New indicator molecules visualise the activation of auto-aggressive T cells in the body as never before.
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to examine individual cells and their activity directly in the tissue. The development of new microscopes and fluorescent dyes in recent years has brought this scientific dream tantalisingly close. Scientists from the Max Planck Institute of Neurobiology in Martinsried have now presented not one, but two studies introducing new indicator molecules which can visualise the activation of T cells. Their findings provide new insight into the role of these cells in the autoimmune disease multiple sclerosis (MS). The new indicators are set to be an important tool in the study of other immune reactions as well.
Inflammation is the body’s defence response to a potentially harmful stimulus. The purpose of an inflammation is to fight and remove the stimulus – whether it be disease-causing pathogens or tissue. As an inflammation progresses, significant steps that occur thus include the recruitment of immune cells, the interactions of these cells in the affected tissue and the resulting activation pattern of the immune cells. The more scientists understand about these steps, the better they can develop more effective drugs and treatments to support them. This is particularly true for diseases like multiple sclerosis. In this autoimmune disorder cells from the body’s immune system penetrate into the central nervous system where they cause massive damage in the course of an inflammation.
In order to truly understand the cellular processes involved in MS, scientists ideally need to study them in real time at the exact location where they take place – directly in the affected tissue. In recent years, new microscopic techniques and fluorescent dyes have been developed to make this possible for the first time. These coloured indicators make individual cells, their components or certain cell processes visible under the microscope. For example, scientists from the Max Planck Institute of Neurobiology have developed a genetic calcium indicator, TN-XXL, which the cells themselves form, and which highlights the activity of individual nerve cells reliably and for an unlimited time. However, the gene for the indicator was not expressed by immune cells. That is why it was previously impossible to track where in the body and when a contact between immune cells and other cells led to the immune cell’s activation.
Now the Martinsried-based neuroimmunologists report two major advances in this field simultaneously. One is their development of a new indicator which visualises the activation of T cells. These cells, which are important components of the immune system, detect and fight pathogens or substances classified as foreign (antigens). Multiple sclerosis, for example, is one of the diseases in which T cells play an important role: here, however, they detect and attack the body’s brain tissue. If a T cell detects "its own" antigen, the NFAT signal protein migrates from the cell plasma to the nucleus of the T cell. "This movement of the NFAT shows us that the cell has been activated, in other words it has been ‘armed’," explains Marija Pesic, lead author of the study published in the Journal of Clinical Investigation. "We took advantage of this to bind the fluorescent dye called GFP to the NFAT, thereby visualising the activation of these cells." The scientists are thus now able to conclusively show in the organism whether an antigen leads to the activation of a T cell. The new indicator is an important new tool for researching autoimmune diseases and also for studying immune cells during their development, during infections or in the course of tumour reactions.
In parallel to these studies, the neuroimmunologists in Martinsried developed a slightly different, complementary method. They modified the calcium indicator TN-XXL to enable, for the first time, T cell activation patterns to be observed live under the microscope, even while the cells are wandering about the body. When a T cell detects an antigen, a rapid rise in the calcium concentration within the cell ensues. The TN-XXL makes this alteration in the calcium level apparent by changing colour, giving the scientists a direct view of when and where the T cells are being activated.
"This method has enabled us to demonstrate that these cells really can be activated in the brain," says a pleased Marsilius Mues, lead author of the study which has just been published in Nature Medicine. Until now, scientists had only suspected this to be the case. In the animal model of multiple sclerosis, scientists are now able to track not only the migration of the T cells, but also their activation pattern in the course of the disease. Initial investigations have already shown, besides the expected activation by antigen detection, that numerous fluctuations in calcium levels also take place which bear no relation to an antigen. "These fluctuations can tell us something about how potent the T cell is, how strong the antigen is, or it may have something to do with the environment," speculates Marsilius Mues. These observations could indicate new research approaches for drugs – or they could even show whether a drug actually has an effect on T cell activation.
Source: Health Canal (23/05/13)
Scientists have identified an influential link in a chain of events that leads to autoimmune inflammation of the central nervous system in a mouse model of multiple sclerosis (MS).
An international team of researchers led by scientists in The University of Texas MD Anderson Cancer Center Department of Immunology reported their results in an advance online publication in Nature Medicine.
The researchers spell out the pivotal role of Peli1 in the activation of immune cells called microglia that promote inflammation in the central nervous system in response to tissue damage or invasion by microbes.
