Unrelated Comments & Questions – November 2017

Sometimes you want to say something unrelated to the thread or ask a clinical question or some other MS-related question that has not been answered in past. This is the place for you.

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  • To md

    Aparently she know the answer (why anti BAFF did´nt work)

    Professor Fabienne Mackay

    Project Details

    Multiple Sclerosis (MS) is a chronic neuroinflammatory disease of the brain and spinal cord that is a common cause of serious physical disability in young adults. This disease is considered an autoimmune condition as autoreactive lymphocytes mount aberrant responses against the central nervous system (CNS).

    Current treatments focus on reducing immune cell activity and their entry into the CNS, but these therapies are often associated with side effects and are not suitable for all patients. None of the available treatments cure MS, and we still do not fully understand the exact nature of the immune anomaly leading to pathology. While remitting/relapsing MS can be reasonably controlled in some patients, progressive MS remains a very important clinical challenge resulting in disability and death with no effective treatment to date.

    Recently, some contradicting results have emerged from clinical trials. Indeed, clinical trials using a depleting antibody directed at the molecule CD20 used as a specific agent depleting B-lymphocytes showed efficacy of this treatment in patients with MS. This success sparked the development of another antibody blocking the cytokine BAFF, which prevents BAFF-mediated B cell survival, with the expectation that this agent, which also reduced B cell numbers, would be as good as anti-CD20. To everyone’s surprise blocking BAFF in patients with MS made the disease worse, and forced clinical researchers to abandon this trial.

    We believe we have an explanation for these conflicting results in the clinic, which possibly could be attributed to regulatory B cells or Bregs. Bregs are characterised by the production of IL-10 and are an immunosuppressive subset of B lymphocytes. Many studies have shown that Bregs are essential for the prevention of MS severity. We have data confirming that the BAFF system is important to maintain Bregs. This project aims to understand the role of BAFF and Bregs by using a murine model of MS called Experimental Autoimmune Encephalopathy (EAE).

    This project will dissect the role of the cytokines BAFF/APRIL and their receptors in the development of MS. We will analyse how the genetic deficiency of BAFF, its related ligand APRIL or their respective receptors (BAFF-R, TACI, and BCMA) affects Breg numbers in the EAE model of MS. Bregs can be measured by in vitro activation followed by intracellular staining for IL-10 and flow cytometry analysis. Additionally, spinal chord pathology and inflammation will be studied using histology. We will also assess how the lack of a member from the BAFF/APRIL system affects the ratio of Bregs versus inflammatory cells such as effector Th17 T cells.

    This work is likely to provide information on how we can better harness the regulatory function of Bregs to treat MS.

    Ps: Should you contact her?


    • Maybe but as B memory go down, Bregs go up…..based on percentages so what is more important..I am trying to remember why I plumbed for B memory I think it was fingo

      Remember IL-10 is not just an immunosuppressive cytokine it is a B cell growth/differentiation factor

    • Hi Luis, thanks for giving us yet more to read!

      This doesn't quite figure, if alemtuzumab (sledgehammer) depletes everything then this must include B regs too? Or anti CD20? Ditto nataluzimab keeps everything out of CNS? So reason for failure of atacicept can't be that it also decreased B regs? Am I being too simplistic?

      Yep MD, would be good to know about anti-BAFF….

    • The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells

      Our study confirmed that increased IL-10 production was not a reflection of a BAFF-driven increase in B cell numbers. Instead, our work has shown a role for BAFF in directly stimulating increased IL-10 production by B cells

      Many reports have posited a role for B10 cells in the control of autoimmune inflammation such as multiple sclerosis (MS) (51, 52), and as pivotal inducers of Treg activity (52, 53).

