Saturday, 31 October 2015

Bad B cells make GM-CSF

Li et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy.Sci Transl Med. 2015 Oct 21;7:310ra166.

Background: B cells are not limited to producing protective antibodies; they also perform additional functions relevant to both health and disease. However, the relative contribution of functionally distinct B cell subsets in human disease, the signals that regulate the balance between such subsets, and which of these subsets underlie the benefits of B cell depletion therapy (BCDT) are only partially elucidated. We describe a proinflammatory, granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing human memory B cell subset that is increased in frequency and more readily induced in multiple sclerosis (MS) patients compared to healthy controls. In vitro, GM-CSF-expressing B cells efficiently activated myeloid cells in a GM-CSF-dependent manner, and in vivo, BCDT resulted in a GM-CSF-dependent decrease in proinflammatory myeloid responses of MS patients. A signal transducer and activator of transcription 5 (STAT5)- and STAT6-dependent mechanism was required for B cell GM-CSF production and reciprocally regulated the generation of regulatory IL-10-expressing B cells. STAT5/6 signaling was enhanced in B cells of untreated MS patients compared with healthy controls, and B cells reemerging in patients after BCDT normalized their STAT5/6 signaling as well as their GM-CSF/IL-10 cytokine secretion ratios. The diminished proinflammatory myeloid cell responses observed after BCDT persisted even as new B cells reconstituted. These data implicate a pro-inflammatory B cell/myeloid cell axis in disease and underscore the rationale for selective targeting of distinct B cell populations in MS and other human autoimmune diseases.

Immunology is complex and gets more complex as more discoveries occur. We know that the B cell is where the action is. With the exception of daclizumab all highly effective DMTs have an effect on B cells. The fact that targeting mainly B cells with anti-CD20 therapy has proven to be very effective is proof that the B cell is likely to be the main target of these therapies.  This is associated with the loss of B cell population that makes a cytkine called GM-CSF which controls a B regulatory cell that produces interleukin 10. So we have pathogenic and regulatory B cells will they replace pathogenic and regulatory B cells

Myelin Autoimmunity is lacking

van Nierop GP, Janssen M, Mitterreiter JG, van de Vijver DA, de Swart RL, Haagmans BL, Verjans GM, Hintzen RQ. Intrathecal CD4+ and CD8+ T cell responses to endogenously synthesized candidate disease-associated human autoantigens in multiple sclerosis patients. Eur J Immunol. 2015 Oct 28. doi: 10.1002/eji.201545921. [Epub ahead of print]

Multiple sclerosis (MS) pathology is potentially orchestrated by autoreactive T cells, but the antigens recognized remain unknown. A novel APC/T cell platform was developed to determine intrathecal CD4+ and CD8+ T cell responses to candidate MS-associated autoantigens (cMSAg) in clinically isolated syndrome (CIS, n = 7) and MS (n = 6) patients. Human cMSAg encoding open reading frames (n = 8) were cloned into an Epstein-Barr virus (EBV)-based vector to express cMSAg at high levels in EBV-transformed B-cells (BLCLs). Human cMSAg cloned were myelin-associated and -oligodendrocyte glycoprotein, myelin basic protein (MBP), proteolipid protein, ATP-dependent potassium channel KIR4.1, S100 calcium-binding protein B, contactin-2 and neurofascin. Transduced BLCL were used as autologous APC in functional T cell assays to determine cMSAg-specific T cell frequencies in cerebrospinal fluid derived T cell lines (CSF-TCLs) by intracellular IFN-γ flow cytometry. Whereas all CSF-TCL responded strongly to mitogenic stimulation, no substantial T cell reactivity to cMSAg was observed. Contrastingly, measles virus fusion protein-specific CD4+ and CD8+ T cell clones, used as control of the APC/T cell platform, efficiently recognized transduced BLCL expressing their cognate antigen. The inability to detect substantial T cell reactivity to eight human endogenously synthesized cMSAg in autologous APC do not support their role as prominent intrathecal T cell target antigens in CIS and MS patients early after onset of disease.

So yesterday we had the B cell autoimmunity and not to be outdone we get T cell autoimmunity. In this study they get B cells to express a number of antigens and then see if T cells present in the CNS respond to them and surprise, surprise they don't respond to the common myelin antigens although they can be stimulated with a mitogenic (stimulates T cells independent of there T cell receptor). About twenty years ago this type of study was done on blood cells and they found that T cells did not respond to myelin antigens but responded to alpha B crystallin which wasn't examined here. But yesterday we were showing B cells respond to nerves and glia and not myelin and today we see that T cells are not responding to myelin, so some ideas of autoimmunity masy need abit of a think. However, many cells in the CNS will be attracted in by the inflammatory environment and the majority have nothing to do with disease. Furthermore we have to remember the target in MS is the oligodendrocyte, but it ain't MBP

Friday, 30 October 2015

There is autoimmunity in MS. B means Bad!

Blauth K, Soltys J, Matschulat A, Reiter CR, Ritchie A, Baird NL, Bennett JL, Owens GP. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants. Acta Neuropathol. 2015 Oct 28. [Epub ahead of print]

B cells are implicated in the aetiology of multiple sclerosis (MS). Intrathecal IgG synthesis, cerebrospinal fluid (CSF) oligoclonal bands and lesional IgG deposition suggest a role for antibody-mediated pathology. We examined the binding of IgG1 monoclonal recombinant antibodies (rAbs) derived from MS patient CSF expanded B cell clones to central nervous system (CNS) tissue. MS rAbs displaying CNS binding to mouse and human CNS tissue were further tested for their ability to induce complement-mediated tissue injury in ex vivo spinal cord explant cultures. The staining of CNS tissue, primary human astrocytes and human neurons revealed a measurable bias in MS rAb binding to antigens preferentially expressed on astrocytes and neurons. MS rAbs that recognize myelin-enriched antigens were rarely detected. Both myelin-specific and some astrocyte/neuronal-specific MS rAbs caused significant myelin loss and astrocyte activation when applied to spinal cord explant cultures in the presence of complement. Overall, the intrathecal B cell response in multiple sclerosis binds to both glial and neuronal targets and produces demyelination in spinal cord explant cultures implicating intrathecal IgG in MS pathogenesis.

