Tag: T cells

Check-point charlie

Barts-MS rose-tinted-odometer ★★★★★ 

The argument about whether or not MS is primarily a T-cell or B-cell disease is academic. Almost all the data suggests that both cell types are involved. Clinical trial data also suggests MS outcomes when it comes to end-organ damage (brain volume loss) is superior for therapies that target both  T and B cells, i.e. alemtuzumab and HSCT over say mainly B-cell therapies (rituximab, ocrelizumab, ofatumumab and cladribine). I have posted on the latter topic in the past, i.e. see ‘Beyond NEDA’. 

Another big clue is worsening MS and new-onset MS after the treatment of cancer with the relatively new class of treatments called immune checkpoint inhibitors (ICI). These drugs target cell surface receptors that inhibit T-cell activation. Remove the inhibition and you lower the threshold for T-cell activation. About 50% of patients treated with ICI develop immune-mediated complications including new-onset MS. 

The study below identifies 14 cases of MS after ICI, which I suspect is just the tip of the iceberg. The type of MS induced by ICI appears to be much more aggressive in onset and disease course. Why? I suspect because the activated T-cells are not being regulated as a result of ICI  treatment. 

I am aware that some people argue that these cases don’t represent true MS, but a different disease. I don’t agree. Why? There is an increasing number of people with established MS who develop malignancies requiring treatment with ICI.  In many of these cases, ICI triggers major relapses and rebound disease activity. The sceptics can’t really argue that these patients don’t have MS. 

The use of ICI in patients with established MS is creating a treatment dilemma. They clearly need the ICI to treat their cancer, but how do you manage their MS during the high-risk period when they are on ICI? 

I recently recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The potential downside of this strategy is that if she had occult secondaries in her CNS and gut, areas of the body that natalizumab reduced lymphocyte trafficking, natalizumab will prevent her activated T-cells finding and clearing cancer cells in these organs. As bowel cancer rarely metastasizes to the CNS we thought this was a risk worth taking. 

The last update I had about this patient was that she was doing well from the MS perspective (natalizumab is a very effective DMT), but she was not doing that well in relation to her bowel cancer. She, unfortunately, had liver metastases that had not responded as hoped to the ICI. 

I am also sure that natalizumab will prevent the CNS complications associated with CAR-T cell therapies. Could this be a repurposing opportunity for natalizumab? I have informed Biogen about this possibility. 

So in conclusion, don’t let anyone try and convince you that MS is only a B-cell disease. It is a T-cell and B-cell disease and we are really lulling ourselves into a false sense of security by thinking anti-B-cell monotherapy is sufficient to treat MS. The anti-B-cell therapies may appear very effective and safer in the short term, but as a class, their impact on brain volume loss (end-organ damage) is just not good enough for me (see NEDADI post). This is why we need to think about using anti-B-cell therapies differently, i.e. as part of an induction-maintenance strategy or in combination with other therapies that target other disease processes. 

Garcia et al. Multiple Sclerosis Outcomes After Cancer Immunotherapy. Clin Transl Oncol, 21 (10), 1336-1342 Oct 2019. 

Introduction: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes.

Methods: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution.

Results: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors.

Conclusions: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.

CoI: multiple

Beyond NEDA

Prof G are we being lulled into a false sense of security by being told that we have no evident disease activity (NEDA)?

A patient of mine, who I have been looking after now for over 11 years, asked me in clinic a few weeks ago why despite being NEDA for 6 years, on a highly effective maintenance DMT (fingolimod), has she gone from being able to run 5-10 km to needing a stick and barely managing to walk from the Whitechapel Underground Station to my clinic (~200m), without having to stop and rest?

What this patient doesn’t know, despite no new visible T2 lesions, is that she has developed obvious, to the naked eye, progressive brain atrophy.  This particular patient prompted me to write a few blog posts to try and explain what is happening to her brain. Before reading the remainder of this post you may want to read the following posts:

An important question in relation to this patient is why do some DMTs have such a profound impact on end-organ damage markers, in particular, brain volume loss and others do not? Not all DMTs are made equal when it comes to preventing, or slowing down, brain volume loss.

At the top of the league table are alemtuzumab and HSCT (~0.2-0.25% loss per annum). Both these treatments are NIRTs (non-selective immune reconstitution therapies). Natalizumab is next with an annual brain volume loss in region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes fourth with a rate of brain volume loss of ~0.30-0.35% per annum. Fingolimod 5th at ~0.4% per annum. Cladribine has a rate of loss of brain volume of ~0.55% per annum with the other runs after that.