    • B regs and regs act diferenctly in the course of the disease its a question of timming (acordind to this paper)

      Experimental autoimmune encephalomyelitis (EAE) is a T lymphocyte-mediated autoimmune
      disease of the CNS. Significant roles for B cells and a rare IL-10-producing CD1d
      regulatory B cell subset (B10 cells) have been identified during the initiation and progression of
      EAE. Whether and how the regulatory functions of B10 cells and regulatory FoxP3
      T cells (Treg)
      overlap or influence EAE immunopathogenesis independently has remained unanswered. The
      current studies demonstrate that the number of endogenous or adoptively transferred B10 cells
      directly influenced EAE pathogenesis through their production of IL-10. B10 cell numbers
      expanded quickly within the spleen but not CNS following myelin oligodendrocyte glycoprotein
      ) immunization, which paralleled B10 cell regulation of disease initiation. The adoptive
      transfer of MOG
      -sensitized B10 cells into wild type mice reduced EAE initiation
      dramatically. However, B10 cells did not suppress ongoing EAE disease. Rather, Treg cell
      numbers expanded significantly within the CNS during disease progression, which paralleled their
      negative regulation of late-phase disease. Likewise, the preferential depletion of B10 cells
      in vivo
      during disease initiation enhanced EAE pathogenesis, while Treg cell depletion enhanced late-
      phase disease. B10 cells did not regulate T cell proliferation during
      in vitro
      assays, but
      significantly altered CD4
      T cell IFN-
      and TNF-
      production. Furthermore, B10 cells down-
      regulated the ability of DCs to act as antigen-presenting cells and thereby indirectly modulated T
      cell proliferation. Thus, B10 cells predominantly control disease initiation, while Treg cells
      reciprocally inhibit late-phase disease, with overlapping B10 cell and Treg cell functions shaping
      the normal course of EAE immunopathogenesis

      Although therapeutic B cell
      depletion has shown clinical efficacy in treating MS patients (8, 9), B cell depletion may
      also remove B10 cells and exacerbate MS severity, induce disease in some undiagnosed
      cases, or promote relapses in some rare cases (55)

      Regulatory B Cells (B10 cells) and Regulatory T Cells Have
      Independent Roles in Controlling EAE Initiation and Late-Phase



    • Prof. F. Mackay has received a grant last year for the development of a safer new treatment for SLE that preserves B cell immunity (I guess the same approach can apply to any a.i.d).

      They state "Our lab has shown that the molecules BAFF and its receptor TACI play a vital role in autoimmune diseases. Excess BAFF leads to autoimmunity in mice and is also associated with human autoimmunity, in particular Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome. We have demonstrated that TACI-mediated production of autoantibodies is key to drive BAFF-mediated autoimmunity and that loss of TACI on B cells protects from the disease without compromising B cell adaptive immunity in general. We are currently developing strategies targeting TACI to provide a therapy with a higher safety profile that avoids the serious adverse effects of global B cell depletion."

      B cell depletion is a working but sloppy solution. Ideas on how to restore the immune system should be promoted.

  • What is the case for not using Mavenclad as a first line treatment, or on a patient with stabile disease on DMF

    • Q1: Don't know (regulators might?).
      Q2: Not sure you are asking whether there is or isn't a case for switching from Tec to Mav, however patients with persistent side effects and/or ongoing lymphopenia on Tec "should" in my view be eligible. Whether UK colleagues agree/act accordingly I don't know given the NHS generally cares less about side-effects and convenience (as long as these factors remain cost-neutral) than the efficacy of MS drugs.

  • After taking your first course of Alemtuzimab. Some patients havea relapse? When there are no white blood cells left to attack the mylien? How is relapse possible? Also the steroids given during the treatment really makes my MS disappear. Why not just give periodic steroids every 3 months?

    • Remember alemtuzumab does not penetrate the CNS and so will not touch this response, so the relapse may have generated from inside the brain. It may have trigger before the alemtuzumab, also there are people on rituximab that relapse when there are no B cells in the blood but you only need a few

    • They are using EAE to investigate:-(…the anti-BAFF result in marmoset EAE was not consistent with the human result.

    • Not sure it is….I've been a naughty mouse and made the post…prompted by a request from the readers.

      Maybe in the dog house again:-( r could get a pet for being agood.

  • Cladribine WILL be made available in England and Wales on the NHS within the next three months! great news, so around Jan/early Feb 2018.

    https://www.mssociety.org.uk/ms-news/2017/11/cladribine-new-oral-treatment-be-available-people-relapsing-ms 03/10/17
    A new oral treatment for relapsing MS, called cladribine, will be made available on the NHS in England and Wales within the next three months.
    Decision makers in Scotland and Northern Ireland are still considering whether to make cladribine available on the NHS.

  • Did Dr. Fox mention anything else at ECTRIMS about Ibudilast? How did the patients make out clinically? Does this make you believe MD that maybe "hot" microglia is the APC driving progression and relapses of MS?