This study clearly shows what we have been saying....for ever..and that is B cells are bad news.

So it is not surprising that all drugs (bar one) that really work well in MS, block B cell function.

Immunologists have spent years trying to drive a Th1 (Autoimmunity causing) response into a Th2 (antibody/allergy causing) response..that is until Tregs came along :-), which would have made T cells that help B cells to produce antibodies would be bad news. Just as well we did not waste any energy trying to do this. It was always clear to us that both Th1 and Th2 are bad news despite the dogma, get rid of both of them.

In this study they take B cells from the cells in the CNS and manufacture the antibodies that they produce and make some synthetic antibodies. It is clear that some of these respond to brain tissue and so there is autoimmunity in MS

It is equally clear that they are largely not against myelin. So where does this put the idea held by some that mylein basic protein as the main target in MS, but many years ago it was shown that T cell reaction of MBP was a minor thing and when you do react you get peripheral neuropathy.

The antibodies targeted nerves and glia and could easily cause nerve damage and demyelination and this could drive progressive nerve damage and tells us that we need to get rid of plasma cells in the CNS. 

We have to remember that they may not be the real cause but a consequence of events whereby damage caused release of nerve and glial components that caused an antibody response and this is perhaps part of the reason that pwMS produce anti-neurafilments

We have known that there are damaging antibodies in the CSF because when we purified them and then injected them into the brains of meeces it was not a pretty sight. So we need to get rid of plasma cells from the CNS and the body to cut down antibody production.

None of the anti-B cell antibody treatments will do this effectively although anti-CD20 can block the production of cells that will become plasma cells, but there is a way and yes you can guess what I will say. So are you up for a study? 

We (I mean ProfG & DrK) have been discussing this for a while and hope we can get people, who have been ignored for trials, into a study to test this idea and hopefully save some brain in the process. Who is going to fund it?

Will Teva and Biogen Come together for the sake of DMF, laquinimod polypill

Hund AC, Lockmann A, Schön MP. Mutually enhancing anti-inflammatory activities of dimethyl fumarate and NF-κB inhibitors - Implications for dose-sparing combination therapies. Exp Dermatol. 2015 Oct 29. doi: 10.1111/exd.12892. [Epub ahead of print]

Fumaric acid esters, dimethyl fumarate (DMF) in particular, have been established for the therapy of psoriasis and, more recently, multiple sclerosis. In light of therapy-limiting dose-dependent side effects, such as gastrointestinal irritation, reducing the effective doses of FAE is a worthwhile goal. In search of strategies to maintain the anti-inflammatory activity of DMF at reduced concentrations, we found that NF-κB inhibition augmented key anti-inflammatory effects of DMF in two complementary experimental settings in vitro. At non-toxic concentrations, both proteasome inhibition with bortezomib as well as blocking NF-κB activation through KINK-1, a small-molecule inhibitor of IKKβ, profoundly enhanced DMF-dependent inhibition of nuclear NF-κB translocation in TNFα-stimulated human endothelial cells. This resulted in significant and selective co-operative down-regulation of endothelial adhesion molecules crucial for leukocyte extravasation, namely E-selectin (CD62E), VCAM-1 (CD106) and ICAM-1 (CD54), on both mRNA and protein levels. Functionally, these molecular changes led to synergistically decreased rolling and firm adhesion of human lymphocytes on TNF-activated endothelial cells, as demonstrated in a dynamic flow chamber system. If our in vitro findings can be translated into clinical settings, it is conceivable that anti-inflammatory effects of DMF can be achieved with lower doses than currently used, thus potentially reducing unwanted side effects
Tecfidera has poor pharmacokinetics meaning repeated administraion over the day and it has some problems associated with gut. This study indicaes that tecfidera has some affect on NF-kappa B, which is a factor that is involved in activating cells to produce cytokines and other pro-inflammatory things. In this study they inhibit the NF-kappa B  and this augumented the action of Tecfidera. So if you could do this could you reduce the dose and the side effects of tecfidera. So what drug inhibits tNF-kappa B and an answer is Laquinimod. This is a not very good DMT interms of blocking relapses but it may be neuroprotective. Do you think that they Biogen and Teva would form an alliance to see if a combination of the two would work...... Yep my thoughts too.

However this highlights the importance of understanding how drugs interact and whether the action of one interferes or augments another. It is important and it is also another reason why induction therapy has advantages as it allows you to add drugs on top of immunomodulation without the worry of drug interactions as the first drug.

Thursday, 29 October 2015

Take two - PoliticalSpeak: Off-patent Drugs Bill - 6th November

Here's the email I sent Chuka Umunna on 18 Oct: 

Dear Mr Umunna

I am contacting you about the drug re-purposing Bill to ask for your support to see it become Law. I believe it comes before the house on November 6. I attach some documents setting out the case for the Bill and please excuse me if you are already familiar with the arguments.

Breakthroughs in research have meant that several existing drugs have been found to be effective in treating conditions other than the ones they were originally made and patented for. They are referred to as “off patent” drugs. Repurposing these could have potentially huge benefits for many people suffering from conditions like multiple sclerosis (MS) and Cancer. They can be supplied at low cost by Generic Drug companies. The annual treatment for a patient may be less than £1,000 versus over 20x the cost for patented alternatives if in fact they exist. The savings would be of great benefit to patients, the NHS and the taxpayer, and could lead to treatment for many people whose treatment is denied by NICE on the grounds of cost.

However, drugs need to be licensed and approved for their new uses in order to be made available and there is little commercial incentive for pharmaceutical companies, who normally sponsor this process, to do so for off patent treatments. This is largely because prices generally fall a great deal once the patent has expired. There is no mechanism in place to enable licensing of drugs for uses other than their original purpose. Even if a doctor can refer to strong evidence in support of prescribing an off-patent drug to a patient, they would likely be put off by the potential personal liability they may face in doing so. 

There are thus political, legal and commercial barriers in place to prescribing off patent drugs. The Bill seeks to overcome these barriers by obliging the Government to act in the public interest through the process of the Medicines and Healthcare Regulatory Agency (MHRA) to license and approve off-patent, repurposed drugs for use on the NHS. 