"The major implication of discovering a signaling role for Peli1 in this animal model is that it might also be significant in the pathogenesis of MS," said senior author Shao-Cong Sun, Ph.D., professor in MD Anderson's Department of Immunology.
Microglia cells involved in multiple sclerosis
Sun and colleagues found that Peli1 is heavily expressed in microglial cells and promotes their activation and subsequent damaging immune response. Peli1 also protects that autoimmune reaction by initiating the destruction of a protein that otherwise would inhibit inflammation.
Microglia are known to be crucial to the initiation of MS, an immune system assault on nerve fibers called axons and on myelin, the protective sheath around the axons. They also were previously known to play a similar role in experimental autoimmune encephalomyelitis (EAE), an animal model of MS.
The precise mechanism of this autoimmune-stimulating effect has been unknown. Sun and colleagues fill an important gap with their Peli1 discovery.
Microglia sense tissue damage. They secrete chemokines and inflammatory cytokines in response, drawing infection-fighting T cells into the central nervous system, leading to inflammation.
Infections genetic overreaction that inflames
The authors note that microbial infections are a known environmental trigger for the onset and maintenance of multiple sclerosis and the induction of EAE in mice. Toll-like receptors that detect pathogens play a roll in MS and EAE. They were suspected of involvement in microglial activation and inflammation.
Upon sensing microbes or cell damage, toll-like receptors launch a signaling cascade that activates a variety of genes involved in inflammation and white blood cell homing to the microbes or injury site.
Peli1 is known as a targeting agent, marking proteins with molecules called ubiquitins, ensuring they are functionally modified or found by cellular protein-destruction machinery. In this case, Sun and colleagues found that Peli1 ubiquitinates another targeting agent as a signal, which in turn marks a crucial anti-inflammatory protein for destruction.
The team found:
Mice with Peli1 knocked out were resistant to EAE. Those with Peli1 developed severe symptoms including a gradual increase in paralysis.
Mice with intact Peli1 had high levels of microglial activation after EAE began and low levels of resting microglia. Mice with Peli1 knocked out had high levels of resting microglia.
Expression of proinflammatory chemokines and cytokines was impaired in microglia taken from Peli1 knockout mice. Peli1 sends signal to destroy Traf3
Sun and colleagues then tracked down the role Peli1 plays in protecting one of the molecular networks that is set off when toll-like receptors detect microbes or injury. The MAPK pathway activates a variety of genes involved in inflammation and T cell response.
MAPK is kept in check by a protein called Traf3. The team found that Peli1 signals another ubiquitin ligase that in turn marks Traf3 for destruction, liberating the MAPK network.
After EAE is induced, mice with intact Peli1 have a gradual depletion of Traf3 in their microglia. Traf3 accumulated in the microglia of Peli1 knockout mice. EAE was restored in Peli1 knockout mice when Traf3 was inhibited.
Sun said the team is studying the pathway in human multiple sclerosis to replicate their findings and explore the possibilities for potentially treating MS.
Source: Medical News Today © MediLexicon International Ltd 2004-2013 (07/05/13)
A team of basic and clinical scientists led by the University of Montreal Hospital* Research Centre’s (CRCHUM) Dr. Nathalie Arbour has opened the door to significantly improved treatments for the symptoms of Multiple Sclerosis (MS). In a study selected as among the top 10% most interesting articles published in the Journal of Immunology, the team identifies the elevated presence in MS patients of a type of white blood cell (CD4 T cell) that expresses NKG2C, a highly-toxic molecule harmful to brain tissues.
In close collaboration with clinicians at the University of Montreal Hospital and the Montreal Neurological Institute, McGill University, Dr. Arbour’s team studied tissues from healthy subjects and MS patients. This approach enabled the team to uncover a novel mechanism by which CD4 T cells expressing NKG2C can directly target brain cells having a specific corresponding ligand found only in MS patients. “These results are very encouraging,” says Arbour, “since they provide us with a much more refined picture of how the brain cells of MS patients are targeted by the immune system and provide us with a clearer understanding of how to go about blocking their action.”
There is no known cure for this auto-immune disease of the central nervous system. While there are a number of approved MS therapies targeting molecules expressed by immune cells, they are sometimes too broad in their application. They can suppress the efficiency of the immune system but also open the way for serious infections in some MS patients such as progressive multifocal leukoencephalopathy, a serious viral disease that can cause death in people with severe immune deficiency, such as MS patients on immunosuppressive medication.
