November 12, 2015
The Innate Immune System Modulates the Severity of Multiple Sclerosis
Cellular Stress Signals Sent by Macrophages Amplify Neuroinflammation,
Provide Novel Drug Targets for MS Therapy
Multiple Sclerosis, a debilitating neurological disease, is triggered by self-reactive T cells that successfully infiltrate the brain and spinal cord where they launch an aggressive autoimmune attack against myelin, the fatty substance that surrounds and insulates nerve fibers. Over time, the resulting bouts of inflammation permanently damage the myelin sheath and the nerve fibers it protects, disrupting nerve signals traveling to and from the brain.
But the molecular cues that enable autoimmune T cells, which are usually kept at bay by the blood-brain barrier, to slip into the central nervous system had remained unclear. In their latest study, published in the Nov. 2, advance on-line issue of Nature Immunology, researchers at the La Jolla Institute for Allergy and Immunology report that these disease-causing autoimmune T cells are lured into the nervous system by monocytes and macrophages, a subset of immune cells better known as the immune system’s cleanup crew.
“Our results show that macrophages and monocytes actively participate in the initiation and progression of Multiple Sclerosis, which has long been considered a primarily T cell driven disease,” says the study’s senior author Catherine Hedrick, Ph. D., a professor in the Division of Inflammation Biology. “They exacerbate the severity of the disease by sending out chemical signals that boost inflammation and attract autoimmune T cells to the central nervous system.”
By revealing the molecular mechanisms that control neuroinflammation, these findings add a new layer of complexity to our understanding of multiple sclerosis and support the growing appreciation of the significance of the crosstalk between the peripheral immune system and the brain. They also open up new avenues for potential Multiple Sclerosis (MS) therapies via manipulating the levels of immune regulators that contribute to inflammation in the central nervous system.
“Multiple Sclerosis affects millions of people worldwide,” says the study’s lead author, Iftach Shaked, Ph.D., a postdoctoral researcher in the laboratory of LJI professor Klaus Ley, Ph.D. “But what’s really puzzling is that we all have autoimmune T cells that recognize myelin basic protein but normally they do not infiltrate the central nervous system and cause disease.“
Stress can worsen symptoms of inflammatory diseases such as MS but the molecular mechanisms linking cellular stress signaling and neuroinflammation had remained unclear.
A chance hallway encounter between Shaked and co-first author Richard Hanna, Ph.D., an immunologist in Hedrick’s laboratory, sparked a collaboration that provided a starting point to track the elusive link. Hanna studies a protein known as Nr4a1, which responds to both inflammatory and stress signals and the researchers hypothesized that it may be a key factor in the prevention of autoimmunity affecting the central nervous system.
To address the importance of Nr4a1 in brain autoimmunity, the researchers induced experimental autoimmune encephalomyelitis (EAE), a model of MS, in mice with and without Nr4a1. In the absence of Nr4a1, auto-reactive T cells infiltrated the central nervous system much earlier and in greater numbers exacerbating the progression and severity of the disease when compared to the control group.
When Shaked and Hanna dug deeper, they discovered that Nr4a1 represses the production of norepinephrine, a major mediator of the body’s response to physiological and psychological stressors. Without Nr4a1 to put a damper on production, monocytes and macrophages increase secretion of norepinephrine, which in turn leads to the activation of macrophages, thereby amplifying neuroinflammation and causing a massive influx of T cells into the central nervous system.
“Myeloid cells including macrophages have receptors for stress signaling molecules, which allows them to respond to cues from the sympathetic nervous system,” explains Hanna. “But is seems they not only listen to the nervous system but that they can also send their own signals.”
Nr4a1 regulates the production of norepinephrine by limiting the amount of tyrosine hydroxylase, the enzyme that controls a bottleneck in the biosynthesis of norepinephrine. When Nr4a1 is missing, tyrosine hydroxylase is highly expressed in monocytes and macrophages leading to more severe disease. Conversely, deletion of tyrosine hydroxylase in myeloid cells protects mice from the disease.
A small pilot study indicated that the same communications channels might be used to send messages between the brain and the peripheral immune system in patients with MS. “Monocytes and macrophages have a way to amplify inflammation in the central nervous system,” says Shaked, “which really shows that myeloid cells play an unexpected and important role in diseases of the brain.”
Source: La Jolla Institute for Allergy and Immunology
October 01, 2015
Could Genentech’s Ocrelizumab Become the First Effective Primary Progressive MS Therapy?
Genentech announced that the experimental monoclonal antibody ocrelizumab significantly reduced relapse rates after two years compared to the established MS treatment, Rebif® (interferon beta-1a, EMD Serono and Pfizer) in two phase III studies. Ocrelizumab is administered by intravenous infusion every six months. The studies, known as OPERA I and OPERA II, included a total of 1,656 people with relapsing MS (people with relapsing-remitting MS and those with secondary-progressive MS who were experiencing relapses).
Data analysis is ongoing and the company expects to provide a full report at an upcoming medical meeting. The release stated that the company plans to submit these data to the FDA and European drug regulators for marketing approval in 2016. Ocrelizumab binds to a molecule (CD20) on the surface of immune cells called B cells, and depletes them from the circulation. B cells have several functions including making antibodies, and they may play a role in the immune attacks on brain and spinal cord tissues in MS. Ocrelizumab is a “humanized” version of rituximab, a therapy for cancers and other disorders that has previously shown benefit in people with relapsing-remitting MS.
In each study, participants were randomly assigned to receive ocrelizumab (IV infusions every six months) or Rebif (44 micrograms injected under the skin three times weekly) for 96 weeks. Participants in the ocrelizumab group received an inactive placebo version of Rebif, and those in the Rebif group received an inactive placebo version of ocrelizumab.
In each study, the primary outcome being measured was the effect on relapse rate. Secondary outcomes included time to onset of sustained disability progression (an increase in the EDSS disability scale that is sustained for at least 12 weeks), change in disease activity on MRI scans, change in brain tissue volume, and safety and tolerability.
