Researchers at Immco Diagnostics and the State University of New York have reported in the journal PLoS One that the frequency of specific auto reactive antibodies does not differ between patients with multiple sclerosis (MS) and people without the condition — a finding that could lead to improvements in diagnosis. The study is entitled “Humoral Responses to Diverse Autoimmune Disease-Associated Antigens in Multiple Sclerosis.”
Patients with the progressive form of MS usually have a poor response to treatment, say researchers, as all approved therapies are currently indicated for the relapsing-remitting form. The progressive forms can be either primary progressive MS, where patients develop this form from the time of diagnosis, or secondary progressive MS, where patients initially experience a relapsing-remitting phase of neurological dysfunction that later evolves into a secondary progressive disease.
Immune auto reactive B cells and their antibody response have been reported previously by researchers to play a key role in MS development. In this study, the goal was to assess auto reactive antibodies’ frequency in patients with different MS forms, and see if they match up with clinical and magnetic resonance imaging (MRI) measures of MS disease progression. Possible co-morbidities were also evaluated, including infection by the Epstein-Barr virus (EBV), a common human herpes virus that targets B cells and which has been linked to an increased risk of MS.
Researchers analysed serum samples from patients and healthy controls for autoantibodies against three known antigens related to MS [CSF114(Glc), KIR4.1a and KIR4.1b] and against 26 different antigens linked to other autoimmune disorders, including systemic sclerosis, lupus, rheumatoid arthritis, among others.
Researchers found the frequencies of auto reactive antibodies against CSF114(Glc), KIR4.1a and KIRK4.1b were similar between healthy controls and RRMS, PPMS and SPMS patients, suggesting that these antibodies are not associated with MS or disease progression. In fact, none of the several autoreactive antibodies analysed, including anti-EBV antibodies, were found to differ in terms of frequency between MS patients and healthy controls.
The research team concluded that the frequency of the autoantibodies analysed in MS patients is similar to the ones in healthy controls, and that the presence of autoreactive antibodies was not associated with clinical and MRI measures of MS disease progression. Researchers expressed their concern that CSF114 and anti-KIR 4.1a and KIR 4.1b peptide antibodies might not have the diagnostic MS properties that were previously thought to have. These new insights could help physicians improve the diagnosis of MS in the future — a key advancement, since diagnosing and treating MS as early as possible is critically important to mitigating the disease.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (26/06/15)
Tags: MS, multiplesclerosis, autoantibodies, F114(GLC), KIR4.1A KIR4.1B, Research
Clinicians at Ludwig-Maximilians-Universitaet (LMU) in Munich have elucidated a mechanism involved in determining 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 humoral immune response is mediated by plasma cells and plays a central role in combating infections. Plasma cells secrete antibodies - a class of proteins that specifically recognise infectious 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 Centre).
Long-term antibody-mediated immunity is provided by so-called long-lived 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 plasma-cell 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.
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 explained. “We have now shown, in cooperation with colleagues in Munich, Berlin and Stockholm, that the membrane-bound enzyme gamma-secretase 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,” said Meinl, “and probably reflects the fact that the extracellular segment of the receptor is unusually short.”
The cleaved fragment is stable, and can be detected in body fluids as soluble BCMA (sBCMA). Analysis of clinical samples from patients with multiple sclerosis or lupus erythematosus has indicated that the molecule could provide a useful biomarker for autoimmune disease. Lupus is a systemic 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,” said 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 regimens 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 multiple sclerosis, 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: News-Medical.net Copyright 2000-2015 AZoM.com Limited (16/06/15)
Researchers solve MS ‘puzzle’(18/05/15)
Evidence has long suggested multiple sclerosis is an autoimmune disease, but researchers have been puzzled because they found the same T cells that attack the myelin sheathing around nerve cells in MS patients are present in healthy subjects as well.
Now researchers from the Yale School of Medicine and colleagues at the Massachusetts Institute of Technology (MIT) report that auto-reactive T cells in MS patients produce different types of inflammatory hormones called cytokines than they do in healthy subjects.