“Our research has made an important step in getting around this problem. Because NKG2C is specifically expressed by a subset of CD4 T cells only found in MS patients, targeting this receptor would not affect large populations of immune cells, but only those which produce the symptoms characteristic of this debilitating disease,” explains Arbour. For patients this discovery could translate into improved treatments aimed at decreasing the progression of the disease and its symptoms, without the risk of potentially lethal infections and therefore improving their quality of life.
About The Study
“Cytotoxic NKG2C+ CD4 T Cells Target Oligodendrocytes in Multiple Sclerosis” was featured in the March 15 issue of the Journal of Immunology, where it was selected as being among the top 10% most interesting articles published in the journal. The research team included basic and clinical scientists from the University of Montreal Hospital and the Montreal Neurological Institute, McGill University.
Source: Science Blog © 2013 ScienceBlog.com (20/03/13)
Increased dietary salt intake can induce a group of aggressive immune cells that are involved in triggering and sustaining autoimmune diseases. This is the result of a study conducted by Dr. Markus Kleinewietfeld, Prof. David Hafler (both Yale University, New Haven and the Broad Institute of the Massachusetts Institute of Technology, MIT, and Harvard University, USA), PD Dr. Ralf Linker (Dept. of Neurology, University Hospital Erlangen), Professor Jens Titze (Vanderbilt University and Friedrich-Alexander-Universitat Erlangen-Nurnberg, FAU, University of Erlangen-Nuremberg) and Professor Dominik N. Muller (Experimental and Clinical Research Center, ECRC, a joint cooperation between the Max-Delbruck Center for Molecular Medicine, MDC, Berlin, and the Charité - Universitatsmedizin Berlin and FAU) (Nature, doi: http://dx.doi.org/10.1038/nature11868)*. In autoimmune diseases, the immune system attacks healthy tissue instead of fighting pathogens.
In recent decades scientists have observed a steady rise in the incidence of autoimmune diseases in the Western world. Since this increase cannot be explained solely by genetic factors, researchers hypothesize that the sharp increase in these diseases is linked to environmental factors. Among the suspected culprits are changes in lifestyle and dietary habits in developed countries, where highly processed food and fast food are often on the daily menu. These foods tend to have substantially higher salt content than home-cooked meals. This study is the first to indicate that excess salt intake may be one of the environmental factors driving the increased incidence of autoimmune diseases.
A few years ago Jens Titze showed that excess dietary salt (sodium chloride) accumulates in tissue and can affect macrophages (a type of scavenger cells) of the immune system. Independent of this study, Markus Kleinewietfeld and David Hafler observed changes in CD4 positive T helper cells (Th) in humans, which were associated with specific dietary habits. The question arose whether salt might drive these changes and thus can also have an impact on other immune cells. Helper T cells are alerted of imminent danger by the cytokines of other cells of the immune system. They activate and "help" other effector cells to fight dangerous pathogens and to clear infections. A specific subset of T helper cells produces the cytokine interleukin 17 and is therefore called Th17 for short. Evidence is mounting that Th17 cells, apart from fighting infections, play a pivotal role in the pathogenesis of autoimmune diseases.
Salt dramatically boosts the induction of aggressive Th17 immune cells
In cell culture experiments the researchers showed that increased sodium chloride can lead to a dramatic induction of Th17 cells in a specific cytokine milieu. "In the presence of elevated salt concentrations this increase can be ten times higher than under usual conditions," Markus Kleinewietfeld and Dominik Müller explained. Under the new high salt conditions, the cells undergo further changes in their cytokine profile, resulting in particularly aggressive Th17 cells.
In mice, increased dietary salt intake resulted in a more severe form of experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Multiple sclerosis is an autoimmune disease of the central nervous system in which the body's own immune system destroys the insulating myelin sheath around the axons of neurons and thus prevents the transduction of signals, which can lead to a variety of neurological deficits and permanent disability. Recently, researchers postulated that autoreactive Th17 cells play a pivotal role in the pathogenesis of multiple sclerosis.