The Bill is strongly supported by medical charities and specialists in the NHS, including myself - I am a Reader in Clinical Neurology at Queen Mary University of London & Consultant Neurologist at Barts Health NHS Trust.  As a clinical academic with an interest in MS, I know that early effective treatment of people with MS is key for a beneficial long term outcome.  I therefore have a particular interest in the re-purposing of Cladribine, a drug licensed in the UK for patients with hairy cell leukaemia.  There is evidence from phase III trials that Cladribine is highly effective and safe for people with MS.  The annual cost of Cladribine treatment in MS would be under £1,000 compared to licensed drugs of lesser efficacy that cost 20x or more.  I would be very happy to expand on this example further if you are interested and have the time; just call me on my mobile xxx.

For now, I do hope you are able to support the Bill. Please let me know if there is anything further I can do to promote it.

With best wishes

Sincerely Yours,
Klaus Schmierer

I'll keep watching out for comments by my MP, over and above his auto-reply...

PoliticalSpeak: Off-patent Drugs Bill - 6th November

Dear Chuka Umunna

I am Professor of Neurology at Barts Health NHS Trust and have a sub-specialty interest in multiple sclerosis (MS).

MS is the most common disabling disease to affect young adults in the UK. An estimated 120,000 people have MS in the UK. As it affects young people its socioeconomic impact is very large. There is a long list of drugs that may be effective in treating MS that are now off-patent. I therefore urge you to support the second reading of the "Off-patent Drugs Bill" on the 6th November 2015, which has been introduced by Nicklaus Thomas-Symonds. Last year a similar bill by Jonathan Peter Evans got little attention by members of the House of Commons. Please do not let this happen again.

Although the issues this bill addresses are complex, it provides an opportunity for the UK to become a world leader in drug repurposing. The latter is not only important for the UK, but helps many people with diseases in resource-poor countries that don't have the resources to develop drugs, or simply cannot afford high-cost innovative new treatments for MS.

We have recently published a paper addressing some of the issues that I have attach for your information.

Giovannoni G, Baker D, Schmierer K. The problem with repurposing: Is there really an alternative to Big Pharma for developing new drugs for multiple sclerosis? Mult Scler Relat Disord. 2015 Jan;4(1):3-5.

If you have any queries I would be willing to meet you to discuss them in more detail.

Yours sincerely


Professor Gavin Giovannoni
Barts and The London
Contact details & Map MS Blog Twitter

Repurposing Bill

Time for Activity as the Repurposing Bill is soon to be given Prime time.

But still time to get your MP to do something useful

Will it get a debate or will it be binned?
Few Private members Bills make it and so be prepared for the worse... 

We should expect,  Pharma lobbying of Government to keep the playing field level and with many MPsappearing to take Pharma Bungs, this is likely to be scuppered 

Can we mobilize enough activity from our £70,000K Lazy-Assed MPs, who probably won't turn up to vote next friday

Will Nicola Sturgeon send her band of merry Scottish MPs to London to create a shock get the Bill debated and so do something useful for Scotland or will they be a load of Kippers?

B cells assume control

Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, Moore CS, Michel L, Althekair F, Rajasekharan S, Gommerman JL, Prat A, Fillatreau S, Bar-Or A; Canadian B cells in MS Team. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy.Sci Transl Med. 2015 Oct 21;7(310):310ra166. doi: 10.1126/scitranslmed.aab4176.

B cells are not limited to producing protective antibodies; they also perform additional functions relevant to both health and disease. However, the relative contribution of functionally distinct B cell subsets in human disease, the signals that regulate the balance between such subsets, and which of these subsets underlie the benefits of B cell depletion therapy (BCDT) are only partially elucidated. We describe a proinflammatory, granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing human memory B cell subset that is increased in frequency and more readily induced in multiple sclerosis (MS) patients compared to healthy controls. In vitro, GM-CSF-expressing B cells efficiently activated myeloid cells in a GM-CSF-dependent manner, and in vivo, BCDT resulted in a GM-CSF-dependent decrease in proinflammatory myeloid responses of MS patients. A signal transducer and activator of transcription 5 (STAT5)- and STAT6-dependent mechanism was required for B cell GM-CSF production and reciprocally regulated the generation of regulatory IL-10-expressing B cells. STAT5/6 signaling was enhanced in B cells of untreated MS patients compared with healthy controls, and B cells reemerging in patients after BCDT normalized their STAT5/6 signaling as well as their GM-CSF/IL-10 cytokine secretion ratios. The diminished proinflammatory myeloid cell responses observed after BCDT persisted even as new B cells reconstituted. These data implicate a proinflammatory B cell/myeloid cell axis in disease and underscore the rationale for selective targeting of distinct B cell populations in MS and other human autoimmune diseases.

A proinflammatory B cell cytokine activates autoimmunity, and B cell depletion treats multiple sclerosis. In this study a cytokine turned on pathogenic cells and countered the IL-10 producing regulatory B cells, so bring on ant-CD19 andti CD20.

We will slow see EAE turned into a B cell disease

Wednesday, 28 October 2015

ClinicSpeak: is it time to ditch regular follow-up visits with your neurologist?

What is the value of regular visits  to your neurologist if you are well? #ClinicSpeak #MSBlog #MSResearch

"How valuable are your 6-monthly, annual, or regular neurological appointments in MS? In the past I would have said very valuable as they allowed us, the neurological team, to interrogate you and identify MS-related problems early and manage them before they cause too many problems. In addition, we would use these sessions to educate you about what to expect. However, with the adoption of early effective treatment we are seeing more, and more, of our patients rendered NEDA with very few problems, and an increasing number of patients with no problems at all. Yes, no problems at all; the secret to this is early treatment. If you wait to accumulate damage and lose brain reserve you are then primed for future problems such as the early development of progressive disease."

"I am beginning to realise that seeing patients that are rendered 'well' by effective early treatment is simply consuming valuable clinical and personal time, that could be better used seeing other patients. The debate we are having about how frequently we see these patients is captured in the wider debate on whether or not the annual physical examination in the general population is cost effective and worth doing. The perspective article below, just published the New England Journal of Medicine, captures the relevant issues very well."