For me, the disappointment are the anti-B cell therapies, ocrelizumab and cladribine. Despite these DMTs being very effective at switching off new focal inflammatory lesions (relapses and new T2 and Gd-enhancing lesions) their impact on end-organ damage is only moderate. These observations have convinced me more than ever that focal inflammation is not MS, but simply the immune system’s response to what is causing MS. The latter hypothesis is what I have been presenting as part of my ‘Field Hypothesis’ for several years on this blog.

What these observations are telling me is that peripheral B-cells are a very important part of the immune response to the cause of MS, but they are not necessarily involved in driving the true pathology, which is causing the progressive brain volume loss. The caveat to this is that anti-CD20 therapies and cladribine may not be eliminating the B-cells and plasma cells within the CNS, which is why we need add-on treatments to try and scrub the brain free of these cells to see if the brain atrophy rate ‘normalises’. This is why we are starting a safety study this year of an add-on myeloma drug to target the CNS B-cell and plasma cell response to test this hypothesis.

What does this mean for the average person with MS? Firstly, you may not want to dismiss alemtuzumab and HSCT as a treatment option. These NIRTS differ from anti-CD20 therapies and cladribine in that they target both B and T cells. We may need to target both these cells types to really get on top of MS. I am aware of the appeal of anti-CD20 therapies and cladribine; they are safer and easier to use because of less monitoring, however, this may come at a cost in the long-term. The SIRTs (selective IRTs) may not be as good as the NEDA data suggests. Please remember that once you have lost brain you can’t get it back.

The tradeoff with alemtuzumab and HSCT is the frontloading of risk to get the greatest efficacy over time. Choosing a DMT on a rung or two down on the therapeutic ladder gives you better short-term safety and makes the lives of your MS team easier, because of less monitoring, but at a potential long-term cost to your brain and spinal cord.  This is why to make an informed decision about which DMT you choose is a very complicated process and subject to subtle and often hidden effects of cognitive biases. The one bias I am very aware of is the ‘Gambler’s Dilemma’, be careful not to be lulled into a false sense of security by your beliefs; most gamblers lose.

Over the last few years you may have seen a theme developing in my thinking as we move the goalposts in terms of our treatment target beyond NEDA-3 to target end-organ damage, i.e. brain volume loss, T1 black holes, the slowly expanding lesions (SELs), neurofilament levels, cognition, sickness behaviour, OCBs, etc. Our treatment aim should be to ‘Maximise Brain Health’ across your life and not just the next decade. Please stop and think!

When I was preparing this post I dropped Prof. Doug Arnold an email about the impact of alemtuzumab and HSCT on the slowly expanding lesion or SEL. Unfortunately, these analyses have not been done despite good trial data sets being available for analysis. He said it was a resource issue; i.e. a euphemism for money and permission to do the analyses. For me, these questions are the most important ones to answer in 2019. Wouldn’t you want to know if alemtuzumab and HSCT were able to switch off those destructive SELs in your brain? Knowing this may impact your decision to go for the most effective DMTs; frontloading risk to maximise outcomes in the long term.

What should I advise my patient; to stay on fingolimod or to escalate to a more effective DMT?

The following articles are the important ones for you to read or at least be aware of:

Article 1

Lee et al. Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. Mult Scler. 2017 Mar;23(3):420-431.

BACKGROUND:  A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.

OBJECTIVE: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT.

METHODS: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions.

RESULTS: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging.

CONCLUSION: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.

Article 2

Arnold et al. Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS. Neurology. 2016 Oct 4;87(14):1464-1472.Neurology. 2016 Oct 4;87(14):1464-1472.

OBJECTIVE: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).

METHODS: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).

RESULTS: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a.

CONCLUSIONS: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS.

CLINICALTRIALSGOV IDENTIFIER: NCT00530348 and NCT00548405.

CLASSIFICATION OF EVIDENCE: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.

Article 3

Vavasour et al. A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab. Mult Scler. 2018 Apr 1:1352458518770085. doi: 10.1177/1352458518770085.

BACKGROUND: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment.

OBJECTIVE: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab.

METHODS: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated.

RESULTS: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year.

CONCLUSION: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.

CoI: multiple

To T or not to T (2)

Prof G what happens to MS disease activity if you stimulate T-cells?