According to their press release, treatment with ocrelizumab significantly reduced the relapse rate at the two year point compared with Rebif. Ocrelizumab also significantly reduced the progression of disability and disease activity on MRI scans.
The most common “adverse events,” or side effects, were mild-to-moderate infusion-related reactions. The press release notes that the incidence of serious effects was similar in both treatment groups, but does not note what these events were.
“We look forward to seeing the detailed safety and effectiveness results from these large clinical trials of ocrelizumab,” says Bruce Bebo, PhD, Executive Vice President, Research at the National MS Society. “Having additional treatment options is important for people with MS, since the currently available therapies don’t work for everyone.”
Progressive forms of MS are estimated to affect at least 40 percent of all MS patients and are characterized by a gradual, steady progression of disability, leading to impaired vision and walking, pain, fatigue, incontinence and cognitive changes. Patients usually have a poor response to treatment and there is little or no recovery. According to the National Multiple Sclerosis Association, progressive forms of the disease include Primary Progressive Multiple Sclerosis (PPMS), which is diagnosed in 10 percent of all MS cases and is characterized by a steady progression of the disease from the time of diagnosis, and Secondary Progressive Multiple Sclerosis (SPMS), where patients initially experience a relapsing-remitting MS phase (RRMS) of neurological dysfunction that later evolves in approximately half of the cases into a secondary progressive disease.
Further research includes the ORATORIO (NCT01194570) study, a multicenter, double-blind, randomized, placebo-controlled, Phase III clinical trial developed to evaluate the efficacy and safety of ocrelizumab (administered intravenously as two 300 mg infusions two weeks apart) in 732 patients with PPMS.
Researchers now report that the ORATORIO study has met its primary endpoint, as ocrelizumab treatment was found to significantly reduce the patients’ clinical disability progression in comparison to a placebo. In the trial, clinical disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) sustained for a period of at least 12 weeks.
In terms of safety, the occurrence of adverse events in the patient group given ocrelizumab was similar to the one in the placebo group. The most common adverse events reported were mild-to-moderate reactions related to the infusion.
“People with the primary progressive form of MS typically experience symptoms that continuously worsen after the onset of their disease, and there are no approved treatments for this debilitating condition,” said the chief medical officer and head of Global Product Development, Dr. Sandra Horning in a press release. “Ocrelizumab is the first investigational medicine to show a clinically meaningful and statistically significant effect on the progression of disease in primary progressive MS.”
The results of an ongoing trial in people with PPMS are expected to be announced later in 2015.
Multiple Sclerosis, an unpredictable, often disabling disease of the central nervous system, interrupts the flow of information within the brain, and between the brain and body. Symptoms range from numbness and tingling to blindness and paralysis. The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are moving us closer to a world free of MS. Most people with MS are diagnosed between the ages of 20 and 50, with at least two to three times more women than men being diagnosed with the disease. MS affects more than 2.5 million people worldwide.
August 27, 2015
Oral Disease Modifying Agents for Multiple Sclerosis Are Now More Preferred by Neurologists
A survey of 97 neurologists conducted in June 2015 revealed specialists within the field of neurology are increasingly avoiding prescribing injectables to patients suffering from Multiple Sclerosis (MS), as orally-available disease modifying-agents (DMAs) continue to gain in popularity.
The survey was conducted and reported by Spherix Global Insights, a newly established business intelligence and market research company headquartered in Zug, Switzerland with US offices in Cambridge, MA. The company’s mission is to apply commercial experience and unique relationships within core specialty markets to translate data into insight, enabling clients to make smarter business decisions. Through their large-scale primary market research service, Spherix was able to identify that a majority of both physicians’ and patients ‘ experience with oral DMAs has been positive, which bodes well for other products under this method of treatment.
Andrew Deslaurier, Franchise Head covering Neurology, states that, “The MS market is highly dynamic with more than ten DMAs currently available and increased switching between the DMA brands. In addition, evolving attitudes around ‘safety’ concerns and heavy promotion aimed at clinicians and patients has made the competitive environment increasingly complex.”
Even though Biogen’s Tecfidera and Novartis’ Gilenya have been gaining popularity as first-line oral treatments for multiple sclerosis, not all non-oral treatments have been met with the same reception in the MS market. Today, Biogen’s Plegridy remains the only platform injectable to show positive growth rate in the survey, steadily garnering new patients switching from its predecessor product, Avonex. Meanwhile, other injectables are struggling to stay relevant in the competition against more established brand names, each with its own favorable disability story.
A key balance for drug developers, physicians and patients living with MS is being prescribed a therapy that is convenient to take, but is all effective in modifying the course of the disease. The challenge in drug development has been to advance orally-available multiple sclerosis therapies so that they can match the efficacy of injectables while making patient compliance less invasive. As orally-available drugs continue to improve, there is likely to be an increased shift away from injectables in making MS treatment easier for patients.
Source: Spherix Global Insights
July 30, 2015
Mitochondria May Play a Role in MS Development and Progression
Recent attention to the role of mitochondria in the etiology of Multiple Sclerosis (what causes the disease) suggests that mitochondrial defects and mitochondrial structural and functional changes may contribute to the disease. Researchers studying mitochondria in Multiple Sclerosis (MS) believe abnormalities in mitochondrial dynamics impact cellular pathways such as inflammation and demyelination, ultimately impacting patients with MS.
Dr. Peizhong Mao and Dr. P. Hemachandra Reddy, of the Neurogenetics Laboratory at Oregon Health & Science University, identified five key abnormalities in the mitochondria that are involved in disease development and progression. Mitochondrial DNA defects, abnormal mitochondrial gene expression, defective mitochondrial enzyme activities, deficient mitochondrial DNA repair activity, and mitochondrial dysfunction have been shown to play a role, according the two researchers’ article, “Is Multiple Sclerosis a Mitochondrial Disease?” that was published in Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease.