"I am not saying we should not see our 'well' patients, but we should put in place systems that prevent unnecessary hospital or clinic visits. Patients on DMTs need monitoring, i.e. periodic blood and urine tests, annual MRI scans and a battery of PROMS (patient-related outcome measures) to monitor the impact of their disease on their functioning. What is needed is for the results of this monitoring to be fed back to them in a timely manner and they only need to see a neurologist if there are problems with their results."

"Would you be prepared to sign-up to a MS service that provides automated monitoring, asynchronous communication, or feedback, of your results with an option of only seeing your MS clinical nurse specialist or neurologist if problems are identified?"

Mehrotra & Prochazka. Improving Value in Health Care — Against the Annual Physical. N Engl J Med 2015; 373:1485-1487.


..... The past few decades have seen numerous calls to eliminate the annual physical examination. In 1979, the Canadian Task Force on the Periodic Health Examination recommended “that the annual checkup, as practised almost ritualistically for several decades in North America, be abandoned.” In 2013, as part of the Choosing Wisely campaign, the Society of General Internal Medicine recommended against annual preventive examinations in asymptomatic patients.....

.... This ongoing practice is not surprising, since surveys reveal that the majority of both patients and physicians are strong proponents of the annual physical. In the face of this disconnect between expert recommendations and real-world practice, how do we move forward?..

..... both randomized trials and observational studies showed that annual physicals do not reduce morbidity or mortality, though they may be associated with reduced patient worry and increased use of preventive care.....

..... the annual physical may actually be harmful. Some aspects of traditional annual physicals, such as the comprehensive physical exam (which might, for example, detect thyroid nodules) and routine tests (such as urinalysis), have low specificity, which means that most positive results in asymptomatic patients will be false positives......

..... Reducing the use of annual physicals could also save money and time.....

......  Many new health care delivery models such as accountable care organizations and primary care medical homes are built on established patient–physician relationships. With that need in mind, these “primary care maintenance” visits could be limited to the minority of patients who have not seen a physician for a given period, perhaps 3 years, or who are switching to a new primary care provider.....

..... Eliminating the annual physical might appear contradictory to our health care system's increased attention to prevention.....

Lower risk of PML in Children

Hennes EM, Kornek B, Huppke P, Reindl M, Rostasy K, Berger T.
Age-Dependent Seroprevalence of JCV Antibody in Children.
Neuropediatrics. 2015 Oct 19. [Epub ahead of print]

Progressive multifocal leukoencephalopathy (PML) is an opportunistic central nervous system infection, caused by the John Cunningham virus (JCV). PML may occur during treatment with immunosuppressive agents or monoclonal antibodies such as natalizumab. The JCV seroprevalence increases with age with a seropositivity of 60% in the adult human population. In this study, we analyzed sera from 109 paediatric multiple sclerosis(MS) patients (mean age 14 years) as well as sera from 162 patients with a wide range of suspected neurologic disorders (mean age 6.3 years). Our results showed a considerably lower seroprevalence for JCV in our paediatric cohort with 33.3% and equal distribution in both subgroups, compared with reported seropositivity in adult population. This could result in a lower risk for drug-induced PML in paediatric patients compared with adult patients and can influence the indication for natalizumab therapy in paediatric MS 

You can read the post above and if you have a child with MS and they are taking tysabri this may give abit more comfort if their children are JC virus negative

MD I don't understand your graphics

Sometimes you are not supposed to.... yet
However they make sense if you know what they are saying

Picture of the left (below) used in

                               Alternative Coat of Arms of the ABN?

You asked "Do you write puzzles" for those of you who have been visiting the blog for some time, can you remember this picture from brain training done some time ago?

I wonder if Tony Fonda (Blogger) remembers saying:

'Moqtada Sadr was having Fish for dinner when he read in the Newspaper that Jimmy Carter (White man's Caricature) had plans with the Saudis (Bearded guy to the left) so Sadr had an Idea (Light Bulb) to raise Cash (Coins) and create a para-military movement.'
How can you not remember that? Did you remember the story? 

        Actually the guy on the left is a Vasilis Vasilopoulos 
      (one time nemesis of TeamG) so now it all makes sense:-).

Now we can check what Pharma is up to. Where is the fingo trial?

On 1 January 2015 a new European Medicines Agency EMA policy on publication of clinical data entered into force. Under this policy, the Agency proactively publishes the clinical reports submitted as part of marketing-authorisation applications for human medicines. 

Since 2010 the Agency has been releasing clinical-trial reports on request, under its access-to-documents policy.
The Agency is committed to continuously extending its approach to transparency. A key goal in this process is the publication of clinical-trial data for medicines once the decision-making process on an application for a European Union (EU)-wide marketing authorisation is complete.

The Agency embarked on this process because it believes that the release of data is about establishing trust and confidence in the system, because it will allow the public to better understand the Agency’s decision-making.

In addition, academics and researchers will be able to re-assess data sets. The publication of clinical reports will also help to avoid duplication of clinical trials, foster innovation and encourage development of new medicines.

The main objectives of the policy by making clinical data available proactively, are to enable 

• public scrutiny 
• and application of new knowledge in future research, all this in the interest of public health.
  • Access to clinical data will allow third parties to verify the original analysis and conclusions, to conduct further analyses, and to examine the regulatory authority's positions and challenge them where appropriate.
  • The Agency also takes the view that transparency should be mutually respected. Those who perform secondary analysis of clinical data, published in accordance with this policy, must be held to the same standard of transparency as those who generate clinical data in the first place. Hence, all secondary analyses are expected to also be in the public domain and accessible for further scrutiny by the scientific community. In addition, those who perform secondary analysis of clinical data published in accordance with this policy, are encouraged to provide the Agency with a copy of any article resulting from such secondary analysis before publication, in particular in those circumstances where the secondary analysis might result in the need for regulatory action to protect public health. This is a critical consideration in view of the Agency’s role and responsibilities for a timely review of all available information which might have an impact on the benefit/risk ratio of centrally authorised products.