About 2 years ago I attended a grand round during which a patient with a history of RRMS had had a catastrophic relapse after receiving ipilimumab for metastatic melanoma. The patient has a massive brain stem relapse and her MRI showed multiple Gd-enhancing lesions with several pseudotumoral lesions. She was in a bad way. Interestingly, this case was not unique as a very similar case had been published. In addition, there are series of other examples of ipilimumab and other immune checkpoint inhibitors exacerbating and/or triggering autoimmune diseases including an MS-like disease. I say MS-like because we don’t know for sure if these cases will turn out to have classic MS on biopsy, or at post-mortem, to prove they have definite MS according to a conventional definition of the disease.

Ipilimumab belongs to the class of drugs called ‘checkpoint inhibitors’ that are designed to remove one of the immunological brakes that control T-cell activation. Ipilimumab is one of many T-cell stimulants that have revolutionised the care of patients with various different cancers. Ipilimumab is a very smart drug it blocks CTLA-4, a cell surface molecule on T cells, which normally blocks or downregulates T cell activation when it binds to CD80 and CD86 on antigen-presenting cells. Ipilimumab enhances the anti-tumoral response while increasing the likelihood of autoimmunity.

So what has this really got to do with MS? Well, these cases are telling us in a not so subtle way that by stimulating T-cells we can exacerbate MS. In other words, T-cells are probably still active in established MS. What this experiment is not telling us is which population of T-cells is the culprit as CD4+, CD8+ and T-regulatory cells express CTLA-4 and are hence affected by Ipilimumab. Nor is it telling us about the APC side, which APC is stimulating the T-cells. Is it the B-cell, the macrophage/microglia or another APC?

The moral of this story is that it takes two to tango; the T-cell and its APC. The question is which APC is the preferred partner for the T-cell in MS. Based on the evidence the B-cell seems to be the dominant partner, but who knows in the presence of peripheral B-cell depletion other less dominant partners may take to the floor.

Gettings et al. Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma. Mult Scler. 2015 Apr;21(5):670.

56-year-old male, diagnosed in December 1997 with RRMS. Treated with glatiramer acetate in February 1998. Relatively good response to GA with only sensory relapses. In 2005 methotrexate was added. His MS stabilized and he was free of relapses from 2005 to 2013 with a slight increase in disability from an Expanded Disability Status Scale (EDSS) score of 1 to 1.5. In September 2009 diagnosed with melanoma. He had a recurrence in November 2012 with metastases to soft tissue and lymph nodes. He was started on ipilimumab. Methotrexate and glatiramer acetate were stopped prior to initiating ipilimumab. Within one month, he presented with subacute onset of left lower extremity hemiparesis, gait dysfunction and ataxia. An MRI revealed a new left centrum semiovale enhancing lesion consistent with active demyelination. His symptoms improved with high dose methylprednisolone. Ipilimumab was continued. In May 2013 he was readmitted for transient left-sided weakness and ataxia. MRI revealed an enhancing lesion in the right corona radiata. Follow-up imaging revealed a second enhancing lesion in the right frontal lobe and he was restarted on glatiramer acetate and steroids.

To T or not to T

I have always wondered why the genomic experts in the field of MS haven’t been able to sort out why specific human leukocyte antigen (HLA) subtypes increase your risk of getting MS and others don’t.



HLA or human leukocyte antigens are the so-called signposting proteins that antigen presenting cells (APCs) use to communicate with T-cells. The APCs continuously sample the environment and present small peptides in their HLA molecules to T-cells. The HLA molecules interact with the so-called T-cell receptor (TCR) and if the peptide (message) that has been loaded in the HLA groove (signpost) and TCR, which acts as a molecular reader, fit perfectly it tells the T-cell that it should go on the attack. In the context of MS, this attack is considered to autoimmune or dysfunctional and against a self-peptide. However, the attack could be entirely appropriate and targeted against a foreign protein or a self-protein that has been altered by a process called post-translational modification. Interestingly, smoking and solvents, exposure to which are both risk factors for developing MS, are two environmental exposures that are known to cause post-translational modifications of proteins.

The following YouTube animation shows you an example of how a TCR (reader) interacts with a specific HLA molecule (signpost) and the peptide (message) in the groove of a specific HLA molecule. By watching this video you may appreciate how specific this interaction really is.

The most important genetic risk factor for deevloping MS is the so-called HLA-DRB1*15:01 molecules. If you have one copy of this gene your risk of getting MS is ~3X greater than someone without this gene. If you have two copies your risk of getting MS is about ~6X greater. In other words from a genetic perspective, you don’t want to have the HLA-DRB1*15:01 signposts.