    I am not sure how EBV driven B-cells in follicles in meninges in the brain could be driving progression of disease. I thought there is an absence of meninges in the spinal cord? Also don't pathology results show an absence of T- and B-cells in grey matter in progressive MS patients?

    • I do not remember Dr Fox saying anything else but he only had about 10-12 minutes for the presentation and do not rememebr anything about clinical being mentioned.

      I have always though that microglia are a central part of the disease process.

      EBV driven follicles could (a) be producing cytotoxic molecules (b) but they could simply be producing antibodies. These will be bound by
      Fc receptors on microglia and may be the signal that juices up microglia, so you don't need a T or B cell anywhere nearby.

      The meninges are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in the subarachnoid space between the arachnoid mater and the pia mater.

  • In this patient it appears new spinal cord lesions are really what drove progression..the edss climbs right along with new spinal lesions.


    This is Prof. Hausers idea how this happens:

    "An increase in the size of a cervical cord lesion and the development of multiple new thoracic spinal cord lesions despite rituximab therapy represented the most likely imaging correlate of the progressive neurological deficit. Notably, nearly complete stabilization of brain white matter lesion burden by anti-CD20 therapy was repeatedly shown on MRI and sustained for nearly a decade.[5-7] As expected for a patient with chronic MS, progressive atrophy of total brain and spinal cord volume were also present. These observations are consistent with converging evidence that increasing cortical pathology underlies progressive MS and that these changes are largely independent of underlying white matter lesions but rather might be associated with adjacent overlying meningeal lymphoid aggregates containing B cells and plasma cells.[8-13] Could the development of SPMS been the consequence of ectopic lymphoid aggregates in the meninges that are resistant to anti-CD20 therapy? In contrast to the cerebral hemispheres, the major white matter tracts in the spinal cord are located in a superficial location adjacent to the meninges where they might be susceptible to damage from effects of cytokines, free radicals, or autoantibodies. This anatomic feature raises the question of whether chronic meningeal inflammation might promote neocortical neurodegeneration in the underlying cerebral hemispheres, and demyelination in adjacent spinal cord white matter tracts."

  • Interesting case study. Does cortical demyelination precede classical white matter plaques as proposed in the neuropathology study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315403/

    The authors propose:"Could the development of resistant B-cells in the meninges be ameliorated by Ritux/ocrelizumab use early on in CIS?" If given intrathecally to CIS patients would the number of lymphoid-like follicles be reduced and subsequent progression be lessened?

    Resistant B-cells in the meningeal follicles could explain the reason intrathecal riuximab failed in the SPMS trial. Also, reduction in white matter lesions are not predictive for progression of the disease.
    Thanks for the reference Adam

  • "Black swan" twin

    EAE is a mouse T cell–mediated autoimmune disease of the CNS used to model the human condition MS. The
    contributions of B cells to EAE initiation and progression are unclear. In this study, we have shown that EAE
    disease initiation and progression are differentially influenced by the depletion of B cells from mice with otherwise
    intact immune systems. CD20 antibody–mediated B cell depletion before EAE induction substantially
    exacerbated disease symptoms and increased encephalitogenic T cell influx into the CNS. Increased symptom
    severity resulted from the depletion of a rare IL-10–producing CD1dhiCD5+ regulatory B cell subset (B10 cells),
    since the adoptive transfer of splenic B10 cells before EAE induction normalized EAE in B cell–depleted mice.
    While transfer of regulatory B10 cells was maximally effective during early EAE initiation, they had no obvious
    role during disease progression. Rather, B cell depletion during EAE disease progression dramatically
    suppressed symptoms. Specifically, B cells were required for the generation of CD4+ T cells specific for CNS
    autoantigen and the entry of encephalitogenic T cells into the CNS during disease progression. These results
    demonstrate reciprocal regulatory roles for B cells during EAE immunopathogenesis. The therapeutic effect
    of B cell depletion for the treatment of autoimmunity may therefore depend on the relative contributions and
    the timing of these opposing B cell activities during the course of disease initiation and pathogenesis