EMA Gearing up to Publish Clinical Data Ahead of New Clinical Trials Regulation

The European Medicines Agency (EMA) is moving forward with its plan to release the clinical data used in marketing authorization applications.

Background: Clinical Trials Regulation

In April 2014, the European Parliament overwhelmingly passed a new regulation governing clinical trials, Regulation (EU) No 536/2015, repealing Directive 2001/20/EC following a transition period lasting through 28 May 2016.

One of the major changes in the new Clinical Trials Regulation is increased transparency measures, which require clinical trials to be registered in a "publicly accessible and free of charge database which is a primary or partner registry of, or a data provider to, the international clinical trials registry platform of the World Health Organization (WHO ICTRP)."

The regulation also calls for the creation of a new, publicly accessible, clinical trials database and portal. The information submitted to the database will be made publicly available, except where certain exceptions apply:

protection of personal data
protection of commercially confidential information
protection of confidential communication between Member States in the preparation of their assessment
protection of the supervision of clinical trials by Member States

Companies are required to publish a summary of the results of all clinical trials within a year of a trial's completion.

So where is the fingolimod PPMS trial?

For trials used to support a product's marketing authorization, companies are required to publish the "clinical study report within 30 days after the day the marketing authorisation has been granted, the procedure for granting the marketing authorisation has been completed, or the applicant for marketing authorisation has withdrawn the application."

Publication of Clinical Data

Shortly after the passage of the Clinical Trials Regulation, EMA adopted a policy on the proactive publication of clinical data.

The policy requires EMA to publish the clinical reports used in all marketing authorization applications submitted after 1 January 2015 once the agency has made a decision on the application. Because of the lengthy nature of the marketing authorization process, EMA expects the first clinical reports released under the policy to be published in mid-2016.
Clarifying the Policy

EMA also released a questions and answers document intended to inform stakeholders about the policy, its interpretation and implementation. The document also explains EMA's rationale for implementing the new policy less than two years before the Clinical Trials Regulation takes effect. The agency says that because new clinical trials will not have to follow the new regulation's requirements until May 2016, the Clinical Trials Regulation will likely not result in publicly available clinical reports in the next four to five years.

Between November 2010 and April 2013, the Agency released over 1.9 million pages of clinical-trial data.

Tuesday, 27 October 2015

Fats and Diet

Haghikia A, Jörg S, Duscha A, Berg J, Manzel A, Waschbisch A, Hammer A, Lee DH, May C, Wilck N, Balogh A, Ostermann AI, Schebb NH, Akkad DA, Grohme DA, Kleinewietfeld M, Kempa S, Thöne J, Demir S, Müller DN, Gold R, Linker RA. Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. Immunity. 2015 Oct 20;43(4):817-829. doi: 10.1016/j.immuni.2015.09.007.

Growing empirical evidence suggests that nutrition and bacterial metabolites might impact the systemic immune response in the context of disease and autoimmunity. We report that long-chain fatty acids (LCFAs) enhanced differentiation and proliferation of T helper 1 (Th1) and/or Th17 cells and impaired their intestinal sequestration via p38-MAPK pathway. Alternatively, dietary short-chain FAs (SCFAs) expanded gut T regulatory (Treg) cells by suppression of the JNK1 and p38 pathway. We used experimental autoimmune encephalomyelitis (EAE) as a model of T cell-mediated autoimmunity to show that LCFAs consistently decreased SCFAs in the gut and exacerbated disease by expanding pathogenic Th1 and/or Th17 cell populations in the small intestine. Treatment with SCFAs ameliorated EAE and reduced axonal damage via long-lasting imprinting on lamina-propria-derived Treg cells. These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, Th cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis.

There has been renewed interest on the gut, the largest zone of interaction between the environment and the human organism,
There is fast-growing quest for possible disease associations involving interactions between diet, the gut, and microbiome components, especially in autoimmunity.

Here, fatty acids (FAs), as an integral component of daily diet, have become a primary focus of investigation. Of particular interest is the role of short-chain FAs (SCFAs), which are broken down by gut bacteria from otherwise indigestible carbohydrates, i.e., from fibre-rich diets, and have been shown to ameliorate disease in animals. Furthermore, long-chain FAs (LCFAs), the most abundant component of the so-called Western diet, have been suspected as a culprit in various diseases.
In  this study they report that LCFA promote the production of TH1/Th17 pro-inflammatory cells and SCFA promote T regulatory cells. The LCFA worked via the gut and the feacal filtrates of the gut microbe metabolities made more Th17 cells. The LCFA changes the type of gut microbes. So if you change your diet then it could make your MS better. This hypothesis could be easy to test in humans to see if the Tregs and TH1/Th17 change in the way they think.

This is all great but then they say "So far, influencing MS via direct Treg cell manipulations, e.g., via superagonistic anti-CD28 antibodies, has been considered worthwhile but not practically feasible outside of controlled experimental conditions" 

WARNING. This first belief led to people loosing their fingers and toes when used in humans because it was a bonkers idea. Hower to be fair the SCFA are not going to work like this. CD28 superagonists works by the weed killer effect stimulating the cells to grow like crazy and turn themselves off They may have make mre T regs but in doing the former they were going to make a cytokine storm that shut done blood vessels causing gangrene and loss of digits. This should never have been tried in humans as the effect of anti-CD3  which does the same thing was known.

Anti-CD25 should get rid of T regs and make MS worse. It doesn't it makes it better.

Accountants Rule Pharma

We have been saying that accountants call the shots for pharma because they work out how many greenbacks that can make.

Now the game that must be sweeping Pharmaland and mirroring just that:

"Can you profit in an industry where illness is good for business and do you have a conscience?"

The Lancet had a go

"I decided to stop production of my drug because it simply wasn’t profitable"

"Big Pharma is a game about trying to be the best drug producer, but it only really hints at the murkier side of the pharmaceutical industry. With luck, players will leave the game in reflective mood wondering whether, if this were real life, they might want to do things differently."