Interestingly, according to the researchers, the number of pro-inflammatory Th17 cells in the nervous system of the mice increased dramatically under a high salt diet. The researchers showed that the high salt diet accelerated the development of helper T cells into pathogenic Th17 cells. The researchers also conducted a closer examination of these effects in cell culture experiments and showed that the increased induction of aggressive Th17 cells is regulated by salt on the molecular level. "These findings are an important contribution to the understanding of multiple sclerosis and may offer new targets for a better treatment of the disease, for which at present there is no known cure," said Ralf Linker, who as head of the Neuroimmunology Section and Attending Physician at the Department of Neurology, University Hospital Erlangen, seeks to utilize new laboratory findings for the benefit of patients.
Besides multiple sclerosis, Dominik Müller and his colleagues want to study psoriasis, another autoimmune disease with strong Th17 components. The skin, as Jens Titze recently discovered, also plays a key role in salt storage and affects the immune system. "It would be interesting to find out if patients with psoriasis can alleviate their symptoms by reducing their salt intake," the researchers said. "However, the development of autoimmune diseases is a very complex process which depends on many genetic and environmental factors," the immunologist Markus Kleinewietfeld said. "Therefore, only further studies under less extreme conditions can show the extent to which increased salt intake actually contributes to the development of autoimmune diseases."
*Sodium Chloride Drives Autoimmune Disease by the Induction of Pathogenic Th17 Cells
Source: Medical News Today © MediLexicon International Ltd 2004-2013 (07/03/13)
Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status(04/03/13)
Macrophages play a dual role in multiple sclerosis (MS) pathology. They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators.
The effector function of macrophages is determined by the way they are activated. Stimulation of monocyte-derived macrophages in vitro with interferon-gamma and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages.
Methods: For this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry.
This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively. Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples.
Results: Our data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions.
M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages. Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status.
Conclusions: Our findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status.
Author: Daphne YS Vogel Elly JF Vereyken Judith E Glim Priscilla DAM Heijnen Martina Moeton Paul van der Valk Sandra Amor Charlotte E Teunissen Jack van Horssen Christine D Dijkstra
Credits/Source: Journal of Neuroinflammation 2013, 10:35
Source: 7th Space Interactive© 2013 7thSpace Interactive (02/03/13)
Findings offer a better understanding of the development and progression of multiple sclerosis and potential future therapeutic target
Researchers from Benaroya Research Institute at Virginia Mason (BRI) have found that proteins in the IL-6 signaling pathway may be leveraged as novel biomarkers of multiple sclerosis (MS) to gauge disease activity and as a target for new therapies. The research, which investigated how several components involved in immune response differ between MS patient and control samples, was conducted by a team of researchers at BRI led by Dr. Jane Buckner in collaboration with Dr. Mariko Kita at Virginia Mason Medical Center and was published today in Science Translational Medicine.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system affecting an estimated 400,000 people in the United States. MS is more prevalent in the Northwest region of the U.S. than almost anywhere else in the world. In the Northwest, the likelihood of being diagnosed with MS (2 in 1,000) is double that across the U.S. (1 in 1,000).
Under normal circumstances, effector T cells protect us from infection and cancer and it is the job of regulatory T cells to keep the effector T cells from attacking healthy tissue, thereby preventing autoimmune diseases such as MS. MS occurs when the immune system's effector T cells mistakenly attack myelin, which surrounds and protects the central nervous system. When the myelin is damaged, nerve impulses are not transmitted quickly or efficiently, resulting in symptoms such as numbness, weakness, vision problems, cognitive impairment or fatigue, among others. In Relapsing Remitting MS (RRMS), individuals experience episodes of active disease, which include attacks of neurologic dysfunction, followed by periods of improvement.
Buckner's group found that the T cells of RRMS patients with active disease were able to avoid suppression by regulatory T cells, while those from patients with mild or well controlled MS did not exhibit this resistance to suppression. These results suggest that the presence or absence of T cell resistance to regulatory T cells could provide patients and physicians with valuable information about an individual's disease activity level and the potential for disease progression. The researchers also discovered that resistance to T cell suppression in RRMS patients was correlated with increased sensitivity to IL-6, a protein that is produced by the immune system that has been shown to contribute to the resistance of effector T cells to suppression. Buckner's group demonstrated that the patient samples that exhibited T cell resistance to suppression also were more sensitive to IL-6. Furthermore, when the signals generated by IL-6 were blocked in these T cells, the resistance to suppression was reversed, suggesting that therapies targeting the IL-6 pathway could potentially be used to modulate T cell resistance to suppression.
"These findings are an exciting step toward better understanding why MS occurs. They will help us to better assess the degree of disease activity in MS patients and lead us to consider new therapeutic approaches for MS" noted Dr. Buckner. "Therapies that target the IL-6 pathway are already available for treatment of other autoimmune diseases and should now be tested in MS."