“In most people, these T cells are acting to repair tissue, but in MS patients, they do damage to the nervous system,” said Dr. David Hafler, the William S. and Lois Stiles Edgerly Professor of Neurology and senior author of the study, published May 14 in the journal Science Translational Medicine.
The Yale-led team analysed T cell populations from 23 MS patients and 22 healthy controls. Existing drugs target the MS-specific cytokines identified in the study and should be a promising new treatment for the disease, the authors say.
Hafler also noted the same sort of process might be found in other autoimmune diseases, such as rheumatoid arthritis and Type 1 diabetes.
Yonghao Cao of Yale and Brittany A. Goods of MIT are co-first authors of the paper.
The research was funded by the National Institutes of Health and the National Multiple Sclerosis Society.
Source: Bioscience Technology © Copyright 2015 Advantage Business Media (18/05/15)
Cytokines may play major role in MS(29/04/15)
Researchers say they have discovered the role of a major cytokine in multiple sclerosis that could be a target for new therapy against the disease.
MS is caused by immune cells that activate a cascade of chemicals in the brain, attacking and degrading the insulation that keeps neuronal signals moving. These chemicals, called cytokines, drive the inflammation in the brain, attracting more immune cells, and so causing the condition.
Researchers have long debated which cytokines drive the condition and which are merely accessory. Now a study published in the Journal of Immunology confirms the cytokine GM-CSF (Granulocyte macrophage colony-stimulating factor) likely plays an important role in human disease and offers a new explanation for why the MS treatment interferon-Beta is often so effective.
"After our animal studies showed GM-CSF was important in the development of an MS-like disease, we were excited to see these results confirmed using samples from MS patients in the current study," says Abdolmohamad Rostami, M.D., Ph.D., Chair of the Department of Neurology at Thomas Jefferson University and director of its neuroimmunology laboratory.
A few years ago, MS researchers were focused on a new type of immune cell called the Th-17 cell, which appeared to be a key player in driving the neuronal damage in MS. Because Th-17 cells produce the cytokine IL-17, researchers likewise thought this chemical was essential to the condition. IL-17, however, turned out to be something of a red herring.
In a paper published in Nature Immunology in 2011, Dr. Rostami and colleagues showed the Th-17 cells also produced another cytokine called GM-CSF, which created a chain reaction with another cell type ultimately increasing the GM-CSF levels in the brain of mouse models significantly. In addition, the researchers showed that in experimental models of MS, mice that were unable to produce GM-CSF never developed the condition, whereas mice lacking IL-17 did develop the disease, though generally developed a milder form.
In the new study, to test whether the same observation was true in humans, Dr. Rostami and colleagues tested blood samples of patients with MS who had not yet received therapy, and those currently being treated with interferon-Beta, a commonly used therapy. On average, untreated patients had two to three times as many immune cells producing GM-CSF as did patients being treated with interferon-Beta, or normal subjects. In addition, the researchers looked at brain samples of deceased patients with MS and found increased numbers of GM-CSF-producing cells in comparison to normal brain samples.
"The study demonstrates a new mechanism of action for interferon-Beta therapies," says Dr. Rostami.
In addition, a recent Phase 1 clinical trial of an antibody that blocks GM-CSF showed early signs of effect. Phase 1 trials are typically only designed to determine if a new drug is safe, and can't answer whether a new drug works. However, these results together with the work from the Rostami lab suggest that GM-CSF is a target worth pursuing for the treatment of MS.
"We hope that this research showing GM-CSF is an important target will lead us toward therapies that more effectively block the damaging immune reaction in the central nervous system of MS patients," says Dr. Rostami.
Source: EurekaAlert! Copyright © 2015 by the American Association for the Advancement of Science (AAAS) (29/04/15)
Scientists from the Gladstone Institutes have discovered a way to prevent the development of multiple sclerosis 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."
Other Gladstone investigators on the study include Jae Kyu Ryu, Mingjian Fei, Intelly Lee, Kotaro Shirakawa, Herbert Kasler, Hye-Sook Kwon, Katerina Akassoglou, and Melanie Ott, who was a co-senior author on the paper. Scientists from the University of California San Francisco, Scripps Research Institute, Buck Institute for Research on Aging, National Institute of Infectious Diseases Japan, German Cancer Research Center, New York University School of Medicine, and Howard Hughes Medical Institute also took part in the research. Funding was provided by the Kurtzig and Mulholland families, the National Center for Research Resources, and the National Center for Biotechnology Information.
