Dankers W, Verjans GMGM, de Vries HE, Lubberts E, Hintzen RQ, van Luijn MM. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention. Brain. 2018 Apr 5. doi: 10.1093/brain/awy069. [Epub ahead of print]

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosispatients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4-) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.


  1. "The prominent association of Th1-like Th17 cells, in particular Th17.1, with multiple sclerosis activity"

    Association says nothing about causation until a simple question is answered:

    What comes first, lesions or Th?? cells?

    150 years of MS and still no one has ever found immune cells in pre-lesional sites of CNS. Is it time to change your tune?

    Why, oh why is it so difficult to hypothesize that all these fancy immune populations and interactions is just a healthy inflammatory response that causes transient trouble (relapses) because of the strict enclosure of the CNS within non-expandable bone structures (skull, spinal cord)?

    1. Because the inflammatory model, EAE, is predicated on the influx of lymphocytes due to priming of the immune system. This approach has given many immune modulators with modest efficacy. The question remains....what is priming the immune response inside the CNS? Latent EBV in memory B cells? Is there correlation between EBNA-2 and Th-17.1 cells in the CNS?

    2. Lymphocytes flood the CNS in ischemic stroke also. Invading a damaged territory is what they do. How can you tell the difference between a primed immune response and a normal immune reaction? Simple: check whether infiltration precedes or follows the CNS damage.

      Up to now there is no record of CNS infiltration of lymphocytes prior to CNS damage in MS. All available evidence point to the exact opposite: that damage precedes infiltration.

    3. Any normal immune reaction tends to stop after some time

    4. All the evidence does not point to CNS "damage" preceding inflammation. The picture is as ever, much more nuanced. So you can't cherry-pick to fit your hypothesis.
      This is worth a read, if you haven't already done so.

    5. Are the predominant lesions in early MS: type I/II, mediated by activated T-cell infiltrates, or type III, more of an innate immune response characterized by activated microglia( possibly due to fibrin accumulation on microglia) with limited T-cells involvement and little or no demyelination?

      The paper is from 2007 and the Lucchinetti paper in from 2000. Where are we now on the pathology? You seem to favor peripheral inflammation leading to oligodendrocyte damage.

    6. luis,
      the immune reaction is normal and stops. That is why lesions don't take over the CNS in a single wave. The problem is that CNS trauma is recurrent and so is the immune reaction. What makes MS chronic is the repetitive nature of CNS trauma.

    7. MD2, you argue that activated microglia are responsible for early damage in the CNS that leads to lesion development, right? The fact behind this argument is that activated microglia co-exist with "mild axonal injury in the absence of overt demyelination" as mentioned in the study (2007) you provide.

      1. Never have activated microglia been observed in absence of mild axonal injury nearby, so there is still no proof that microglial activation precedes early axonal damage.

      2. What is more, the study you provided is largely outdated. Here is a fresh one from 2017:

      "We conclude that C3d+ microglial clusters in MS are not part of an acute attack against myelinated axons. As such it is unlikely that they drive formation of new lesions but could represent a physiological mechanism to remove irreversibly damaged axons in chronic disease."

      MD2, You can hardly accuse me of cherry-picking. Anyone reading carefully both the studies we provided will conclude that it is far more plausible that even the earliest immune activation is just a response to pre-existing damage.

    8. No, I'm arguing that activated microglia lead to disease progression. There is much evidence to support that. As to what is the trigger for lesion formation, that's still to be determined. I'm not ruling out activation of microglia as an initiator but whether that is in response to to axonal/oligodendendrocyte damage or activation by other means such as cytokine release from intrathecal immune cells is still to be proved. it's very difficult in humans to absolutely determine this for obvious reasons as the only way to absolutely determine it is by pathological examination and yet that is but a snap-shot of existing disease at that time.

    9. Disease progression?
      I thought we were talking about what comes first, damage or immune activation. Since you are not ruling out microglial activation "in response to to axonal/oligodendendrocyte damage", i must assume that you are also overwhelmed by the data that support the purely responsive nature of the immune reaction.

      So, the big question remains: What causes CNS damage in the very first place?

      It is not the T cells, it is not the B cells, it is not microglia. Well, what is it?

    10. "EBV"
      Ok, where are the data to support this?

      Please provide a study that found EBV particles or EBV infected cells within the CNS in absence of any visible CNS damage.

      Please provide any proof of EBV-inflicted CNS damage.

      Please explain lesion formation in terms of EBV.

      The question was what causes CNS damage in the very first place.

    11. Abundant data, seek and ye shall find Also there will be an excellent upcoming team G publication pulling everything together for you in one handy source.
      You'll love it ;-)

    12. Evading questions, giving promises, talking about the future.
      Old MS tune.

    13. Let's face it VV, whatever I say will never satisfy you ;-)

    14. Re "The problem is that CNS trauma is recurrent and so is the immune reaction. What makes MS chronic is the repetitive nature of CNS trauma"

      do you have any ideas about what causes this trauma?
      Why should there be repeated trauma in the brain?

    15. VV used to be an ardent of the CCSVI theory, which has now been convincingly demonstrated to be fallacious, including by its proponent Dr Zamboni.

    16. MD2, please allow me.

      Dear Anon, imagine brain lesions as the result of hemorrhagic stroke within veins, not arteries, caused by spontaneous, momentary and very swift, reversed blood flow rising from the chest and going up into the brain.