Future research directions will include investigation of the role of T cell resistance to suppression and IL-6 signaling in MS onset and whether the IL-6 signaling components can be used as biomarkers to predict the severity of disease at the time of diagnosis or anticipate flares and disease progression. The samples used in this study were obtained through the BRI's Translational Research Program's Biorepository. Research funding was provided by Life Sciences Discovery Fund and JDRF.
Source: Eureka Alert! ©2013 by AAAS (31/01/13)
Misguided killer T cells may be the missing link in sustained tissue damage in the brains and spines of people with multiple sclerosis, findings from the University of Washington reveal. Cytoxic T cells, also known as CD8+ T cells, are white blood cells that normally are in the body’s arsenal to fight disease.
Multiple sclerosis is characterized by inflamed lesions that damage the insulation surrounding nerve fibers and destroy the axons, electrical impulse conductors that look like long, branching projections. Affected nerves fail to transmit signals effectively.
Intriguingly, the UW study, published this week in Nature Immunology, also raises the possibility that misdirected killer T cells might at other times act protectively and not add to lesion formation. Instead they might retaliate against the cells that tried to make them mistake the wrappings around nerve endings as dangerous.
Scientists Qingyong Ji and Luca Castelli performed the research with Joan Goverman, UW professor and chair of immunology. Goverman is noted for her work on the cells involved in autoimmune disorders of the central nervous system and on laboratory models of multiple sclerosis.
Multiple sclerosis generally first appears between ages 20 to 40. It is believed to stem from corruption of the body’s normal defense against pathogens, so that it now attacks itself. For reasons not yet known, the immune system, which wards off cancer and infection, is provoked to vandalize the myelin sheath around nerve cells. The myelin sheath resembles the coating on an electrical wire. When it frays, nerve impulses are impaired.
Depending on which nerves are harmed, vision problems, an inability to walk, or other debilitating symptoms may arise. Sometimes the lesions heal partially or temporarily, leading to a see-saw of remissions and flare ups. In other cases, nerve damage is unrelenting.
The myelin sheaths on nerve cell projections are fashioned by support cells called oligodendrocytes. Newborn’s brains contain just a few sections with myelinated nerve cells. An adult’s brains cells are not fully myelinated until age 25 to 30.
For T cells to recognize proteins from a pathogen, a myelin sheath or any source, other cells must break the desired proteins into small pieces, called peptides, and then present the peptides in a specific molecular package to the T cells. Scientists had previously determined which cells present pieces of a myelin protein to a type of T cell involved in the pathology of multiple sclerosis called a CD4+ T cell. Before the current study, no cells had yet been found that present myelin protein to CD8+ T cells.
Scientists strongly suspect that CD8+ T cells, whose job is to kill other cells, play an important role in the myelin-damage of multiple sclerosis. In experimental autoimmune encephalitis, which is an animal model of multiple sclerosis in humans, CD4+T cells have a significant part in the inflammatory response. However, scientists observed that, in acute and chronic multiple sclerosis lesions, CD8+T cells actually outnumber CD4+ T cells and their numbers correlate with the extent of damage to nerve cell projections. Other studies suggest the opposite: that CD8+T cells may tone down the myelin attack.
The differing observations pointed to a conflicting role for CD8 + T cells in exacerbating or ameliorating episodes of multiple sclerosis. Still, how CD8+T cells actually contributed to regulating the autoimmune response in the central nervous system, for better or worse, was poorly understood.
Goverman and her team showed for the first time that naive CD8+ T cells were activated and turned into myelin-recognizing cells by special cells called Tip-dendritic cells. These cells are derived from a type of inflammatory white blood cell that accumulates in the brain and the spinal cord during experimental autoimmune encephalitis originally mediated by CD4+ T cells. The membrane folds and protrusions of mature dendritic cells often look like branched tentacles or cupped petals well-suited to probing the surroundings.
The researchers proposed that the Tip dendritic cells can not only engulf myelin debris or dead oligodendrocytes and then present myelin peptides to CD4 + T cells, they also have the unusual ability to load a myelin peptide onto a specific type of molecule that also presents it to CD8+ T cells. In this way, the Tip dendritic cells can spread the immune response from CD4+ T cells to CD8+ T cells. This presentation enables CD8+ T cells to recognize myelin protein segments from oligodendrocytes, the cells that form the myelin sheath. The phenomenon establishes a second-wave of autoimmune reactivity in which the CD8+ T cells respond to the presence of oligodendrocytes by splitting them open and spilling their contents.