“Neurons are highly dependent on oxidative energy metabolism,” wrote Dr. Mao and Dr. Reddy. “Deficient mitochondrial metabolism may generate more reactive oxygen species (ROS) that can wreak havoc in the cell.” A recent study published in Neurology, entitled “Mitochondrial DNA Sequence Variation in Multiple Sclerosis,” demonstrated that certain mitochondrial genetic variants are associated with MS. For example, patients with haplogroup J variants were at a 1.5-times increased risk for developing primary progressive Multiple Sclerosis (PPMS).
Another look into mitochondrial involvement in Multiple Sclerosis (MS) was conducted by Dr. Lukas Haider at the Medical University of Vienna. “Recent data indicate that mitochondrial injury and subsequent energy failure are key factors in the induction of demyelination and neurodegeneration,” wrote Dr. Haider in the article, “Inflammation, Iron, Energy Failure, and Oxidative Stress in the Pathogenesis of Multiple Sclerosis,” which was published in Oxidative Medicine and Cellular Longevity. Since the brain accounts for such a large proportion of oxygen consumption in the mitochondria, cells in the brain are especially susceptible to oxidative stress, leading to the previously identified genetic variants as a result of damage. Without properly functioning mitochondria, cells within the brain cannot thrive.
Dr. Mao and Dr. Reddy discussed a few therapeutic approaches to treat MS by targeting the mitochondria. These therapies are considered more neuroprotective than immunomodulatory and are different from current treatments for MS. Inhibitors of proteins that allow oxidative stress to damage the mitochondria, such as intravenous mitoxantrone, might delay the progression of MS in relapsing-remitting or secondary progressive MS.
Enhancing mitochondrial DNA repair by targeting repair proteins to the mitochondria may also prove to be an effective means for treating MS, while also addressing the direct problem of mitochondrial dysfunction in the disease. At present, mitochondria-targeted antioxidants such as MitoQ and others can help address oxidative stress in the development of diseases such as Multiple Sclerosis by decreasing mitochondrial oxidative damage. Ubiquinone, the active ingredient in MitoQ, is identical to Coenzyme Q10, a well-known antioxidant. Some researchers believe that therapies such as these offer a novel approach to addressing the underlying cause of MS, and patients have reported it success in improving symptoms and quality of life as an alternative the currently FDA-approved Multiple Sclerosis therapies.
July 16, 2015
Report Shows MS Patients Miss Out on Access to Palliative Care Services
A recent report by Marie Curie fellows organization suggests that those suffering from neurological conditions such as Multiple Sclerosis (MS)are missing out on care that could make a major difference in the quality of their lives. When it comes to palliative care, the report contends that there is a limited understanding about the need for it among both public policy makers and health professionals. In a recent post by the MS Trust, the organization seeks to highlight what palliative care can offer, who can benefit from it and when is the right time to access this type of holistic care.
According to the report, people often associate palliative care with cancer treatment and end of life care. However, the truth is that the goal of palliative care is much broader and includes achieving the best quality of life possible for patients and their families by managing symptoms and providing spiritual and emotional support. Palliative care can start sooner to help manage a condition even in its early stages — particularly progressive ones such as MS.
It is hard to live with a serious illness that has no cure. You may feel lonely, angry, scared, or sad. You may feel that your treatment is doing more harm than good. You may have pain, increasing disability or other disturbing symptoms. Palliative care can help you and your loved ones cope with all of these things.
Palliative care is a kind of care for people who have serious illnesses. It is different from care to cure your illness, called curative treatment. Palliative care focuses on improving your quality of life—not just in your body, but also in your mind and spirit. Sometimes palliative care is combined with curative treatment.
The kind of care you get depends on what you need. Your goals guide your care. Palliative care can help reduce pain or treatment side effects. Palliative care may help you and your loved ones better understand your illness, talk more openly about your feelings, or decide what treatment you want or do not want. It can also help with communication among your doctors, nurses, and loved ones.
The report also emphasizes the issues concerning limited access to timely palliative care for those suffering from MS despite having symptoms like pain, swallowing problems, recurrent infection, and emotional and psychological obstacles that palliative care can treat. Research has shown that receiving earlier palliative care can improve symptoms and decrease the burden for caregivers. For patients suffering from MS, a flexible approach for palliative care services is required and the intervention might change over time according to the course of the disease.
Suggestions for improved palliative care services include:
• More commitment from health authorities to provide resources to everyone with palliative needs so they can have access to more appropriate services independently of their condition.
• Advancement of stronger relationships between palliative care specialists and condition-specific health professionals.
• All health agencies should recognize the relevance of making sure that everyone understands the concept of palliative care and what it can provide to people and how it can be accessed.
The MS Trust Director of Service Development, Amy Bowen, noted: “Palliative care can be a vital element of improving quality of life for people managing more advanced symptoms of MS and also for their families. Access to this care is essential and it is important that people with MS, their families and health professionals understand what palliative care services can offer.”
Source: Marie Curie fellows organization, MS Trust
July 09, 2015
Study Reveals Brain Network Responsible for Cognitive Changes in MS
Over 2.5 million individuals are living with Multiple Sclerosis (MS) worldwide. Approximately half of all individuals with MS experience changes in cognition such as impaired concentration, attention, memory, and judgment. The underlying brain basis for these deleterious effects has been largely elusive. New findings published in Neuropsychology reveal that decreased connectivity between network-specific brain regions are to blame for the central deficit common to the various cognitive changes associated with MS, slowed cognitive speed.
In the first study of its kind, researchers at the Center for BrainHealth at The University of Texas at Dallas and The University of Texas Southwestern Medical Center found that, compared to healthy controls, individuals with MS exhibit weaker brain connections between the dorsolateral prefrontal cortex and posterior brain regions. The change amounts to a breakdown in communication between the part of the brain responsible for executing goal-directed thought and action and the regions responsible for carrying out tasks related to cognitive speed such as visual processing, motor execution, and object recognition. The researchers believe that the diminished connections are likely the result of decreased white matter surrounding the neurons in the brain.