It turns out that there, not all HLA-DRB1*15:01 molecules are made equal and that if you have the African variety, compared to the European variety, your risk of getting MS is 3x lower. Interestingly, the African and European varieties of the HLA-DRB1*15:01 genes differ in their sequence in a way that would affect the so-called peptide binding groove of the HLA molecule. This would mean that they would bind peptides differently and hence affect the way that T-cells may or may not be activated. How interesting?

The African variety of HLA-DRB1*15:01 is presumably older and the genetic change in HLA-DRB1*15:01 that is now known as the European variant must have been selected for after man left Africa and migrated into Europe. The most likely evolutionary selection pressure for this selection was repeated exposure to an infection, which selected for this variant, with the later consequence of being an increased risk of getting MS.

What is the significance of these findings? It is telling us that MS risk is related to a very specific HLA-DRB1*15:01 variant and this variant, by definition, must be interacting with a specific family of peptides or possibly a single peptide in our environment or body. Wouldn’t it be great if we could find this peptide or family of peptides? It could potentially lead us to the cause of MS.

It is important to realise that the HLA-DRB1*15:01 association with MS, and these new findings in relation to the African and European variants, is telling us that the T-cell must be the central player, or conductor, in the pathogenesis of MS and must be upstream of the B-cell. I have mulled over this for many years and I can’t think of another way of interpreting these results. Do you agree?

Chic et al. Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry. PLoS Genet. 2019 Jan 17;15(1):e1007808. doi: 10.1371/journal.pgen.1007808.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.

To B or not to B

Is targeting the B-cell sufficient to get on top of MS or do we need something extra?

I spoke at the MS Nurses’ MS@TheLimits2019 meeting at the Royal College of Physicians yesterday. My brief was to cover the role of B-cells in the pathogenesis of MS and to review the converging evidence that supports B-cells being the central player in the pathogenesis of MS.

It is clear that depleting B-cell therapies are very effective in controlling relapses and MRI activity. With a very favourable safety profile and relatively low treatment and monitoring burden, B cell therapies are likely to become one of the most widely prescribed classes of DMT. However, B-cell therapies don’t match HSCT, alemtuzumab and natalizumab when it comes to downstream end-organ damage markers, in particular, brain volume loss. Why? I wish I knew. But if I knew the answer to this question I would have a pretty good idea about the cause of MS.

A clue may be in the ‘Field Hypothesis‘. It is clear to me that relapses and focal MRI activity are not the primary events in MS. Focal inflammation is not MS. Focal inflammation is in response to what is causing MS and the cause is likely to be something in the CNS. Focal changes occur in the white matter weeks to months before you get a Gd-enhancing lesion. When you stop natalizumab and allow re-trafficking of lymphocytes you get rebound disease activity way and above what one would expect from pre-treatment baseline levels of disease activity. What is happening in the brain, or field, of these patients to trigger such a vigorous inflammatory response? Could it be a virus? Importantly, B-cells appear to be needed for the rebound response. Rituximab, and I suspect ocrelizumab, are very effective in preventing rebound. However, as both these agents target a small subset of T-cells you can’t claim categorically that the rebound is only driven by B-cells.

The difference between HSCT, alemtuzumab and natalizumab and the anti-B cell therapies (rituximab, ocrelizumab and possibly cladribine) is the former take out or inhibit trafficking of both T & B cells. As HSCT and Alemtuzumab have the best data in relation to long-term remission, or potential cures, you have to conclude that you need to target both B cell and T cells (substantial peripheral depletion) if this is your treatment aim.

Please note that I classify cladribine as a B-cell depelter and not a dual B and T cell depelter. The level of T-cell depletion with cladribine is modest at the licensed dose (~50%) which is not sufficient to put it into the same class as alemtuzumab and HSCT. This is one of the reasons why I refer to cladribine as being a SIRT (selective immune reconstitution therapy) and the others as NIRTs (non-selective immune reconstitution therapies).

I have always made the point that to treat MS you need much more than an anti-inflammatory and that you also have to have neuroprotective therapies and potentially remyelinating agents on board as well. If you have disabilities we need to be thinking about neurorestorative therapies and finally you need to target lifestyle and wellness to tackle the issue of comorbidities and ageing.

So in short, targeting B-cells is important, but not sufficient to get on top of the shredder.

You will see that a large part of my talk was covering the link between EBV, B–cells and MS. The B-cell hypothesis at least strengthens the case for EBV being the cause of MS and the need for an EBV vaccine for MS prevention trials. Please don’t forget that EBV lives inside memory B cells and hijacks the B cell’s biology in many ways that have potential relevance to MS and other autoimmune diseases.

My talk will be available online in a few weeks to help you interpret my presentation. In the interim you can download my talk from my slide sharing site.

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