“Our findings are consistent,” the researchers said, “with the critical role of dendritic cells in promoting inflammation in autoimmune diseases of the central nervous system.” They mentioned that mature dendritic cells might possibly wait in the blood vessels of normal brain tissue to activate T-cells that have infiltrated the blood/brain barrier.
The oligodendrocytes, under the inflammatory situation of experimental autoimmune encephalitis, also present peptides that elicit an immune response from CD8+T cells. Under healthy conditions, oligodendrocytes wouldn’t do this.
The researchers proposed that myelin-specific CD8+T cells might play a role in the ongoing destruction of nerve-cell endings in “slow burning” multiple sclerosis lesions. A drop in inflammation accompanied by an increased degeneration of axons (electrical impulse-conducting structures) coincides with multiple sclerosis leaving the relapsing-remitting stage of disease and entering a more progressive state.
Medical scientists are studying the roles of a variety of immune cells in multiple sclerosis in the hopes of discovering pathways that could be therapeutic targets to prevent or control the disease, or to find ways to harness the body’s own protective mechanisms. This could lead to highly specific treatments that might avoid the unpleasant or dangerous side effects of generalized immunosuppressants like corticosteroids or methotrexate.
The study was funding by grants AI072737 and AI073748 from the National Institutes of Health. The authors declared no competing financial interests.
Source: University of Washington © 2013 UNIVERSITY OF WASHINGTON (11/01/13)
Multiple sclerosis (MS) is characterised by the infiltration of the central nervous system (CNS) by immune cells.
A particular type of immune cell, Tc17, has been found in MS lesions in humans, but it is unclear what role these cells play in disease pathogenesis. In the Journal of Clinical Investigation, researchers led by Magdalena Huber at the University of Marburg in Germany used a mouse model of MS to determine the role of Tc17 cells.
They found that Tc17 cells help Th17 immune cells to invade the CNS by secreting the protein IL-17. Without Tc17 cells, the Th17 cells did not accumulate in the CNS, preventing the development of MS.
This study demonstrates that Tc17 cells help initiate MS by allowing immune cells to reach the CNS and suggests that therapies targeting Tc17 cells might be helpful in treating early MS.
Article: IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis
Source: Science Codex (02/01/13)
About 2.5 Million people worldwide have multiple sclerosis, a chronic central nervous system disease that can cause blurred vision, poor coordination, slurred speech, numbness and paralysis, among other things.
Despite the serious symptoms, diagnosis is often tricky because symptoms vary and can be hard for physicians to interpret. Gaithersburg, Maryland company DioGenix Inc. started up in 2008 to commercialize work on a lab test that could improve the diagnostic process.
A 150-patient clinical trial has just begun enrolling, the trial will validate its test, MS Precise, for early identification and diagnosis of multiple sclerosis.
Multiple sclerosis is characterised by scarring of the myelin sheath in nerve cells that disrupts the transmission of messages from the brain and causes inflammation. Because MS signs and symptoms are also characteristic of other nervous system disorders, the disease is typically diagnosed through a deductive process that includes medical history,
physical exams, an MRI and analysis of spinal fluid. The analysis of spinal fluid typically looks for evidence of general inflammation that’s not seen in the blood, DioGenix CEO Larry Tiffany said. But even that can’t give a definitive diagnosis and produces false positives. According to the Multiple Sclerosis Foundation, diagnosis is correct 90-95 percent of the time.
DioGenix’s lab test takes the cerebral spinal fluid test a step further, looking for gene mutations in certain spots within the B-cell genome that research has suggested are driven specifically by MS. Tiffany said the team thinks the specificity of the test could help clinicians distinguish MS from other immune-mediated neurological diseases that share similar biological features. It may also someday be able to help physicians identify more aggressive cases of MS.
In a recent study, the test outperformed the current method of analysis in patients suspected of having MS, according to the company. A more confident diagnosis would hopefully lead to better use of prescription of MS drugs, which suppress or alter the immune system and shouldn’t be used by people without the condition.
DioGenix’s test is an extension of the work of Dr. Nancy Monson’s team at the University of Texas Southwestern Medical Center. A blood test based on the same technology is also in development.