“Our study is the first to really zero in on the physiology of cognitive speed, the central cognitive deficit in MS,” explained Center for BrainHealth principal investigator Bart Rypma, Ph.D., who also holds the Meadows Foundation Chair at UT Dallas. “While white matter is essential to efficient network communication, white matter degradation is symptomatic of MS. This study really highlights how tightly coupled connectivity is to performance and illuminates the larger, emerging picture of white matter’s importance in human cognitive performance.”
Collaborating with Elliot Frohman, M.D., Ph.D., director of the Multiple Sclerosis Program and Clinical Center at UT Southwestern, the study recruited 29 participants with relapsing-remitting MS and 23 age- and sex- matched healthy controls. Participants underwent functional magnetic resonance imaging (fMRI) while completing a measure of cognitive processing speed. Participants were given four seconds to view a nine-item key of number and symbol pairs (for example ‘+’ above the number three) and one number-symbol pair probe. Participants were asked to indicate with a left or right thumb button press whether or not the probe appeared in the key.
While accuracy was similar for both healthy controls and individuals with MS, response times for individuals with MS were much slower. Analysis of the fMRI data revealed that while completing this measure, MS patients showed weaker functional connections with dorsolateral prefrontal cortex.
“These findings reveal a diffuse pattern of disconnectivity with executive areas of the brain,” explained the study’s lead author, Nicholas Hubbard, a doctoral candidate at the Center for BrainHealth working with Dr. Rypma. “Importantly, these decreases in connectivity predicted MS-related cognitive slowing both in and out of the fMRI environment suggesting that these results were not specific to our task, but rather were able to generalize to other situations where cognitive speed is required.”
This research supports the need for therapies that target white matter structures and white matter proliferation. Rypma and Hubbard are currently conducting research to further explore the physiology of white matter to better understand cognitive speed reductions not only in MS, but also in healthy aging individuals.
Source: The Center for BrainHealth at The University of Texas at Dallas, The University of Texas Southwestern Medical Center
July 02, 2015
Novel Discovery Offers New Insight into Why Women More Likely to Develop MS Than Men
An innocent mistake made by a graduate student in a Northwestern Medicine lab (she accidentally used male mice instead of female mice during an experiment) has led scientists to a novel discovery that offers new insight into why women are more likely than men to develop autoimmune diseases such as Multiple Sclerosis (MS).
The finding, detailed in a paper published in The Journal of Immunology, focuses on a type of white blood cell, the innate lymphoid cell, that exhibits different immune activities in males versus females.
MS is a disease that affects the brain and spinal cord and is the result of a dysregulated immune response. Using a mouse model of MS in which only females get disease, this study showed that innate lymphoid cells are activated and protect male mice from the disease. Although female mice have these same cells, they remain inactive and do not protect them.
The research opens up new avenues for investigation into sex-determined disease susceptibility and could one day lead to better therapies for both men and women with MS and other autoimmune diseases.
"Women are three to four times more likely than men to develop MS, and much of the current research focuses on the question, 'Why do females get worse disease?'" said Melissa Brown, lead author of the study and professor of microbiology-immunology at Northwestern University Feinberg School of Medicine.
"Now, thanks to a serendipitous moment in the laboratory, we are approaching this research from the opposite way, asking, 'Why are males protected from disease?'" Brown said. "Understanding the mechanisms that limit disease in men can provide information that could be used in future therapy to block disease progression in women."
Like most laboratories that study the mouse model of MS, female mice were used in almost all of Brown's experiments.
"When we induce the disease in this strain of female mice, virtually 100 percent of them get very sick," Brown said. "Male mice either get no disease or very little, so MS researchers typically use females in their studies."
A few years ago, a new graduate student in Brown's laboratory was asked to run an experiment using two groups of female mice. One group was normal; the other had a genetic mutation in a growth factor receptor (c-kit) that prevented the development of a subset of immune cells.
Previous experiments in Brown's lab showed that female mice with the mutation didn't get as sick as normal mice, and Brown was looking into reasons why. However, instead of using females, the graduate student chose male littermates from each group.
"It was an honest mistake, but the results were striking; the male mice with the mutation got very, very sick," Brown said. "Because this strain of male mice never get very sick, I thought there was some sort of mistake, so I asked the student to repeat the experiment."
The results were the same. Brown and colleagues realized that the mutation was behaving differently in males and females. Brown asked Abigail Russi, a Feinberg MD/PhD student working in her lab, to investigate further.
Russi found that mice with the c-kit mutation lacked type 2 innate lymphoid cells. These cells are normally present in bone marrow, lymph nodes and the thymus of both males and females. The researchers think that in males these cells produce a protein that may help to protect from the disease by interfering with the damaging immune response.
"In the paper we show that when these cells are missing in the males with the mutation, that changes the whole immune response of the male animals and causes this lack of protection," Russi said. "We are now looking at what activates these cells preferentially in males and not in females. The next question is can we activate the innate lymphoid cells in females to decrease disease susceptibility?"
This isn't the first sex difference study in the field of MS research. In the 1990s, scientists found that testosterone was a protective hormone for women with MS, but long-term treatment of women with MS with testosterone is not a viable option because of undesirable side effects.
Type 2 innate lymphoid cells have been well studied in allergy, where they are thought to promote allergic inflammation. But this is the first study to show these cells exhibit sex differences in their activity and actually can protect in autoimmune disease. Early trials are underway, and the scientists are hoping they will find clues to explain potential activators of these cells and whether those activators can be used in therapy.
The findings could lead to a new approach to designing drug therapy that modulates instead of completely suppresses the immune system of MS patients, shifting the response to one that is not so damaging.
"The hope is to target these cells in a sex-specific way and provide a therapy with fewer side effects," Brown said. "This early research may have implications for understanding other diseases such as lupus and rheumatoid arthritis, which also show a female bias."