      This can happen to any person and usually causes no harm as long as there is enough draining capacity of the venous system, which sends this extra blood volume back outside the skull. However, some people, at times, lack this draining capacity. That's when the reversed blood has nowhere else to go and exerts its kinetic energy on the less durable part of the reversed venous path it takes.

      That part of the vein swells like a balloon, damaging the Blood Brain Barrier locally and destroying the thin projections of oligodendrocytes that feed the myelin seeth around the axons. Thus, wounded oligos and damaged myelin attract microglia, which unable as the are to handle the blow, call blood immune cells for backup. They come to help clear the damaged area, kill the half-living cells and apply a scar. Unfortunately, their presence creates swelling which increases pressure on the nearby axons and relapse emerges. After the swelling is gone and remission restored, remaining damage is revealed.

      This is roughly the underlying mechanism of brain lesions, described by Dr. Franz Schelling more than 30 years ago, so has little to do with Dr Zamboni, as MD2 says. Spinal lesions are created in a very different way as D.R Oppenheimer has proposed nearly 40 years ago. I would be glad to elaborate on spinal lesions if anyone is interested.

      I can justify every part of the above story with links to relevant studies.

      Anon, what do you think?

    17. Thank you VV

      I got some idea about Dr Oppenheimer's spinal lesions ideas from the discussion after

      What I think:

      With my level of background knowledge (lack of knowledge) - at first reading, this trauma and venous mini-strokes idea seems as plausible as the immune system and EBV ideas.
      If it is true, how can these mini strokes be prevented? Alemtuzumab, rituximab, etc may be excellent ways of keeping the damage within control.

      Now some other questions/objections:

      1. People with MS normally have both spinal and brain lesions. If the root causes of the two are different and independent, why should the same people be susceptible to both?

      2. How does the trauma idea explain the clustering of (so-called) autoimmune diseases within families? Treatments for different diseases will obviously differ. But any attempts to identify a cause for MS and prevent MS must cover other diseases too.

      3. Why have researchers not taken forward Dr Schelling and Dr Oppenheimer's ideas? Why does everyone jump onto an already crowded bandwagon?
      If someone wants to make a name and/or make a difference, offbeat ideas are surely more promising

    18. Yes, EBV.

      Find out, read more about the ability to infiltrate this virus. It's now known that it infects astrocytes, and that there is somehow "communication, signals" between infected astrocytes and EBV-infected B cells.

    19. Dear Anon, the venous back-jets idea readily explains a single distinctive feature of MS, Dawson's fingers. It also explains the wider topology of MS brain lesions: All of them have a vein (not venule) within or adjacent. What is more, lesions appear where veins turn or ramify. Now, try to imagine two veins meeting to form a larger vein. This confluence is identifiable only by blood moving opposite to its normal direction.

      1. They mechanisms of brain and spinal lesions are different, but not independent. For spinal lesions to emerge, venous back-jets of the abdomen are necessary. These back-jets expand the epidural veins of the lower spinal canal and force swift shifts of the CSF upwards. The shifts, when amplified enough, stress the spinal cord and lead to scaring along its flanks, through the denticulate ligament anchoring points. Brain and spinal venous back-jets create the conditions for mutual enhancing.

      2. Are you talking about Hashimoto and MS? Simple, the vein draining the thyroid gland is used to drain the brain and is thus overloaded, leading to poor thyroid perfusion. As for other, so called, autoimmune diseases, the fact is they are of unknown etiology. So, similarities with venous MS can't be excluded.

      3. This is an epistemological question: In order to shine in a certain establishment you first have to fully embrace it, otherwise you get expelled. Then you find out that offbeat ideas don't get any financial support and don't pay the rent. So, you go with the flow and survive happily.

    20. I can't imagine any venous origin for ulcerative colitis. Or for psoriasis.
      Not sure about Type 1 Diabetes

      Maybe the doctors can respond to your other points

    21. Why should they be strictly venous in origin? Not being autoimmune means having any other cause.

      However, type 2 diabetes seems to be a problem of vascular compression:

      The same may hold for Parkinson's:

  2. Alemtuzumab cutts off B and T cells completely, and generally This treatment shows the best atrophy datas. Cladribine cutts of B cells almost completely, and T cells partially, but the atrophy datas shows a bit less effect (like fingolimod). Ocrelizumab has a very similar effect, it has 'only' good but not perfect... (but we don't have long term datas)

    So finally maybe T and B cells are also involved or not?

  3. How can we not believe that both T-cells and B-cells are involved. The immune system is an elegant dance that involves not only B-cells and T-cells but many other cells as well as many other reactants. It is time to stop looking at just one cell population in any study and document all that we can.

  4. Nice article MD. However, regardless of this and any other future articles questioning or promoting b cell theory. All this purely academic. Until Ocrelizumab is proven to be more effective than Alemtuzumab. Which current results show its not. Consequently, B cell theory is incomplete or more likely incorrect.

    1. Maybe but it needs to head to head as the trial data was based on early MS in alemtuzumab

    2. Thanks MD. However there is no way roche will do a head to head with lemtrada simply because they will be scared of losing and sabotage their attempt to corner the ms treatment market.

    3. Agreed but academic neurologists will do it

  5. I have been diagnosed with pons about 2 years ago and have had 2 ocrevus infusions. Has ANYONE reported worsening of symptoms? All I hear is "that's unusual. No one has reported that". My walking has deteriorated, spasticity increased, increased difficulty with swallowing and coughing, increased weakness and fatigue. I'm getting frustrated with my doctors. Any helpful insights or recommendations?

    1. Report it to FDA and Genentech. There is the Unrelated comments of the month for these questions.


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