    These studies show that B cells play critical positive and negative
    regulatory roles in EAE immunopathogenesis. Consequently,
    B cell depletion had 2 opposing effects on disease. Early B cell
    depletion (day –7) in mice with otherwise normal immune systems
    exacerbated not only the early and peak phase of EAE induction
    but also the recovery phase of disease (Figure 1). Moreover, the
    adoptive transfer of IL-10–producing regulatory CD1dhiCD5+ B10
    cells, but not other B cells, normalized EAE pathogenesis (Figure 8).
    B cell depletion during the course of EAE development (day
    14) dramatically reduced disease symptoms (Figures 1 and 2),
    impaired MOG-specific T cell expansion (Figure 6, B and C), and
    significantly inhibited the influx or expansion of encephalitogenic
    T cells within the CNS and draining lymph nodes (Figures 5 and 6).
    Thereby, B cells are essential for generating optimal pathogenic
    CD4+ T cell responses following MOG immunizations, while B10
    cells appeared to exert their antiinflammatory effects early, but
    not late, during the course of EAE
    The current findings resolve previously unexplained contradictions
    between studies showing the importance of B cells in EAE.
    As in the current studies, B cell IL-10 production has been previously
    shown to suppress EAE severity (10). IL-10–produced by
    B cells can also down-regulate other autoimmune and inflammatory
    diseases such as collagen-induced arthritis, inflammatory
    bowel disease, and contact hypersensitivity (17, 41, 42). By
    contrast, mice genetically deficient for B cells appear to develop
    EAE normally but fail to resolve the disease (7, 10).
    Under these conditions, B cell
    depletion may only reduce disease during EAE progression, while
    B10 cell function may be most obvious during disease induction.
    The current studies also suggest the possibility that the selective
    depletion of mature B cells while sparing IL-10–producing B10
    cells may offer a potent therapeutic approach for treating patients
    with MS and other autoimmune or inflammatory diseases

  • B cell depletion after the onset
    of EAE symptoms ameliorated disease
    progression (Figure 1), making
    this strategy applicable for
    treating human MS after disease
    onset. However, adverse disease following
    B cell depletion before EAE
    induction in the current study also
    suggests that B cell depletion may
    promote the occurrence of MS in
    some undiagnosed cases. Nonetheless,
    B cell depletion during EAE
    development reduced EAE severity
    both clinically and histologically
    (Figures 1 and 2) and was accompanied
    by significantly reduced autoantibody
    levels (Figure 4). Reduced
    autoantibody production may be
    clinically important since plasma exchange can reduce clinical
    disease activity in a subset of MS patients (46, 47). CD20 mAb
    treatment depletes memory cells in mice but does not deplete
    long-lived plasma cells (32). Thus, CD20+ B cell depletion may
    be most beneficial when carried out before the long-lived plasma
    cell pool is established. Similarly, B cell depletion significantly
    attenuates early foreign- and autoantigen-specific CD4+ T cell
    proliferation in vivo (34). Also, B cell depletion early in the course
    of autoimmune mouse models has maximal benefit, as it is often
    not possible to reverse T cell expansion or disease progression
    once inflammatory disease is initiated (37–40). Thereby, B cell
    depletion shortly after diagnosis of autoimmune disease may
    offer the most optimal strategy for disease management

    Ps: Sorry if its to long.. 🙂

    Regulatory B cells inhibit EAE initiation
    in mice while other B cells
    promote disease progression



  • Just wondering if you're able to comment on the possible link between MS and osteoporosis (in terms of inflammation), as outlined here: https://www.healthline.com/health-news/multiple-sclerosis-osteoporosis-connection-080214#2. I have stable RRMS, no disability & no history of significant steroid use, but have recently been diagnosed with borderline osteoroposis at a relatively young age (30), & am curious about the potential role of MS in this, beyond the diseases' overlapping risk factors.

  • Monash University scientists are one step closer to solving the riddle of how nerves can self-heal.

    The scientists from the Biomedicine Discovery Institute (BDI) have found signals in the tiny transparent roundworm that control the mechanism by which severed nerves self-heal.

    Moreover, they have demonstrated how to control this process genetically, raising hopes for treating nerve injuries in humans in the future.

    The latest research, published in the journal Proceedings of the National Academy of Sciences (PNAS), established that axonal fusion restores full function to damaged nerves.