Source: Northwestern University, The Journal of Immunology
June 25, 2015
Key Regulator of Inflammation Disrupted by Gene Variants Linked to MS
With genetic roots of many diseases pinpointed, scientists are zeroing in on the variety of molecular mechanisms triggered by these harmful variants. A team led by Yale School of Medicine researchers has implicated a central regulator of inflammation as a cause of many cases of Multiple Sclerosis (MS) — and intriguingly, the researchers note — ulcerative colitis as well. The study was published in the June 10 issue of the journal Science Translational Medicine. “After identifying the genes that cause MS, we are starting to generate a comprehensive roadmap of the how these genes operate together in allowing immune cells to become activated and attack the myelin,” says David A. Hafler, the William S. and Lois Stiles Professor of Neurology and Immunobiology at Yale and chair of Yale’s Department of Neurology. Last fall, a consortium of researchers identified genetic variants that play a role in onset of 21 different autoimmune diseases. Ninety-seven variants were associated with multiple sclerosis. The new Yale research led by Hafler and first author William J. Housley shows that 17 of these MS variants affect the NFkB pathway, which controls a host of immune system responses to environmental threats, and that one variant associated
with MS near the NFkB gene profoundly increased gene activity. The findings illustrate the complexity of individual diseases like MS, in which variants can contribute to small increases in risk of disease through different molecular mechanisms. They also illustrate how same molecular pathways, such as NFkB, can trigger a variety of autoimmune
diseases with fundamentally different symptoms — such as MS and ulcerative colitis. “Identifying these like-minded genes that by themselves contribute only a small risk to disease but together lead to major alterations in immune function may allow a more precise approach in deciding which drug should be used to treat patients,” Hafler said.
Primary funding for the research came from grants from the National Institute of Health and the National Multiple Sclerosis Society. Source: Yale School of Medicine, Neuroscience News
Armed with knowledge of the genetic roots of autoimmune diseases like MS, scientists are zeroing in on their molecular causes. Image credit: Michael S. Helfenbein.
June 18, 2015
Autoimmunity: New Immunoregulation and Biomarker
Clinicians at Ludwig-Maximilians-Universitaet (LMU) in Munich have elucidated a mechanism involved indetermining the lifespan of antibody-producing cells, and identified a promising new biomarker for monitoring autoimmune diseases like Multiple Sclerosis and Lupus Erythematosus.
The so-called humoralimmune response is mediated by plasma cells and plays a central role in combating infections. Plasma cells ecrete antibodies -- a class of proteins that specifically recognize nfectious pathogens and facilitate their destruction. Individual plasma cells make only a single species of antibody that normally recognizes a single structure. Nevertheless, antibodies with certain specificities may erroneously attack the tissues of their host, causing autoimmune diseases such as Multiple Sclerosis (MS) or Lupus Erythematosus (SLE). “Balanced regulation of the production and activity of plasma cells is therefore vital,” says Professor Edgar Meinl (LMU Medical Center). Long-term antibody-mediated immunity is provided by so-called longlived plasma cells, and Meinl and his research team have now identified a novel mechanism involved in regulating the lifespan of these antibody producing cells. This involves the shedding of a particular cell-surface receptor, named BCMA, which is known to bind factors that promote plasmacell survival. The released segment that is cut off the receptor can be detected in the circulation, and the LMU group has shown that it provides a useful biomarker for monitoring the severity of autoimmune conditions. The new findings appear in the online journal Nature Communications.
Protease g-secretase truncates receptor Plasma cells develop from progenitors called B-cells that carry specific membrane- bound receptors which recognize foreign proteins termed antigens. When a B cell encounters its cognate antigen, it differentiates into a clone of plasma cells that secrete the antigen-binding protein in soluble form as antibody. How long an antibody-producing plasma cell survives in the body depends largely on the survival receptor BCMA. When the BCMA binds its ligands, the survival factors BAFF and APRIL, a genetic program is activated which effectively extends the lifespan of the plasma cell. “However, the lifetime of plasma cells cannot be prolonged indefinitely. Otherwise the organism would become swamped with antibodies, increasing the risk of an autoimmune reaction,” Meinl explains. “We have now shown, in cooperation with colleagues in Munich, Berlin and Stockholm, that the membrane- bound enzyme gammasecretase acts as a brake on immune reactions by fragmenting BCMA.”
As a so-called transmembrane receptor, BCMA extends through the cell membrane and projects into the extracellular medium. Gamma-secretase removes the exposed portion by cutting the protein inside of the plasma membrane. That this enzyme cleaves the receptor directly was a surprise: “Up to now, it was only known to be involved in the degradation of membrane proteins that had already been cleaved by other enzymes. “BCMA is the first natural substrate of gamma-secretase to be identified that is directly cleaved by the enzyme,” says Meinl, “and probably reflects the fact that the extracellular segment of the receptor is unusually short.”