Accountants rule the pharma world!

p.s. We are not advertising for BigPharma

Another LINGO in the making or will it be a NOGO? Anti-repulsive guidance molecule for regeneration

ABT-555, a human anti-RGMa monoclonal antibody promotes axon regeneration and neuroprotection in multiple sclerosis models
(Abstract release date: Sep 23, 2015) ECTRIMS Online Library. Mueller B. Oct 8, 2015; 115435

Summary: Repulsive Guidance Molecule a (RGMa) is a potent inhibitor of axon regeneration and remyelination and is involved in neuronal cell death. In addition RGMa plays an important role in neuroinflammation. Targeting RGMa by the selective antibody ABT-555 promotes axon regeneration, enhances neuroprotection, stimulates remyelination and decreases microglial inflammation.

Objective: To present the preclinical data of ABT-555 in several different MS-related animal models.

Methods: Anti-RGMa antibodies, including ABT-555, were evaluated in a rat spinal cord targeted experimental autoimmune encephalitis (tEAE) model induced by myelin oligodendrocyte glycoprotein (MOG)-sensitization followed by local injection of tumor necrosis factor-beta (TNF)-b and gamma interferon (IFN)-g; in an optic neuritis model using the same protocol of MOG sensitization; and in a mouse MOG disseminated EAE model (dEAE) immunized with MOG in complete Freund´s adjuvant and boosted with pertussis toxin.

Results: Administration of ABT-555 accelerated functional recovery in both EAE models, enhanced axonal regeneration within inflammatory lesions, and stimulated remyelination. Treatment with RGMa antibodies also decreased the inflammatory signal by CD68+ cells within the spinal cord. ABT-555 stimulated regenerative axon growth within the inflammatory optic nerve lesion in a dose dependent manner on immunohistochemistry (IHC) and reduced degeneration of the retinal nerve fiber layer measured using optical coherence tomography (OCT), proving its potent neuroprotective efficacy .

Conclusions: The specific targeting of RGMa by ABT-555 in several animal models of autoimmune inflammatory disease of the CNS resulted in immune modulation and neuroprotection and neuroregeneration and this new therapeutic strategy may provide novel benefit in patients with MS and warrants further study. The early clinical evaluation of ABT-555 in healthy volunteers and MS patients is currently underway.

Disclosure: All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Repulsive guidance molecule isoform a (RGMa) is another repulsive/inhibitory cue for axonal elongation. Theoretically, by blocking the activity of RGMa you can do the opposite, which is promote axonal elongation. The authors demonstrate that an antibody to RGMa (ABT-555) can stimulate regeneration within MS-like lesions in mice spinal cord and in optic neuritis. In the optic neuritis model they demonstrate that compared to the control eye which did not receive treatment, the ABT-555 treated eyes had up to 30% regenerative growth.

You would imagine AbbVie would like to get this into a clinical trial? And this may be their intention. But I would say there has been a deluge of these therapeutics now in the regenerative field, not excluding LINGO-1 in MS, and may not be the panacea they are purported to be. Moreover, there is a reason why humans and other organisms express these molecules in normal circumstances, since they play a prominent role in the topographical architecture of central nervous system during development. By blocking them, is there a chance that we would also mess up the design of our central nervous system, which any sensible neuroscientist will not deny is plastic?!

Monday, 26 October 2015

ResearchSpeak: MS risk and socioeconomic status matters in Canada

What is your socioeconomic status? Did it affect your risk of getting MS? #'ResearchSpeak #MSBlog #MSResearch

"The effect of socioeconomic status (SES) on MS risk appears to be disappearing. In the past your risk of MS increased with increasing SES; if you were in the upper social strata 1 & 2 you had a higher risk of getting MS compared to people living in lower strata 4 & 5. These SES observations were used to support the hygiene hypothesis; the cleaner your living environment (upper strata) the less germs you were exposed to in childhood, the less educated your immune system were, the more likely you were to develop MS when you were exposed to infectious triggers later in life. The good news is that the SES and MS risk appears to be disappearing; at least in most countries. Some would argue that this is because economic development has lifted the majority of people in high-prevalence areas out of poverty and hence most people in developed countries now live in 'clean environments'. However, not all countries are  equal with low SES in Canada still protecting you from getting MS. Interesting, or not? Maybe we should be studying developing countries where the disparity between hygienic environments between people living in the upper and lower socioeconomic strata is greatest."

Goulden et al. Does low socioeconomic status in early life protect against multiple sclerosis? A multinational, case-control study.Eur J Neurol. 2015 Oct 16. doi: 10.1111/ene.12830.

BACKGROUND AND PURPOSE: The findings from existing research on the association between socioeconomic status (SES) and multiple sclerosis (MS) are inconsistent. Most previous studies are limited to one country and do not adequately adjust for other risk factors for the disease.

METHODS: The association between SES and MS was examined using data from the multinational Environmental Risk Factors in Multiple Sclerosis (EnvIMS) case-control study, comprising 2144 cases and 3859 controls from Norway, Canada and Italy. Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals for the association between early life SES, measured by parental educational level, and MS. Analyses were adjusted for age, sex, sunlight exposure, history of infectious mononucleosis, smoking, obesity and family size.

RESULTS: Relative to those whose parents had primary school education or below, the adjusted odds ratio (95% confidence interval) for MS amongst individuals with university-educated parents, and the P value for trend across education levels, were 1.45 (1.03-2.05) in Canada (P for trend 0.030), 1.09 (0.85-1.39) in Norway (P for trend 0.395) and 0.65 (0.39-1.07) in Italy (P for trend 0.158).

CONCLUSION: There is no consistent association between parental SES and MS risk in Norway, Canada and Italy, with a protective effect of low SES only found in Canada

The repurposing Bill

We are asking for your support to get a second reading of the Repurposng Bill

Please support this and get your MP to attend and get this debated

The Bill would:

  • Create a route to market for off-patent drugs that have been repurposed.
  • Put a duty on the government to step in in the public interest where there is currently a market failure preventing some drug indications from being licensed by MHRA and appraised by NICE.
  • Seek to replicate the existing system for drug licensing and appraisal.
  • Provide clarity for both prescribers and patients by ensuring that the only factor that affects whether a drug is licensed and NICE-appraised is the strength of the evidence, and not commercial viability.
  • Only take effect where there is a published (or anticipated) phase 3 clinical trial proving benefit in the new indication.
  • Require the government to partner with an existing manufacturer of the generic drug to provide it and undertake pharmacovigilance for its new indication. Alternatively, it could partner with Porton Down Ltd, a pharmaceutical company owned solely by the Secretary of State for Health.