Source: EurekaAlert Copyright © 2015 by the American Association for the Advancement of Science (AAAS)(27/04/15)
A study published in PLOS ONE provides new insights into the relationship between the immune system and neurodegeneration and clinical disability in MS, reports Multiple Sclerosis News Today.
A team of researchers led by Dr. Shahin Aeinehband from the Neuroimmunology Unit at the Karolinska Institutet in Sweden looked at the association between a central component of the innate immune system, C3 protein, with the activity of cholinergic metabolism and neurodegeneration markers in both relapsing-remitting and primary progressive MS.
In the study Complement Component C3 And Butyrylcholinesterase Activity Are Associated With Neurodegeneration And Clinical Disability In Multiple Sclerosis, Dr. Shahin Aeinehband and his team analysed 48 samples of cerebrospinal fluid (CSF) from MS patients and compared them to 18 samples of CSF from healthy individuals. Levels of C3 protein; neurofilament-light (NFL), a marker for ongoing nerve injury; and activity of the two main acetylcholine degrading enzymes, acetylcholinesterase and butyrylcholinesterase (BuChE) were measured.
C3 protein levels were elevated in MS patients when compared to controls and were correlated both to disability and neurodegeneration (as showed by NFL levels). This finding supports the theory that the complement system influences MS and is compatible with previous findings in other neurodegenerative conditions. Additionally, the C3 protein levels were increased in patients with more cerebral lesions on magnetic resonance imaging and in patients with progressive disease. Finally, BuChE activity correlated with both C3 and NFL levels in individual samples.
In conclusion, the study found that C3 protein is a marker for ongoing nerve injury and degree of disease disability, with this relationship appearing to be especially important in late stage disease (i.e., with more cerebral lesions or clinically progressive disease). It also suggests a link between the expression of complement C3 and the cholinergic tone (BuChE activity).
Although further studies are needed to clearly establish the cause of these processes, these findings can offer future novel targets for MS therapy.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (07/04/15)
Scientists at America's National Institutes of Health (NIH) say they may have discovered a critical immune system switch that could affect genes involved in autoimmune diseases. The ground-breaking work, published in the journal Nature, may be useful for developing treatments for autoimmune disorders such as multiple sclerosis (MS).
Finding autoimmune disease susceptibility genes, such as those involved in MS, is difficult due to environment-gene interactions that likely occur. Switches to control gene activities, known as enhancers, have been proposed to play a possible role.
Led by John J. O’Shea, M.D., the scientific director at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases, the researchers decided to study a newly discovered type of enhancer called a super-enhancer (SE). SEs are powerful switches that control genes. Dr. O’Shea and his collaborators looked for SEs in T cells, immune cells that are important for contributing to the autoimmune disease rheumatoid arthritis.
“We now know more about the genetics of autoimmune diseases,” stated NIAMS Director Stephen I. Katz, M.D., Ph.D. “Knowledge of the genetic risk factors helps us assess a person’s susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual.”
“Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach,” remarked Dr. O’Shea. “From the locations of their super-enhancers, T cells are telling us where in the genome these cells invest their assets—their key proteins—and thereby where we are most likely to find genetic alterations that confer disease susceptibility.”
The researchers searched the genetic material of T cells and found that many identified mutations associated with autoimmune diseases could be localized to T cell SEs. The scientists then treated human T cells with a drug used for rheumatoid arthritis, called tofacitinib. They discovered that genes controlled by SEs changed dramatically compared to other genes without SEs. They concluded that tofacitinib may work by acting on SEs to affect T cell genes.
“Three types of data — the genetics of rheumatoid arthritis, a genomic feature of T cells, and the pharmacological effects of a rheumatoid arthritis drug—are all pointing to the importance of super-enhancers,” said lead author, Golnaz Vahedi, Ph.D. “These regions are where we plan to search for insights into the mechanisms that underlie rheumatoid arthritis and other autoimmune diseases, and for novel therapeutic targets for these conditions.”