Informative immunological indicator
The cleaved fragment is stable, and can be detected in body fluids as soluble BCMA (sBCMA). Analysis of clinical samples from patients with MS or lupus erythematosus has indicated that the molecule could provide a useful biomarker for autoimmune condition which affects the whole organism. In lupus patients, levels of sBCMA in the blood were found to be abnormally high -- and were correlated with the severity of the disease. Multiple Sclerosis is an organ-specific disease, which targets the central nervous system. “Correspondingly, in MS patients sBCMA levels were increased specifically in the cerebrospinal fluid, which bathes the brain and the spinal cord,” says Meinl. “So, sBCMA is an indicator of the intensity of ongoing immune reactions. sBCMA is therefore well suited to serve as an informative clinical parameter for the assessment of the therapeutic effects of different treatment regimes on plasma cells.” These findings could facilitate the development of optimized and personalized modes of therapy. Both B cells and the BCMA / BAFF /APRIL system constitute promising targets for the treatment of lupus and MS as blocking their activity could inhibit the production of the autoimmune antibodies. In the case of lupus, an agent directed against BAFF has already been approved for clinical use. Unfortunately, for unknown reasons, it is effective in only a subset of patients. Further clinical studies on agents that target BAFF, APRIL and their receptors are currently underway. In future, sBCMA could be used to measure and optimize the impact not only of these new therapies but also of already proven treatments, since it enables one to monitor the levels of plasma cells. Source: Ludwig-Maximilians-Universitaet Muenchen (LMU), Nature Communications
June 11, 2015
Multiple Sclerosis Patient Lifespan, Comorbidities Studied in New Research
Researchers at the University of Manitoba in Canada recently conducted a study that explored the differences in lifespan and comorbidities in patients with multiple sclerosis (MS) compared to healthy individuals. The study was recently published in the journal Neurology and is entitled “Effect of comorbidity on mortality in Multiple Sclerosis.” MS is a progressive neurodegenerative disorder that results from the attack to the central nervous system (brain, spinal cord and optical nerves) by the body’s own immune system, causing inflammation and damage to the myelin layer that covers and protects neurons. Myelin loss leads to impairment in signal transmission along nerve fibers, affecting motor function and causing irreversible neurological disability and paralysis. In the study, researchers analyzed 5,797 MS patients and a matched cohort of 28,807 healthy individuals of the same sex, same age and from the same region, to compare mortality rates and causes of death. The association between comorbidity status and mortality was also assessed. The team found that MS patients lived a median of 76 years while healthy individuals lived a median of 83 years. In total, 44 percent of the patients died from the disease and associated complications, followed by circulatory system disorders, cancer and respiratory disease. Researchers analyzed whether participants had other medical conditions, like diabetes, chronic lung disease, ischemic heart disease, anxiety and depression, and found that overall, the presence of other cormobidities had no impact on the lifespan of MS patients any more than it did in healthy individuals without the disease. However MS patients with other conditions, such as diabetes, had a shorter life span than those without. “Treating other conditions better may be a way of improving survival,” noted the study’s lead author Dr. Ruth Ann Marrie in a news release. The team concluded that MS patients have double the risk of premature death when compared to individu als without the disease, with patients younger than 59 years exhibiting a three times higher risk. Within the MS population, comorbidities were found to be associated to an increased mortality risk. “Despite studies that show MS survival may be improving over time, the more than 2.5 million people affected worldwide by this disabling disease still face a risk of dying earlier, specifically those who are diagnosed younger,” concluded Dr. Marrie. Source: University of Manitoba in Canada.
June 04, 2015
Missing Link Found Between Brain, Immune System; Major Disease Implications
In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist. That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped through-out the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from Autism to Alzheimer’s disease to Multiple Sclerosis (MS).“Instead of asking, ‘How do we study the immune response of the brain?’ ‘Why do Multiple Sclerosis patients have the immune attacks?’ Now we can approach this mechanistically. Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels,” said Jonathan Kipnis, PhD, professor in the UVA
Department of Neuroscience and director of UVA’s Center for Brain Immunology and Glia (BIG). “It changes entirely the way we perceive the neuroimmune interaction. We always perceived it before as something esoteric that can’t be studied. But now we can ask mechanistic questions.”“We believe that for every neurological disease that has an immune component to it, these vessels may play a major role,” Kipnis said. “Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component.”New Discovery in Human BodyKevin Lee, PhD, chairman of the UVA Department of Neusels was crucial to demonstrate their function, and it would not be possible without collaboration with Tajie Harris,” Kipnis noted. Harris, a PhD, is an assistant professor of neuroscience and a member of the BIG center. Kipnis also saluted the “phenomenal” surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study. Alzheimer’s, Autism, MS and Beyond The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer’s disease. “In Alzheimer’s, there are accumulations of big protein chunks in the brain,” Kipnis said. “We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.” He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there’s an enormous array of other neurological diseases, from autism to MS, that must be reconsidered in light of the presence of something science insisted did not exist. Source: University of Virginia Health System veau developed a method to mount a mouse’s meninges -- the membranes covering the brain -- on a single slide so that they could be examined as a whole. “It was fairly easy, actually,” he said. “There was one trick: We fixed the meninges within the skullcap, so that the tissue is secured in its physiological condition, and then we dissected it. If we had done it the other way around, it wouldn’t have worked.”After noticing vessel-like patterns in the distribution of immune cells on his slides, he tested for lymphatic vessels and there they were. The impossible existed. The soft-spoken Louveau recalled the moment: “I called Jony [Kipnis] to the microscope and I said, ‘I think we have something.’” As to how the brain’s lymphatic vessels managed to escape notice all this time, Kipnis described them as “very well hidden” and noted that they follow a major blood vessel down into the sinuses, an area difficult to image. “It’s so close to the blood vessel, you just miss it,” he said. “If you don’t know what you’re after, you just miss it.”“Live imaging of these vessels was crucial to demonstrate their function, and it would not be possible without collaboration with Tajie Harris,” Kipnis noted. Harris, a PhD, is an assistant professor of neuroscience and a member of the BIG center. Kipnis also saluted the “phenomenal” surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study. Alzheimer’s, Autism, MS and Beyond the unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer’s disease. “In Alzheimer’s, there are accumulations of big protein chunks in the brain,” Kipnis said. “We think they may be accumulating in the brain because they’re not being efficiently removed by these vessels.” He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there’s an enormous array of other neurological diseases, from autism to MS, that must be reconsidered in light of the presence of something science insisted did not exist. Source: University of Virginia Health System
May 28, 2015
Discovery of a Treatment to Block the Progression of Multiple Sclerosis
A drug that could halt the progression of Multiple Sclerosis may soon be developed thanks to a discovery by a team at the CHUM Research Centre and the University of Montreal. The researchers have identified a molecule called MCAM, and they have shown that blocking this molecule could delay the onset of the disease and significantly slow its progression. These encouraging results from in vitro tests in humans and in vivo tests in mice were published today in the Annals of Neurology. “We believe we have identified the first therapy that will impact the quality of life of people with Multiple Sclerosis by significantly reducing the disability and the disease’s progression,” said Dr. Alexandre Prat, lead author of the study, researcher at the CRCHUM, and professor in the Department of Neurosciences at the University of Montreal.
Multiple Sclerosis (MS) is a neurological disease that is characterized by paralysis, numbness, loss of vision, and gait and balance deficits that lead to chronic disability. There is no effective cure. The disease particularly affects young adults in northern countries.