    Phosphatidylserine save-me signals drive functional recovery of severed axons in Caenorhabditis elegans

    Nervous system injury can cause lifelong disability, because repair rarely leads to reconnection with the target tissue. In the nematode Caenorhabditis elegans and in several other species, regeneration can proceed through a mechanism of axonal fusion, whereby regrowing axons reconnect and fuse with their own separated fragments, rapidly and efficiently restoring the original axonal tract. We have found that the process of axonal fusion restores full function to damaged neurons. In addition, we show that injury-induced changes to the axonal membrane that result in exposure of lipid “save-me” signals mediate the level of axonal fusion. Thus, our results establish axonal fusion as a complete regenerative mechanism that can be modulated by changing the level of save-me signals exposed after injury.


  • Quick question. Is there any evidence acupuncture can tame the immune system in MS? My academic training is screaming no. But hey worth asking as someone has recommended to me.

  • I'm a fan of your memory B cell hypothesis, while I also agree with the general ECTRIMS referendum that T cells contribute too.

    I wonder though, have you any thorough hypothesis on exactly how these B cells promote pathology, be it within or outside the CNS, in MS patients?

    We've got an idea, and we'd love to hear your thoughts: What if the memory B cells with their class-switches and somatic hypermutation generate antigens within their BCR variable regions?

    • Dear Rune
      Will you please write a guest post on this. It was on my to do list, have not got round to this but you will first need to explain what an idiotope is in lay language so people will understand.

  • With two powerful drugs approved and one available straight away. All other MS related news seems boring. I had my first course of Alemtuzimab 2 months ago. Is it likely my 3rd course if needed of even 2nd course will be cancelled to have caldribine instead? Is Alemtuzimab on its way out as a first or even 2nd line therapy?

    • In the US Alemtuzumab is only 3rd line. In Europe it will be interesting to see how choice works.

      If you are in NHS England your second course of alemtuzumab will be supported, I'm sure.

  • Interesting!

    Sanofi Genzyme and Principia Biopharma have entered into a license agreement to advance the clinical development of PRN2246, an oral drug candidate for the treatment of multiple sclerosis and other diseases of the central nervous system.

    PRN2246 is an orally available therapy designed to easily access the central nervous system (brain and spinal cord) by crossing the blood-brain barrier, and impact the signaling of immune cells and brain cells involved in autoimmunity and inflammatory processes. The drug is designed to safely and effectively modulate B-cell function without depleting these cells.


    • Yes this is a BTK inhibitor aimed at inhibiting B cells. This is not the only one. I will do a post on them when I have a moment

    • We have seen this. On the FDA website it indicates that there have been a few hundred adverse events reported in 2017 compared to 1 in 2016. However the drug has only been marketed in 2017. These adverse events needs to be put in the context of the thousands of people taking the drug.

      In the FDA website it is evident there have been deaths = 6, life threatening = 3 and hospitalisations >50 and a "number of adverse events associated with infections and infestations"

      People die as part of life and I am sure the company will investigate each and every death…as a responsible company will do. They may be deemed unrelated and if related they will no doubt try risk mitigation.

      But at present one can only speculate

    Opened the R.Times to a page article by Caroline Wyatt about the lawyer Mark Lewis going to Jerusalem for treatment. I just know I'm gonna be inundated with caring family and friends asking me about it. If the team can provide us with a post on the pertinent facts, then I'm sure I won't be the only grateful PwMS.

    • It's not actually HSCT. There's no chemo involved. It's actually collecting stem cells placing them in cns to repair damage. If it works and it's producing miraculous results. It's the like finding the fountain of youth.

    • "Opened the R.Times to a page article by Caroline Wyatt about the lawyer Mark Lewis going to Jerusalem for treatment."

      Google is stumped. Can we get a link for this ?

      Not to single you out but seems lately many other
      posts are coming in w/o direct links to a source which is inefficient.

    • Prof. Karussis of Hadassah Medical and Brain Storm Cell Therapuetics treats with intraethecal stem cells and nerve
      growth factors

    • Thanks Anon (Sat 18th, 7.27pm) for your facilitiative reply to my comment requesting that the Bart's team provide some feedback on the TV documentary.

      It was unintentional to cause frustration by not having provided clear enough information. I should have added that the documentary is on C4 this Thursday 23rd at 10pm.

      I'm sorry, Adam, but I have lousy IT skills and genuinely don't have a clue how to add the sort of direct link that Anon has kindly provided. To be honest, I didnt even know such links were available for things like the RT article – a dinosaur, as I say! So, I can't commit to definitely providing links as part of my replies/comments in the future.