Source: Multiple Sclerosis News Today © BioNews-tx.com 2015 (13/03/15)
A study published by a team of investigators at the University of Tokyo’s Institute of Medical Science and Osaka University’s Graduate School of Engineering has presented new evidence demonstrating how Toll-like receptor 9 (TLR9) binds to pathogenic DNA, turning on the functions of the innate immune system. This novel discovery is important for the design of new therapeutic drugs for autoimmune diseases, such as multiple sclerosis (MS), targeting TLR9. The study was published in the new issue of Nature.
Toll-Like Receptors (TLRs) play a critical role in the early innate immune (non-specific first line of defense against pathogens) response to invading bacteria, viruses, and other foreign agents and are also involved in sensing the body’s internal alarm system to help activate other important components of its immune defenses. TLR9 detects the alarm system by recognizing a DNA sequence called Cytosine-phosphate-Guanine dinucleotide (CpG), a pattern that is specific to bacteria and viruses. This induces the release of interferon (IFN) and initiates the inflammatory response process. For autoimmune disease such as MS, studies have shown that TLRs and the release of IFN play a major role in the initiation of disease, triggering of relapses and regulation of damage.
Unfortunately, the exact structure of TLR9 and how it functions remained unknown, inhibiting advancement of treatments that specifically targeted these receptors. This study conducted by Professor Toshiyuki Shimizu PhD’s research group used crystallographic (molecular structure) data to evaluate TLR9’s ring-shaped form in three crucial states: as a free protein, bound to an inhibitor DNA, and bound to an agonist DNA. In the first two cases, TLR9 exists as a single ring, but when it binds to an agonist, like a DNA segment containing the CpG motif, two of its rings are bound together and form a dimer (chemical structure formed from two similar sub-units) that shares two DNA molecules.
In a statement explaining the importance of the study findings, Professor Shimizu said, “TLR9 is a promising drug target for treating viral infections, cancer, autoimmune diseases, and so on, so researchers have been trying to elucidate structurally how TLR9 recognizes pathogenic DNA ever since it was discovered more than a decade ago. This work represents a big step forward for drug development targeting TLR9, and also for our understanding of nucleic acid sensing by TLR9. TLRs have received significant attention due to their critical roles in the innate immune system, and our group has been focusing on the structural study of TLRs for many years. We believe that a precise understanding of TLR function should come from its visualization by structural analyses. Actually, we were quite surprised at the result of this study: the two DNA molecules, agonist and inhibitor, bound to completely different sites on TLR9, and the DNA molecules themselves had completely different structures, both of which we could never have predicted.”
Source: Multiple Sclerosis News Today © BioNews-tx.com 2015 (20/02/15)
A team of scientists have uncovered a molecule that fights one of the main causes of inflammatory diseases and could be the key to improved treatments for diseases like Alzheimer's, arthritis and multiple sclerosis. The research team, led by Trinity and the University of Queensland Australia, showed the molecule, MCC950, could suppress the key activator in inflammatory diseases, NLRP3. The finding also confirms that inflammatory diseases all share a common process, even though the part of the body becoming inflamed might differ.
Researcher Luke O'Neill said drugs like aspirin or steroids can work in several diseases, but can have side effects or be ineffective, and what they have found is a potentially transformative medicine, which targets what appears to be the common disease-causing process in a myriad of inflammatory diseases. There is huge interest in NLRP3, both among medical researchers and pharmaceutical companies, and they feel their work makes a significant contribution to the efforts to find new medicines to limit it. MCC950 can be administered orally and will be cheaper to produce than current protein-based treatments, which are given daily, weekly, or monthly by injection.
More importantly, the new molecule also remains in the body for a shorter duration, allowing clinicians to stop the anti-inflammatory action of the drug if the patient ever needed to switch their immune response back to 100 percent, in order to clear an infection. So far, the results have shown great promise for blocking multiple sclerosis in a model of the disease, as well as in sepsis where, in response to bacteria, potentially fatal blood poisoning occurs. However, the target for MCC950 is strongly implicated in diseases such as Alzheimer's disease, atherosclerosis, gout, Parkinson's disease and rheumatoid arthritis, which means it has the potential to treat all of these conditions. The study is published in medical journal Nature Medicine.