The brain is normally protected from attacks by the blood-brain barrier. The blood-brain barrier prevents immune cells -- lymphocytes -- from entering the central nervous system. In people with MS, there is often leakage. Two types of lymphocytes, CD4 and CD8, find a way to cross this protective barrier. They attack the brain by destroying the myelin sheath that protects neurons, resulting in decreased transmission of nerve impulses, and plaque formation.
In 2008, Dr. Prat’s team identified a cell adhesion molecule, called MCAM (Melanoma Cell Adhesion Molecule), which plays a crucial role in dysregulation of the immune system observed in Multiple Sclerosis. “Our studies have shown that MCAM is necessary for the migration of CD4 and CD8 across the blood-brain barrier. If we block the interaction of MCAM with the protein to which it normally binds, we decrease the disease’s activity,” he said. Independently, the biotechnology company Prothena Corporation plc also discovered complementary data regarding MCAM, which led to an ongoing collaboration between the CRCHUM and Prothena.
The results are extremely positive. “We observed a decrease of approximately 50 percent of the disease in mice with experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. What is especially significant is that we can stop the disease from the first symptoms in addition to having an impact on its progression, which is a first,” noted Prat.
MS develops in most patients in two phases. For 10 to 15 years, there are outbreaks of symptoms interspersed with remissions. Later, the diseases progresses and the disability worsens, leading to the use of a cane or wheelchair. Currently, none of the drugs available on the market affect the disease’s progression.
Prothena has developed a potentially disease-modifying antibody, called PRX003, which is designed, to inhibit MCAM function and thus prevent migration of destructive lymphocytes into tissue. Prothena expects to initiate clinical trials of PRX003 in healthy volunteers by the end of June, and anticipates a study in patients with psoriasis in 2016. Beyond psoriasis, anti-MCAM antibodies may be useful for treating a variety of diseases, including progressive forms of Multiple Sclerosis.
Source: University of Montreal
May 20, 2015
Multiple Sclerosis: Scientists Identify Cause of Movement, Balance Problems
New research into the causes of the excessive inflammation that drives Multiple Sclerosis (MS) has identified a faulty “brake” within immune cells, a brake that should be controlling the inflammation. This points to a potential target for developing new therapies to treat multiple sclerosis and could have important implications for other autoimmune diseases, such as the colon disease colitis and the chronic skin condition atopic dermatitis.
Further, the work has produced new research models of Multiple Sclerosis symptoms such as movement disorders and balance control problems that have, until now, resisted efforts to mimic them effectively in the lab. These models represent important new tools in the efforts to better understand -- and eventually cure -- MS and other autoimmune conditions.
The researchers determined that a mutation in the gene Nlrp12 was causing immune cells known as T cells to go haywire. Normally, the researchers determined, the protein the gene produces acts as a brake within T cells to control the inflammatory response. But a mutation in that gene disrupts the natural process and provokes severe inflammation -- with effects the researchers found most intriguing.
To the researchers’ surprise, the resulting inflammation did not produce the paralysis often associated with multiple sclerosis. It did, however, produce other MS symptoms -- such as movement disorders and problems with balance control -- which scientists have struggled to replicate in experimental lab settings.
“It’s important to note that MS is a spectrum disorder -- some patients present with paralyzing conditions and some patients don’t,” said researcher John Lukens, PhD, of the University of Virginia School of Medicine Department of Neuroscience and its Center for Brain Immunology and Glia. “Not everybody’s symptoms are the same, so this might give us a glimpse into the etiology or pathogenesis of that family of MS.”
By blocking the inflammatory response, doctors may one day be able to control the symptoms it causes, both in MS and in other diseases driven by hyperinflammation.
Source: University of Virginia Health System
May 14, 2015
Myelin Repair Foundation and NIH to Study Guanabenz for MS
The Myelin Repair Foundation (MRF) and National Institutes of Health (NIH) will initiate a clinical trial of guanabenz in people with Multiple Sclerosis (MS). Guanabenz is FDA-approved for high blood pressure, but it may also prevent myelin loss. The drug could be the first for MS to protect myelin from degeneration, instead of suppressing the immune system — which is how all current MS drugs work.
MS is a chronic disease, estimated to affect over 2.5 million people worldwide. The cause of MS is unknown and symptoms include loss of movement, problems with vision and sensation as well as pain, among others. These problems are caused when myelin — the fatty substance that surrounds and insulates nerve cells — degenerates. When myelin is damaged, cells in the nervous system can no longer communicate effectively. MS drugs seeks to prevent the immune system from attacking myelin, but guanabenz would instead protect myelin from damage.
MRF-funded researchers reported in a Nature Communications paper that guanabenz blocks the degeneration of myelin and halts MS in animal models. Guanabenz may specifically protect oligodendrocytes from dying. The results support guanabenz as a new therapy for MS, but naturally human trials are needed.
“Guanabenz appears to enhance the cell’s own protective machinery to diminish the loss of myelin,” remarked senior study author Brian Popko, Ph.D., Jack Miller Professor of Neurological Disorders at the University of Chicago and a member of the Myelin Repair Foundation’s Research Consortium. “While there have been many efforts to stimulate remyelination, this now represents a unique protective approach. You don’t have to repair the myelin if you don’t lose it in the first place.”
“We are very pleased that guanabenz is now moving into studies in MS patients,” stated Tassie Collins, Ph.D., Vice President of Translational Medicine at the Myelin Repair Foundation. “This is a promising therapeutic approach, but it might not have been able to move forward without MRF’s participation.”
In terms of plans for the clinical trials, Phase 1 clinical studies will measure the safety and tolerability of the drug and identify an optimal dose for Phase II clinical studies.
Treatment outcomes for the Phase II trials will include measuring not just new lesions using magnetic resonance imagining (MRI), but also the status of existing lesions. This is a new measurement approach that may provide a more complete assessment of MS progression.
“Success of a trial design using this outcome measure would enable rapid and cost-effective screening of neuroprotective therapies,” noted Dr. Cortese. “This would definitively lead us into the next era of treatment strategies in MS, just as contrast-enhancing lesions did for disease-modifying immunomodulatory therapies in the 1990s.”