Source: MedCity News Copyright 2012 MedCity News. (19/12/12)
Researchers from Queen Mary, University of London have discovered that two proteins which are believed to play a key role in controlling the body's immune response are found in lower levels in T lymphocytes from patients with multiple sclerosis (MS).
The study found that MS patients' T lymphocytes - types of white blood cells which play an important role in the immune system - were defective at producing the proteins and that this was associated with increased levels of molecules which promote inflammation. The findings are reported in the Journal of Immunology-. The work follows on from a recent study published in the journal Immunity- in which the lead scientists first identified the two proteins - known as Egr2 and Egr3 - as being important in both protecting against the development of inflammatory autoimmune diseases, like MS and arthritis, and also in preventing chronic virus infections such as HIV and hepatitis.
B and T lymphocytes are essential for defending the body from viruses and eradicating cancer cells. However, their function is regulated to prevent uncontrolled reaction against the body's own tissues, which can lead to the development of inflammatory autoimmune diseases. In contrast, chronic viral infections are associated with reduced function of these cells.
Dr Ping Wang, from the Blizard Institute at Queen Mary, University of London, who supervised the research, said: "Using mice models we initially showed how Egr2 and Egr3 molecules play a role in both promoting the immune response to pathogens and also suppressing the inflammatory response to prevent an overreaction. This was interesting as previously most people had assumed different molecules would be involved in the ramping up and the dampening down of the immune response, not the same ones.
"In this study we have presented evidence that T lymphocytes from MS patients show defective production of these proteins which increases the hope that further understanding what they are doing will lead to new treatment options."
The researchers looked at certain types of T lymphocytes from blood samples from patients with MS and compared them to healthy individuals. They found that the expression of Egr2 was reduced in T lymphocytes from MS patients and that this was associated with increased levels of IL-17, a molecule which promotes inflammation. The researchers are now working on disease models and further patient samples to understand more about how Egr2 and Egr3 help to control autoimmune diseases and immune defence against virus infection. It is hoped the findings will lead to the development of new therapeutic strategies for the treatment of autoimmune diseases and also the development of vaccines for chronic virus infections such as HIV and hepatitis.
Source: News-Medical.Net (13/12/12)
DNA sequences obtained from a handful of patients with multiple sclerosis at the University of California, San Francisco (UCSF) Medical Center have revealed the existence of an "immune exchange" that allows the disease-causing cells to move in and out of the brain.
The cells in question, obtained from spinal fluid and blood samples, are called B cells, which normally help to clear foreign infections from the body but sometimes react strongly with the body itself. One of the current theories of multiple sclerosis, which strikes hundreds of thousands of Americans and millions more worldwide, holds that the disease manifests when self-reactive B cells in the brain become activated and cause inflammation there.
The apparent exchange of the cells between the brain and the blood may be a key to unlocking better treatments and diagnostics, because the activated B cells causing problems in the brain may be accessible when they move from the brain to the periphery.
"The hope is that if we can identify culprit B cells, using precise tools, we will be able to better diagnose multiple sclerosis and monitor disease activity. In addition, in ways that may have to be tailored for each patient, this may also allow us to develop therapies that directly target disease-causing B cells," said UCSF neurologist Hans Christian von Büdingen, MD, who led the research.
Described this week in the Journal of Clinical Investigation, the work is the latest from the UCSF Multiple Sclerosis Center, part of the UCSF Department of Neurology and one of the leading programs in multiple sclerosis research and patient care worldwide. Since 2008, a UCSF team led by the chair of the Department of Neurology, Stephen Hauser, MD, has completed two clinical trials that showed, in essence, that blocking B cells may stop the attacks, or flare-ups, that occur in people with multiple sclerosis.
These trials used Rituximab and Ocrelizumab, both of which target a molecule called CD20 found on the surface of B cells. The new work suggests that targeting B cells could be extended into a precision strategy that would specifically tailor treatments to the exact identity of the B cells at work in any one patient.
Background on B cells and Multiple Sclerosis
Multiple sclerosis is a common, chronic disease affecting some 400,000 Americans whose immune systems periodically attack the myelin sheaths that insulates nerve fibers in the brains and spinal cord. Damage to the sheaths can short-circuit signals traveling along the nerve fibers, disrupting the normal flow of communication from the brain and causing a range of symptoms.
The disease is about three times more prevalent among women than men, and for reasons scientists do not understand, the number of women who have the disease has been increasing in proportion to men. Decades ago, there were about as many men as women with multiple sclerosis.