Source: dna © 2015 Diligent Media Corporation Ltd (18/02/15)
NUS researchers make breakthrough discovery that could lead to future treatment for multiple sclerosis(24/11/14)
The latest findings may provide an avenue for therapeutic intervention of multiple sclerosis. A multi-disciplinary research team from the National University of Singapore (NUS) has made a breakthrough discovery of a new type of immune cells that may help in the development of a future treatment for multiple sclerosis (MS).
Led by Professor Xin-Yuan Fu, Senior Principal Investigator from CSI Singapore and Professor at the Department of Biochemistry at the NUS Yong Loo Lin School of Medicine, and Dr Wanqiang Sheng, post-doctoral fellow at CSI Singapore, the team found that a new type of immune T helper cells named TH-GM cells play a crucial role in the immune system and pathogenesis of neuronal inflammation. The findings shed light on a possible new avenue for therapeutic intervention, which can be used independently or in conjunction with other treatment options to improve outcomes in the treatment of MS.
Working with Dr Yong-Liang Zhang from the Department of Microbiology at the NUS Yong Loo Lin School of Medicine, Prof Fu and his team showed that STAT5, a member of the STAT family of proteins, programs TH-GM and initiates the immune response to an auto-antigen in responding to a signal from an interleukin, IL-7, causing neuro-inflammation, pathogenesis and damage in the central nervous system. Blocking IL-7 or STAT5 would provide a significant therapeutic benefit for this disease. The study was first published online on 21 November in the journal Cell Research by Nature Publishing Group.
MS is the most prevalent autoimmune disease of the central nervous system, affecting about 2.5 million people globally, with cases showing a higher prevalence in Northern Europe. Despite many years of research, the causes of MS are largely unclear and the disease remains incurable.
This study offers an important insight into the mechanisms behind MS. Dr Richard Flavell, Chair of the Department of Immunology at Yale University, USA, and a world leader in the immunology field, noted that the results from the study may now provide a mechanistic link between IL-7/STAT5-mediated signalling and T helper cell-mediated pathogenicity.
The STAT family of proteins and their signalling pathway (called JAK-STAT) were originally discovered by Prof Fu and his colleagues in 1992. Disturbance of this pathway was shown to be a major cause for many kinds of inflammatory diseases. Novel medicines interfering with JAK-STAT have since been approved in the United States, Europe, and Singapore for the treatment of numerous diseases, and annual sales of medicines involving JAK-STAT are expected to exceed US$1.6 billion in 2016. The newly discovered IL-7-STAT5 by Prof Fu and his team in neuro-inflammation significantly expands this line of medical research, development and therapeutic intervention in a number of major diseases.
Moving forward, Prof Fu and his team are researching the physiological function of TH-GM to further the development of therapy for various human autoimmune diseases.
Source: National University of Singapore (24/11/14)
In multiple sclerosis, the immune system goes rogue, improperly attacking the body's own central nervous system. Mobility problems and cognitive impairments may arise as the nerve cells become damaged.
In a new study, researchers from the University of Pennsylvania and co-investigators have identified a key protein that is able to reduce the severity of a disease equivalent to MS in mice. This molecule, Del-1, is the same regulatory protein that has been found to prevent inflammation and bone loss in a mouse model of gum disease.
"We see that two completely different disease entities share a common pathogenic mechanism," said George Hajishengallis, a professor of microbiology in Penn's School of Dental Medicine and an author on the study. "And in this case that means that they can even share therapeutic targets, namely Del-1."
Because Del-1 has been found to be associated with susceptibility to not only multiple sclerosis, but also Alzheimer's, it's possible that a properly functioning version of this protein might help guard again that disease's effects as well.
Penn contributors to the study included Hajishengallis, Penn Dental Medicine postdoctoral researcher Kavita Hosur and Khalil Bdeir, a research associate professor at Penn's Perelman School of Medicine. They collaborated with senior author Triantafyllos Chavakis of Germany's Technical University Dresden and researchers from South Korea's University of Ulsan College of Medicine and other institutions. The work appears online in the journal Molecular Psychiatry.