      No doubt lots of us will watch the documentary with interest and no doubt it will generate lots of debate. Personally I'd feel the benefit of Bart's overview of the content.

    • No worries Fi and thanks for the heads up on the documentary. Yes, it would be good to know a Barts overview of the content.

    • There's a short interview with Mark Lewis about the documentary on the BBC Breakfast Facebook page today. You don't need to be a member of Facebook or log in to watch it. Posted today about 7hrs ago, just scroll down the page a bit to find it. Those outside the UK might be able to watch this.

    • This is very shoddy if the trial is ongoing which based on BBC breakfast appears to be the case and this is going to turn into an advertising thing for the trial. so Israel here we come

      One injection was miraculous the other did nothing. Was he paying for the treatment then it is an advert.

      We can wait to see the programme.

    • Thanks anon for alerting us to the interview.

      Just watched it and my view is similar to yours MD: no disrespect to Mark Lewis, but I had expected a distinguished lawyer to speak in more measured and factual, far less emotive, terms. For him to conclude with: hopefully it won't be long before this is rolled out for the 2.5 million of us world wide who'll benefit, is mind boggling!

      As someone who's fortunate enough to have options and chose Alemtuzumab I'm obviously not risk adverse, but I'm so sorry to think of those who'll be desperate to head to Jerusalem on the basis of the word of one guy for whom only one of two injections had any results. Plus the trial is ongoing!

      I also found it sobering to read in the RT Caroline Wyatt say that her symptoms have all returned since receiving HSCT in Mexico in Jan '17, and that she has been experiencing the most horrendous migraines to boot. As someone who's suffered in the past with terrible migraines, I wouldn't wish that, on top of MS symptoms, on my worst enemy! She states that her immune system won't reboot until sometime in 2018, so she remains hopeful and I really do wish her and Mark and others well.

      My other wish is that these things were dealt with in a balanced, even-handed manner.
      Oh well! I suspect after the documentary it'll be directing family and friends to Bart's Blog once again – MD you and the team are a life-line!

    • The same trial is also happening at the tisch centre in New York. It's also received fda approval for a larger phase 2 trial. In terms of balance. This was the perspective of a patient not a doctor. If his made recovery in couple of hours after the first injection isn't that miraculous? Regardless of the 2nd injection being placebo or not! I only see the interview as positive.

  • Hi. Are we allowed to ask personal ms treatment related questions? I had my first course of Alemtuzimab 2 months ago. The first blood revealed my lymphocyte count want down 2 base line to 0.2. But just after 1 month (2 months after last infusion) it's 1.0. Does this make me a rapid repopulate or non responder. If The first does it effect efficacy of treatment?

    • No we prefer not to answer personal questions so best frame your questions in a non personal way.

      If you look at our paper on alemtuzumab repopulation you will see that the lymphocyte subset is made of lots of different cell subtypes. The
      subtype we think is important is in the memory cell population and the immature B cells fill the space and so may be unrelated to efficacy

    • Thanks MD. Will take a look at your paper. My MS Service provider is so over burdened it's hard to get a response from them.

  • Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation


    To explore how Th1 and Th17 immune cells gain access to neurons in multiple sclerosis, Lutz and her colleagues looked at the blood-brain barrier in mice with experimental autoimmune encephalomyelitis—a mouse version of multiple sclerosis.
    They genetically labeled blood vessel endothelial cell tight junctions with a fluorescent protein to examine if and how tight junctions are involved in autoimmune encephalomyelitis in vivo in their mice. The researchers observed that the tight junctions were significantly deteriorated in the presence of Th17 cells, and that this took place early in the onset of disease. Approximately three days later in the disease process, Lutz and colleagues found that Th1 cells were accessing and degrading myelin and neurons—but these cells did not pass through tight junctions like the Th17 cells did. Instead, the circulating Th1 cells got to neurons by going through the blood vessel endothelial cells using specialized cell membrane structures called caveolae. Caveolae are small pits or "caves" found on the surface of many cell types and help facilitate the passage of various molecules and cells into and/or through cells. In mice with autoimmune encephalomyelitis bred to lack caveolae, the researchers found almost no Th1 cells in the brain and spinal cord. They determined that caveolae on endothelial cells that make up blood vessels are required to help ferry Th1 cells through the blood-brain barrier.