The Bill would not:

  • Change anything about the existing licensing and drug appraisal system in the UK.
  • Change the evidence threshold required for licensing or drug appraisal.
  • Mandate the MHRA to license the drug in its new indication – the MHRA would still be free to approve it or not, based on the strength of the evidence presented.
  • Mandate NICE to recommend the drug in its new indication – NICE would still be free to approve it or not, based on the strength of the evidence presented.

This is not going to plain sailing because if academics have to follow the pharma lead then there are problems ahead. 

It is going to be difficult to get enough money to support two phase III trials or is one now enough? If it is enough for academics why would it not be enough for pharma as this just slows down the process and costs more.

If it has to be to pharma standard then again it could be a problem as pharma spend millions getting their trials monitored properly and the paper work appropriately sorted.

Are the MHRA going to bite off the hand of their pharma paymasters?...They are 100% funded by pharma, so will they accept anything less than what industry have to do?

Maybe academics have put their head in the sand and say we will come to that hurdle when we get there and hope that they can bend their ears. It will be very embarassing if they can not. Pharma have been turned away and told to do trials again.

With a Cheap Drug you don't need the NICE cost effectiveness calculator: It exists to make expensive drugs cheaper!  So with cheapt drugs you don't need NICE.

In phase III trials the companies also put everyone on drug after the trial are academics going to do this?. Where is the cash coming from?

                      YOU HAVE LAZY ARSED MPs IF IT FAILS

                  WILL THE SNP USE THEIR POWER TO 
                       MAKE WESTMINSTER DO THIS.

                     WILL THEY BE AN AMPHIOXUS?:-) 
                           (Spineless fish-like creature)

The Bill is supported by a number of charities including Alzheimer’s Society, Breast Cancer Now, Prostate Cancer UK, Leukaemia Care, The Cure Parkinson’s Trust, and the Institute for Cancer Research,The MS Society

So if this bill fails surely  they mobilise 100,000 signatures to petition the government of debate this. 

15,000 on MS register alone

Orgasms and lesion size

Winder K, Seifert F, Koehn J, Deutsch M, Engelhorn T, Dörfler A, Lee DH, Linker RA, Hilz MJ Site and size of multiple sclerosis lesions predict enhanced or decreased female orgasmic function.J Neurol. 2015 Oct 12. [Epub ahead of print].

Neuroimaging identified brain areas involved in female orgasm. In women with multiple sclerosis (MS), associations between orgasmic function and the site and size of MS-related magnetic resonance imaging (MRI) changes are undetermined. This study intended to correlate MS-associated cerebral lesion load and location with clinical scores of female orgasmic function. In 50 women with MS (mean age 37.0 ± 9.9 years), we assessed Female Sexual Function Index (FSFI) scores for orgasmic frequency, difficulty and satisfaction. We determined disease duration, Expanded Disability Status Scale (EDSS) scores, and cerebral MS-lesion load and location using T2-weighed 1.5 T MRIs. We correlated FSFI scores for orgasm with patient age, disease duration, EDSS scores, and cerebral MS-lesion load (Spearman rank correlation; significance: p < 0.05). 

FSFI scores for orgasm correlated inversely with MS-lesion load in the left temporal periventricular white matter and right middle-inferior occipital area, but directly with MS-lesion load in the right frontal primary motor cortex, left prefrontal/inferior frontal cortex, right amygdala, left temporal middle-inferior and fusiform areas, and midbrain. FSFI scores for orgasm did not correlate with patient age, disease duration and EDSS scores (p > 0.05). 

In conclusion, our results indicate that MS-lesions in left temporal periventricular and right visual association areas deteriorate orgasmic function. In contrast, direct correlations between frontotemporal or midbrain lesions and higher FSFI scores, indicating enhanced or disinhibited orgasmic function, suggest that these brain regions normally buffer orgasmic responses. Moreover, our results indicate that orgasmic dysfunction in women with MS evolves independently of disease duration and physical disability.

If you are interested in Orgasms and brain involvment wiki does not have alot to say and if you want to know the brain regions have a look at our educational post

NewsSpeak: taking the piss ... Prof G loses all credibility

Does Prof G have street cred? #NewsSpeak #MSBlog 

"At ECTRIMS to get into the mood I wore my 2012 marathon racers to show my support for Multiple Sclerosis Society and to raise awareness about MS. My running shoes were designed to reflect the colours of the MS Society, and other MS stakeholders, who have branded themselves black-and-orange. The latter includes our MS policy document on 'Brain Health: time matters in multiple sclerosis'. I thought I was doing something worthwhile, but my colleagues 'took the piss out of me' in true British tradition. They said I had lost all street cred! What do you think? Is wearing MS branded racers worse than taking a luxury limousine between meetings?"
    Taking the piss is a Commonwealth term meaning to take liberties at the expense of others, or to be unreasonable. It is often used to mean (or confused with) taking the piss out of, which is an expression meaning to mock, tease, ridicule, or scoff. (Source Wikipedia)

ResearchSpeak: predicting disease progression

Predicting disease progression #ShiftMS #ResearchSpeak #MSBlog

"The following is another MS Report as part of our collaboration with The topic addresses the issue of prediction; in this case progression." 

CoI: this work has been generously funded by the Wellcome Trust, Thank You. 