In earlier studies, Hajishengallis, Chavakis and colleagues found that Del-1 acts as a gatekeeper that thwarts the movement and accumulation of immune cells like neutrophils, reducing inflammation. While neutrophils are needed to effectively respond to infection or injury, when too many of them accumulate in a tissue, the resulting inflammation can itself be damaging. Hajishengallis has found that gum tissue affected by periodontitis, a severe form of gum disease associated with inflammation and bone loss— had lower levels of Del-1 than healthy tissue.
While researching Del-1 in other tissues, such as gums and lungs, Hajishengallis and Chavakis found that Del-1 was also highly expressed in the brain. In addition, genome-wide screens indicate that the Del-1 gene may contribute to multiple sclerosis risk. For these reasons, the scientists hypothesized that Del-1 might prevent inflammation in the central nervous system just as it does in the gum tissue.
To test their theory, the researchers examined Del-1 expression in brain tissue from people who had died from MS. In MS patients with chronic active MS lesions, Del-1 was reduced compared to both healthy brain tissue and brain tissue from MS patients who were in remission at the time of their death. Similarly, Del-1 expression was reduced in the spinal cords of mice with the rodent equivalent of MS, experimental autoimmune encephalomyelitis (EAE).
Having confirmed this association between reduced Del-1 and MS and EAE, the scientists wanted to see if the reduction itself played a causal role in the disease.
Hajishengallis's and Chavakis's labs had previously utilized mice that lack Del-1 alone or Del-1 together with other molecules of the immune system. The researchers found that mutant mice lacking Del-1 had more severe attacks of the EAE than normal mice, with more damage to myelin, the fatty sheath that coats neurons and helps in the transmission of signals along the cell. Loss of this substance is the hallmark of MS and other neurodegenerative diseases.
Mice without Del-1 that had been induced to get EAE also had significantly higher numbers of inflammatory cells in their spinal cords at the disease's peak, a fact that further experiments revealed was due to increased levels of the signaling molecule IL-17.
Mice that were induced to get EAE that lacked both Del-1 and the receptor for IL-17 had a much milder form of the disease compared to mice that lacked only Del-1. These doubly depleted mice also had fewer neutrophils and inflammation in their spinal cords.
With a greater understanding of how Del-1 acts in EAE, the researchers were curious whether simply replacing Del-1 might act as a therapy for the disease. They waited until mice had had an EAE attack, akin to a flare-up of MS in human patients, and then administered Del-1. They were pleased to find that these mice did not experience further episodes of the disease.
"This treatment prevented further disease relapse," Chavakis said. "Thus, administration of soluble Del-1 may provide the platform for developing novel therapeutic approaches for neuroinflammatory and demyelinating diseases, especially multiple sclerosis."
The team is pursuing further work on Del-1 to see if they can identify a subunit of the protein that could have the same therapeutic effect.
"It's amazing that our work in periodontitis have found application in a central nervous system disease," Hajishengallis said. "This shows that periodontitis can be a paradigm for other medically important inflammatory diseases."
Source: Medical Xpress © Medical Xpress 2011-2014,Science X network (12/11/14)
Type 1 diabetes, ulcerative colitis, and multiple sclerosis are among the more well-known autoimmune diseases. But according to the AARDA, there are more than 150 rare autoimmune diseases, which affect around 50 million Americans. Even with this large number, scientists are still in the dark regarding interventions that can help cure these diseases. But this might change with the discovery of a molecule called NAD+ that has the potential to reverse autoimmunity.
What is autoimmunity?
When an intruding pathogen, such as a virus or bacterium, enters our bodies, our innate immune system gets activated, immediately sending out its soldiers (antibodies and immune cells) to identify and eliminate the pathogen, thus protecting us. But sometimes something goes wrong with this innate immunity and it starts regarding the body’s own tissues as foreign and repeatedly sends out soldier cells to attack them.
Autoimmune diseases can affect any part of the body, including the heart, brain, nerves, muscles, joints, lungs, kidneys, etc. There is still no established cause for autoimmunity, but genetic factors are considered to play a major role.