    • Intravital two-photon microscopy shows that TJ remodeling precedes the onset of EAE
    • Caveolar transcytosis is not required for endothelial TJ remodeling in vivo
    •Effector T cell subsets use distinct mechanisms to cross the inflamed BBB
    • Caveolar transcytosis is required for Th1, but not Th17, cell entry into the CNS


    Lymphocytes cross vascular boundaries via either disrupted tight junctions (TJs) or caveolae to induce tissue inflammation. In the CNS, Th17 lymphocytes cross the blood-brain barrier (BBB) before Th1 cells; yet this differential crossing is poorly understood. We have used intravital two-photon imaging of the spinal cord in wild-type and caveolae-deficient mice with fluorescently labeled endothelial tight junctions to determine how tight junction remodeling and caveolae regulate CNS entry of lymphocytes during the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis. We find that dynamic tight junction remodeling occurs early in EAE but does not depend upon caveolar transport. Moreover, Th1, but not Th17, lymphocytes are significantly reduced in the inflamed CNS of mice lacking caveolae. Therefore, tight junction remodeling facilitates Th17 migration across the BBB, whereas caveolae promote Th1 entry into the CNS. Moreover, therapies that target both tight junction degradation and caveolar transcytosis may limit lymphocyte infiltration during inflammation.

  • Gut bacteria seems to be all in the news these days about being the driver in all autoimmune diseases including ms. Should I be taking supplements of probiotics of "friendly bactera" to rebalance the diversity of Gut? How does this sit with barts team ? Is there any possibility of this being true?

    • Yes, there's certainly a lot of interest in this area but there's also a lot of over-extrapolation and hype too. I'm viewing the area with a degree of scepticism at the moment. Can't see probiotics as doing any harm though.

  • Thanks MD2. Yeah it's worth a punt. As well as 10000iu of vitamin d3, spoon of hemp oil for omega3, and Lipoic acid!

  • Last night's program in search of miracle cure, shows MS is a complicated disease probably caused by a number of pathogens and genetic susceptibility and environment. Although stem cells showed in the trial to be effective in repairing damage. However, the continued immune attack will mean any such treatment is doomed to failure. Until the mechanism of nerve degeneration is fully understood and stopped in Progressive ms. Such treatments will always be futile. No biological repair process will win against immune attack.

  • Increase of inflammatory activity in PMS patients treated with oral high-dose biotin

    In our cohort of PMS patients treated with high-dose biotin we recorded an unexpected high rate, both clinical and radiological, of inflammatory activity. Clinicians should be very cautious when prescribing this drug until its efficacy and safety are definitely proven.


    • Could this inflammatory activity that Biotin produces, a sign that it works? What can it tell us about progressive and relapsing phases?

  • New avenue for drug treatment in neuropathic pain

    Using cellular and mouse models of neuropathic pain the authors studied a cluster of neurons in the dorsal root ganglion (DRG), which are part of the sensory neurons that play an important role in communicating pain information to the brain. They found that after nerve injury, pain neurons in this area released very small biological particles containing microRNA-21. These particles were then taken up by surrounding immune cells, ultimately leading to local inflammation and neuropathic pain.

    The authors showed that when they blocked DRG pain neurons from releasing microRNA-21 in particles, this had an anti-inflammatory effect at a cellular level, which prevented neuropathic pain from occurring in mice. The advantage of this method is that these particles, containing agents that block microRNA-21, do not infiltrate the brain and lead to side effects.

    In humans, a similar method could be applied to block pain neurons from releasing microRNA-21 in particles, which would prevent neuropathic pain from ocurring. If successful, this would be the first drug to target neuropathic pain in specific areas without side effects, which is in stark contrast to the non-specific painkillers currently available.

    Fortunately, similar treatments are already being trialled in cancer patients receiving immunotherapy, making the application to other conditions like neuropathic pain highly feasible.


  • Effects of Bacille Calmette-Guérin after the first demyelinating event in the CNS


    BCG vaccination appears to have early beneficial effects and possibly long-term action in persons with CIS, supporting previous observations in patients with MS.12,13 Compared with placebo, BCG significantly decreased disease activity at MRI and the number of new T1-hypointense lesions during the first 6 months. In addition, BCG may have longer effects: treated people had less T1-hypointense lesions and cumulative number of relapses after 18 months and showed a reduced risk of conversion to CDMS over 5 years.