Source: Myelin Repair Foundation, Nature Communications
May 7, 2015
Two Topical Drugs Show Promise Against MS
Two topical skin drugs that are already approved for dermatology purposes could be beneficial for people with Multiple Sclerosis (MS). The finding comes from a research team at Case Western Reserve.
The investigators made their discovery as they evaluated 727 previously known drugs to see which ones might have the ability to “catalyze the body’s own stem cells to replace the cells lost in Multiple Sclerosis,” according to one of the study’s authors, Paul Tesar, PhD, associate professor in the Department of Genetics & Genome Sciences at the Case Western Reserve School of Medicine.
Basically, researchers want to replace myelin, the protective coating on nerve cells. People with MS experience demyelination, which means the myelin is damaged and destroyed and therefore neural signals cannot be transmitted properly.
Demyelination leads to symptoms of MS such as difficulty walking, bowel and bladder problems, vision loss, spasticity, numbness, fatigue, dizziness, cognitive dysfunction, and balance challenges, among others. Preventing, stopping, and even reversing demyelination has been the goal of many research projects.
In this new study, the researchers found they could use already approved drugs to stimulate a person’s native stem cells in their nervous system and direct them to make new myelin. Tesar noted that “Our ultimate goal was to enhance the body’s ability to repair itself.”
The two drugs chosen were miconazole and clobetasol. The former is found in over-the-counter medications that fight fungal infections, such as athlete’s foot. Clobetasol is available by prescription to treat eczema, scalp problems, and other skin conditions.
The investigators found that both miconazole and clobetasol could stimulate oligodendrocyte progenitor cells (OPCs) to form new myelinating cells. Oligodendrocytes are myelin-forming cells in the brain and spinal cord (the central nervous system), and new oligodendrocytes originate from OPCs.
Both drugs caused native OPCs to make new myelin in the lab mice that had a MS-like disease. Robert Miller, PhD, a co-author of the study and a neurosciences faculty member at Case Western Reserve, noted that “It was a striking reversal of disease severity in the mice,” and that the study “represents a paradigm shift in how we think about restoring function to Multiple Sclerosis patients.”
How these drugs will work in humans is not yet known, but the researchers have tested them using human stem cells and observed a response similar to the one they saw in mice. Now scientists are left with the task of applying what they’ve learned from this work, finding how to transform the topical drugs for internal use, and conducting human clinical trials.
Source: Case Western Reserve School of Medicine, Nature
April 30, 2015
Preventing MS and Other Inflammatory and Autoimmune Diseases Possible?
Scientists from the Gladstone Institutes have discovered a way to prevent the development of Multiple Sclerosis (MS) in mice. Using a drug that blocks the production of a certain type of immune cell linked to inflammation and autoimmunity, the researchers successfully protected against the onset of MS in an animal model of the disease. The scientists say the next step is to test this strategy using other autoimmune disorders.
"We are very excited about these findings," says Eric Verdin, MD, a senior investigator at Gladstone and co-senior author on the study. "In light of the significant effect the treatment had on inflammation, the implications of these results will likely extend beyond multiple sclerosis to other types of autoimmune disorders. We are particularly interested in testing this in type I diabetes given the similar pathways involved, and we are already seeing very promising results in preliminary experiments."
In the immune system, two kinds of T cells strike a delicate balance--T helper cells (Th17) activate the immune system, protecting against infections and cancers, while regulatory T cells (Tregs) suppress the system, keeping it in check. A disparity between these cell types, where there are too many Th17 and not enough Tregs, can lead to a hyperactive immune system, resulting in inflammation, tissue damage, and autoimmune disease.
In the current study, published in the Journal of Experimental Medicine, the researchers discovered that an important regulatory protein, sirtuin 1 (SIRT1), is involved in the production of Th17 cells. By blocking this protein, the scientists can protect against the onset of autoimmunity. SIRT1 also has a negative impact on Treg maturation and maintenance, so inhibiting its expression simultaneously enhances the production of Tregs and suppresses the creation of Th17.
To test this effect on disease, the researchers used a mouse model of MS and treated the animals with a drug that inhibits SIRT1. Typically, MS-model mice experience severe motor problems, eventually leading to paralysis, but when they were given the drug the mice behaved perfectly normally. Moreover, the treated animals showed no signs of inflammation or cell damage in their spines, classic markers for MS.
In contrast with the current research, SIRT1 is typically thought of as having anti-inflammatory properties, and compounds that increase SIRT1--like resveratrol--have been proposed as a way to delay aging. However, first author Hyungwook Lim, PhD, a postdoctoral fellow at Gladstone, says the new research suggests that the protein's effects are more complicated.
"The conventional theory has been that you should activate SIRT1 to improve health and longevity, but we show that this can have negative consequences," says Dr. Lim. "Instead, we think the role of SIRT1 very much depends on the type of tissue being targeted. For instance, in immune cells, instead of being anti-inflammatory SIRT1 appears to have a pro-inflammatory role, which makes it a prime target to treat autoimmune disorders."
Source: Gladstone Institutes
Dean has been fighting Multiple Sclerosis for 28 years. She continually studies and researches the disease to educate herself. She writes this column as a community service to share her findings and to raise public awareness about MS. The opinions and experiences shared are her own. Dean is NOT a medical doctor. ALWAYS check with your doctor first before trying a new therapy. This column is intended for informational purposes only. Dean can be reached at firstname.lastname@example.org.
NOTE: Dean is the recipient of the 2004 STAR Community Outreach Award by the MS Society Dec. 2, 2004, the American Red Cross Real Hero Wendell Cutting Humanitarian Award, Oct. 13, 2006 , the Stoney Community Service Award, February 29, 2008, Women in Leadership Award for Art/Media/Culture Oct. 29, 2010, El Cajon Citizen of The Year Nominee Feb. 2013 and Recipient of the National MS Society’s 2014 Media Partner of The Year, Feb. 10, 2015.
Maps of the lymphatic system: old (left) and updated to reflectUVA’s discovery.
Credit: University of Virginia Health SystemType your paragraph here.
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