Sunday, 25 October 2015

PML risk stratification with CD62L

Schwab N, Schneider-Hohendorf T, Pignolet B, Spadaro M, Görlich D, Meinl I, Windhagen S, Tackenberg B, Breuer J, Cantó E, Kümpfel T, Hohlfeld R, Siffrin V, Luessi F, Posevitz-Fejfár A, Montalban X, Meuth SG, Zipp F, Gold R, Du Pasquier RA, Kleinschnitz C, Jacobi A, Comabella M, Bertolotto A, Brassat D, Wiendl H. PML risk stratification using anti-JCV antibody index and L-selectin. Mult Scler. 2015. pii: 1352458515607651. [Epub ahead of print]

BACKGROUND:Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters.
OBJECTIVE:This study aimed at verifying and integrating both parameters into one algorithm for risk stratification.
METHODS:Multicentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre-PML patients).
RESULTS:CD62L values correlate with JCV serostatus, as well as JCV index values. Low CD62L in natalizumab-treated patients was confirmed and validated as a biomarker for PML risk with the risk factor "CD62L low" increasing a patient's relative risk 55-fold (p < 0.0001). Validation efforts established 86% sensitivity/91% specificity for CD62L and 100% sensitivity/59% specificity for JCV index as predictors of PML. Using both parameters identified 1.9% of natalizumab-treated patients in the reference center as the risk group.
CONCLUSIONS:Both JCV index and CD62L have merit for risk stratification and share a potential biological relationship with implications for general PML aetiology. A risk algorithm incorporating both biomarkers could strongly reduce PML incidence.

We have seen that a number of posts find low CD62L as a risk factor for developing PML

How Do you Like Your News

A neuro commented that the blog may have a "light touch"  (from the MDs) for a very serious condition.

The question is how you want to get your news?  

The old school, straight lace "Here is the News " (get this everywhere) or a more unconventional style.

We are what we are and we have to do it in a way that allows the person contributing to maintain enthusiasm.  

We can bin the abuse or sometimes post and respond as we are not wet blankets and censor freaks. 

Some people like the light touch some don't so we will never please everyone.

Some stuff you may never understand unless you are told what it means

Saturday, 24 October 2015

Killing Oligodendrocytes early in life limits repair potential

Caprariello AV, Batt CE, Zippe I, Romito-DiGiacomo RR, Karl M, Miller RH. Apoptosis of Oligodendrocytes during Early Development Delays Myelination and Impairs Subsequent Responses to Demyelination J Neurosci. 2015 Oct 14;35(41):14031-41. doi: 1

During mammalian development, myelin-forming oligodendrocytes are generated and axons ensheathed according to a tightly regulated sequence of events. Excess premyelinating oligodendrocytes are eliminated by apoptosis and the timing of the onset of myelination in any specific CNS region is highly reproducible. Although the developing CNS recovers more effectively than the adult CNS from similar insults, it is unknown whether early loss of oligodendrocyte lineage cells leads to long-term functional deficits. To directly assess whether the loss of oligodendrocytes during early postnatal spinal cord development impacted oligodendrogenesis, myelination, and remyelination, transgenic mouse lines were generated in which a modified caspase-9 molecule allowed spatial and temporal control of the apoptotic pathway specifically in mature, myelin basic protein expressing oligodendrocytes (MBP-iCP9). Activating apoptosis in MBP(+) cells of the developing spinal cord during the first postnatal week inhibited myelination. This inhibition was transient, and the levels of myelination largely returned to normal after 2 weeks. Despite robust developmental plasticity, MBP-iCP9-induced oligodendrocyte apoptosis compromised the rate and extent of adult remyelination. Remyelination failure correlated with a truncated proliferative response of oligodendrocyte progenitor cells, suggesting that depleting the oligodendrocyte pool during critical developmental periods compromises the regenerative response to subsequent demyelinating lesions.

SIGNIFICANCE STATEMENT:This manuscript demonstrates that early insults leading to oligodendrocyte apoptosis result in the impairment of recovery from demyelinating diseases in the adult. These studies begin to provide an initial understanding of the potential failure of recovery in insults, such as periventricular leukomalacia and multiple sclerosis.

You can read the authors perception of signicance without any need to comment from me

More MS genes identified

Lill CM, Luessi F, Alcina A, Sokolova EA, Ugidos N, de la Hera B, Guillot-Noël L, Malhotra S, Reinthaler E, Schjeide BM, Mescheriakova JY, Mashychev A, Wohlers I, Akkad DA, Aktas O, Alloza I, Antigüedad A, Arroyo R, Astobiza I, Blaschke P, Boyko AN, Buttmann M, Chan A, Dörner T, Epplen JT, Favorova OO, Fedetz M, Fernández O, García-Martínez A, Gerdes LA, Graetz C, Hartung HP, Hoffjan S, Izquierdo G, Korobko DS, Kroner A, Kubisch C, Kümpfel T, Leyva L, Lohse P, Malkova NA, Montalban X, Popova EV, Rieckmann P, Rozhdestvenskii AS, Schmied C, Smagina IV, Tsareva EY, Winkelmann A, Zettl UK, Binder H, Cournu-Rebeix I, Hintzen R, Zimprich A, Comabella M, Fontaine B, Urcelay E, Vandenbroeck K, Filipenko M, Matesanz F, Zipp F, Bertram L.Genome-wide significant association with seven novel multiple sclerosis risk loci. J Med Genet. 2015 Oct 16. pii: jmedgenet-2015-103442. doi: 10.1136/jmedgenet-2015-103442. [Epub ahead of print]

OBJECTIVE:A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors.
METHODS:The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis.
RESULTS:Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10-8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10-12), CD28 (rs6435203, p=1.35×10-9 a protien involved in T cell activation), LPP (rs4686953, p=3.35×10-8. Lipoma-preferred partner is a protien that may be involved in cell-cell adhesion and cell motility), ETS1 (rs3809006, p=7.74×10-9. A gene involed in T and B cell differentiation), DLEU1 (rs806349, p=8.14×10-12. Deleted in lymphocytic leukemia 1 ), LPIN3 (rs6072343, p=7.16×10-12.Lipin complexes are also thought to regulate gene expression as transcriptional co-activators in the nucleus ) and IFNGR2 (rs9808753, p=4.40×10-10. Interferon gamma receptor 2).
CONCLUSIONS:This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

There are over 100 genes identified that cxonfer MS susceptibility. These are immune associated genes or genes that affect the production of the gene products. This study adds 7 more in a large study. There is no MS gene but gene variants comer together in such a way that puts you at risk of developing MS. 

It has been  suggested that there are about 400-450 to find.  These are variants  that are perfectly normal genes that probably influence your ability to deal with infections. The consquence is risk of developing MS