    The long-lasting effects of BCG vaccination are important29,30 and will have to be taken into account if and when phase 3 trials will be initiated. In fact, the proper dose and frequency of BCG remain to be determined. Repeated vaccinations may be an option (as recently reported for patients with insulin-dependent diabetes mellitus).31 However, considering the duration of the favorable effects in MS, more “relaxed” vaccination schedules may be possible, hence reassuring against possible harms of too frequent immunizations (hyperergic reactions, and T helper 17–dependent tissue damage).32 Taken as a whole, our results warrant future phase 3 trials in people with CIS, with additional outcome measures (whole brain and gray matter atrophy, among others) especially aimed at verifying a potential neuroprotective effect. Moreover, our findings demonstrate the feasibility and possible benefit of safe, inexpensive, and handy approaches immediately after the first demyelinating episode.

    (I am posting this as BCG vaccine is in Phase II trial to reverse type 1 diabetes. There is a 2013 post about the paper in the blog).

  • Team develops neuro test that distinguishes demyelinating diseases from multiple sclerosis

    Mayo Clinic has launched a first-in-the-U.S. clinical test that will help patients who recently have been diagnosed with an inflammatory demyelinating disease (IDD) but may be unsure of the exact disorder.

    The test uses live cells to identify patients who are positive for an antibody to myelin oligodendrocyte glycoprotein (or "MOG," for short). But why is this sticky protein so important?

    "From our years of research, we have learned that if patients test positive for MOG antibodies, it generally indicates that it's not classical MS," says Sean Pittock, M.D., a Mayo Clinic neurologist and director of the Mayo Clinic Neuroimmunology Laboratory. "And, more important, some MS treatments have been reported to worsen the disease of patients diagnosed with an IDD that is not classical MS."


    • This topical as it is all over the news today.

      This is a Controlled Trial of Erenumab for Episodic Migraine.
      This work was done by Peter Goadsby who we know very well.

      This is an antibody against calcitonin gene-related peptide.
      CRRP is a potent peptide vasodilator and can function in the transmission of pain. In the spinal cord, the function and expression of CGRP may differ depending on the location of synthesis. CGRP is derived mainly from the cell bodies of motor neurons when synthesized in the ventral horn of the spinal cord and may contribute to the regeneration of nervous tissue after injury. Conversely, CGRP is derived from dorsal root ganglion when synthesized in the dorsal horn of the spinal cord and may be linked to the transmission of pain

      However again my question is why are we using antibodies to try and treat brain problems, if that is where the migraine originates as antibodies are going to have such poor penetration. However they are reporting benefit

    • Erenumab blocks the CRGP receptor to stop it working and treat migraine, in this study they have a lack of CRGP and it makes EAE worse, so if you pay attention to the animal work you will not try it for MS migraine because it would make the MS worse…..Would you risk it?

    • Thank you for your replies. I have PPMS and occasional migraine; when I first saw a news article on this new migraine therapy I wondered – "Ooh, and who knows, maybe there will turn out to be an added bonus of some sort of benefit for MS too." But after seeing that EAE paper I realised it might well rather be a risk of the opposite, as you have confirmed. No, I wouldn't touch this migraine therapy with a barge pole. I'll stick to ibuprofen.

  • A little more Vitamin D??

    Maintaining sufficient vitamin D levels may help to prevent the onset of inflammatory diseases like rheumatoid arthritis, research led by the University of Birmingham has discovered.

    “Our current understanding of vitamin D and rheumatoid arthritis is based on studies of patient blood which may not truly represent the situation at the site of inflammation – the joints.

    “We therefore investigated responses to the active form of vitamin D in immune cells from the inflamed joints of patients with rheumatoid arthritis.

    “Compared to blood from the same patients, the inflamed joint immune cells were much less sensitive to active vitamin D.

    “This appears to be because immune cells from the joints of rheumatoid arthritis patients are more committed to inflammation, and therefore less likely to change, even though they have all the machinery to respond to vitamin D.”

    “However, for patients who already have rheumatoid arthritis, simply providing vitamin D might not be enough. Instead much higher doses of vitamin D may be needed, or possibly a new treatment that bypasses or corrects the vitamin D insensitivity of immune cells within the joint.”


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