This new research conducted by Brigham and Women's Hospital (BWH) has identified NAD+ (Nicotinamide adenine dinucleotide), a naturally occurring molecule in living cells, plants, and food that has the potential to turn “destructive” cells that attack healthy tissues into “protective” cells. The molecule has also been found to reverse disease progression by restoring tissue damaged by the autoimmunity process.
"Our study is the first to show that NAD+ can tune the immune response and restore tissue integrity by activating stem cells," said Abdallah ElKhal, senior author, in a statement. "These findings are very novel and may serve for the development of novel therapeutics." The study is published online Oct. 7, in Nature Communications.
NAD+ plays an essential role in several metabolic processes. To test the action of NAD+ in pre-clinical trials, the scientists used experimental autoimmune encephalomyelitis, a pre-clinical model for human multiple sclerosis. They found that NAD+ could regulate the differentiation of immune cells called CD4+ T cells that have an established role in many aspects of autoimmune inflammation. Mice having NAD+ were administered with CD4+ T cells. They showed a significant delayed onset of disease, as well as a less severe form, therefore demonstrating the molecule's protective properties.
"This is a universal molecule that can potentially treat not only autoimmune diseases, but other acute or chronic conditions such as allergy, chronic obstructive pulmonary disease, sepsis, and immunodeficiency," said coauthor Stefan G. Tullius.
The scientists also successfully demonstrated the tissue-restoring capability of NAD+. This, they say, can benefit patients with advanced tissue damage caused by autoimmune diseases. The scientists are now exploring the other medical benefits of NAD+.
"Since this is a natural molecule found in all living cells, including our body, we hope that it will be well-tolerated by patients," said ElKhal. "Thus, we hope that its potential as a powerful therapeutic agent for the treatment of autoimmune diseases will facilitate its use in future clinical trials."
Source: Medical Daily © 2014 IBT Media Inc (08/10/14)
Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: Boosting autoimmunity to fight-off chronic neuroinflammation.
Schwartz M, Baruch K.
Immune cell infiltration to the brain's territory was considered for decades to reflect a pathological process in which immune cells attack the central nervous system (CNS); such a process is observed in the inflammatory autoimmune disease, multiple sclerosis (MS).
As neuroinflammatory processes within the CNS parenchyma are also common to other CNS pathologies, regardless of their etiology, including neurodegenerative disorders such as Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS), these pathologies have often been compared to MS, a disease that benefits from immunosuppressive therapy.
Yet, over the last decade, it became clear that autoimmunity has a bright side, and that it plays a pivotal role in CNS repair following damage. Specifically, autoimmune T cells were found to facilitate CNS healing processes, such as in the case of sterile mechanical injuries to the brain or the spinal cord, mental stress, or biochemical insults. Even more intriguingly, autoimmune T cells were found to be involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of life-long brain plasticity, including spatial learning and memory, and neurogenesis.
Importantly, autoimmune T cells are part of a cellular network which, to operate efficiently and safely, requires tight regulation by other immune cell populations, such as regulatory T cells, which are indispensable for maintenance of immunological self-tolerance and homeostasis.
Here, we suggest that dysregulation of the balance between peripheral immune suppression, on one hand, and protective autoimmunity, on the other, is an underlying mechanism in the emergence and progression of the neuroinflammatory response associated with chronic neurodegenerative diseases and brain aging.
Mitigating chronic neuroinflammation under these conditions necessitates activation, rather than suppression, of the peripheral immune response directed against self.
Accordingly, we propose that fighting off acute and chronic neurodegenerative conditions requires breaking peripheral immune tolerance to CNS self-antigens, in order to boost protective autoimmunity. Nevertheless, the optimal approach to fine tune such immune response must be individually explored for each condition.
Source: J Autoimmun. 2014 Sep 5. pii: S0896-8411(14)00127-9. doi: 10.1016/j.jaut.2014.08.002 © 2014 Elsevier Ltd & Pubmed PMID: 25199710 (11/09/14)
Breakthrough hope for MS treatment(03/09/14)
Scientists say they have discovered how to "switch off" autoimmune diseases such as multiple sclerosis.
Researchers at the University of Bristol, who describe the work as an "important breakthrough", say it could improve the lives of millions around the world.
In their research, published today in Nature Communications, the team reveal how to stop cells from attacking healthy body tissue.
The team discovered how cells convert from being aggressive to protecting against disease, rather than the body's immune system destroying its own tissue by mistake.
It is hoped the insight will lead to the widespread use of antigen-specific immunotherapy as treatment for many autoimmune disorders.
Conditions which could be affected by the research include multiple sclerosis (MS), type 1 diabetes, Graves' disease and systemic lupus erythematosus.
MS alone affects around 100,000 people in the UK and 2.5 million people worldwide.
Professor David Wraith, of the university's School of Cellular and Molecular Medicine, led the "exciting" research - which was funded by the Wellcome Trust.
"Insight into the molecular basis of antigen-specific immunotherapy opens up exciting new opportunities to enhance the selectivity of the approach while providing valuable markers with which to measure effective treatment," Professor Wraith said.
"These findings have important implications for the many patients suffering from autoimmune conditions that are currently difficult to treat."
In the study, scientists were able to selectively target the cells that cause autoimmune disease by dampening down their aggression against the body's own tissue, while converting them into cells capable of protecting against disease.
This type of conversion has previously been applied to allergies, in a treatment known as "allergic desensitisation", but its application to autoimmune disorders has only recently been appreciated.
The researchers have now revealed how the administration of fragments of the proteins that are normally the target for the attack leads to correction of the autoimmune response.
Their work also shows that effective treatment can be achieved by gradually increasing the dose of antigenic fragment injected.
In order to analyse how this type of immunotherapy works, the scientists looked inside the immune cells themselves to see which genes and proteins were turned off by the treatment.
They found changes in gene expression that help explain how effective treatment leads to conversion of aggressor into protector cells.
The outcome is to reinstate self-tolerance, where an individual's immune system ignores its own tissues while remaining fully armed to protect against infection.
Researchers say that by specifically targeting the cells at fault, the immunotherapeutic approach avoids the need for immune suppressive drugs.
These drugs are often associated with side effects such as infections, development of tumours and disruption of natural regulatory mechanisms.
The treatment approach is currently undergoing clinical development through biotechnology company Apitope, a spin-out from the University of Bristol.
"Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy" is published in Nature Communications today.
Source: The Courier.co.uk © 2014 DC Thomson & Co, Ltd. (03/09/14)
A type of immune cell widely believed to exacerbate chronic adult brain diseases, such as Alzheimer's disease and multiple sclerosis (MS), can actually protect the brain from traumatic brain injury (TBI) and may slow the progression of neurodegenerative diseases, according to Cleveland Clinic research published today in the online journal Nature Communications.
The research team, led by Bruce Trapp, PhD, Chair of the Department of Neurosciences at Cleveland Clinic's Lerner Research Institute, found that microglia can help synchronize brain firing, which protects the brain from TBI and may help alleviate chronic neurological diseases. They provided the most detailed study and visual evidence of the mechanisms involved in that protection.
"Our findings suggest the innate immune system helps protect the brain after injury or during chronic disease, and this role should be further studied," Dr. Trapp said. "We could potentially harness the protective role of microglia to improve prognosis for patients with TBI and delay the progression of Alzheimer's disease, MS, and stroke. The methods we developed will help us further understand mechanisms of neuroprotection."
Microglias are primary responders to the brain after injury or during illness. While researchers have long believed that activated microglia cause harmful inflammation that destroys healthy brain cells, some speculate a more protective role. Dr. Trapp's team used an advanced technique called 3D electron microscopy to visualize the activation of microglia and subsequent events in animal models.
They found that when chemically activated, microglia migrate to inhibitory synapses, connections between brain cells that slow the firing of impulses. They dislodge the synapse (called "synaptic stripping"), thereby increasing neuronal firing and leading to a cascade of events that enhance survival of brain cells.
Trapp is internationally known for his work on mechanisms of neurodegeneration and repair in multiple sclerosis. His past research has included investigation of the cause of neurological disability in MS patients, cellular mechanisms of brain repair in neurodegenerative diseases, and the molecular biology of myelination in the central and peripheral nervous systems.
Source: Medical Xpress © Medical Xpress 2011-2014 (22/07/14)