That disparity is not the only mystery surrounding multiple sclerosis. The severity of the disease can vary wildly, from people who have mild disease, rarely having symptoms, to people who suffer significant deficits for long periods of time, sometimes progressively, with weakness, sensory disturbance, fatigue, visual impairments and loss of coordination.
In addition, scientists do not understand what triggers MS attacks, though researchers at UCSF and elsewhere are actively investigating a number of possible genetic and environmental triggers, including low vitamin D levels. There also is a need to find better ways to diagnose, monitor and track the disease – a need that may be helped by the new discovery. "We don't have any specific diagnostic tool at this point – no biomarker that we can look for to say, 'this is multiple sclerosis'," von Büdingen said.
More information: "B cell exchange across the blood-brain barrier in multiple sclerosis" by H.-Christian von Büdingen et al., Journal of Clinical Investigation on Nov.19, 2012. dx.doi.org/10.1172/JCI63842
Source: Medical Xpress © Medical Xpress 2011-2012 (21/11/12)
Reproducing a rare type of B cell in the laboratory and infusing it back into the body may provide an effective treatment for severe autoimmune diseases such as multiple sclerosis or rheumatoid arthritis, according to researchers at Duke University Medical Center.
The findings, which were demonstrated in mice, highlight the unique properties of a subset of B cells that normally controls immune responses and limits autoimmunity, in which an organism mistakenly attacks its own healthy tissue. The work appears Oct. 14, 2012, in the journal Nature.
B cells are the component of the immune system that creates antibodies, which fight pathogens like bacteria and viruses. However, a small subset of B cells, called regulatory B cells, works to suppress immune responses. These B cells are characterised by a cell-signaling protein called interleukin-10 (IL-10), giving these regulatory B cells the name B10 cells.
While B10 cells are small in number, they are important for controlling inflammation and autoimmunity. B10 cells can also limit normal immune responses during infections, reducing inadvertent damage to healthy body tissue.
"Regulatory B cells are a fairly new finding that we're just beginning to understand," said Thomas F. Tedder, PhD, professor of immunology at Duke and study author. "B10 cells are important because they make sure an immune response doesn't get carried away, resulting in autoimmunity or pathology. This study shows for the first time that there is a highly controlled process that determines when and where these cells produce IL-10."
Tedder and his colleagues studied the process of IL-10 production in the B10 cells of mice. Creating IL-10 requires physical interactions between B10 cells and T cells, which play a role in turning on the immune system.
The researchers found that B10 cells only respond to very specific antigens. Recognising these antigens drives the function of B10 cells, causing them to turn off certain T cells when they bind the same antigen to prevent them from harming healthy tissue.
With this understanding of B10 cells, researchers set out to learn whether B10 cells could be harnessed as a cellular therapy, given their ability to regulate immune responses and autoimmunity.
"Since B10 cells are extremely rare, it was important that we find a feasible solution to reproduce these cells outside the body to make them available," Tedder said. The researchers learned that the B10 cells could be isolated from the body and would maintain their ability to regulate immune responses. Moreover, they could be reproduced in large numbers.
"Normal B cells usually die quickly when cultured, but we have learned how to expand their numbers by about 25,000-fold. However, the rare B10 cells in the cultures expand their numbers by four-million-fold, which is remarkable. Now, we can take the B10 cells from one mouse and increase them in culture over nine days to where we can effectively treat 8,000 mice with autoimmune disease," said Tedder.
When a small amount of B10 cells were introduced into mice with multiple sclerosis-like autoimmune disease, their symptoms were significantly reduced, essentially turning off the disease.
"B10 cells will only shut off what they are programmed to shut off. If you have rheumatoid arthritis, you would want cells that would only go after your rheumatoid arthritis," continued Tedder. "This research shows that we may have the potential to unharness regulatory cells, make millions of copies, and introduce them back into someone with autoimmune disease to shut down the disease. This may also treat transplanted organ rejection."
Additional research is needed to learn how to expand human B10 cells and determine how B10 cells behave in humans, building on the study's insights into the mechanisms behind their function and autoimmunity.
"Autoimmune diseases are very complicated, so creating a single therapy that allows us to go after multiple disease targets without causing immunosuppression has proven to be difficult." Tedder said. "Here, we're hoping to take what Mother Nature has already created, improve on it by expanding the cells outside of the body, and then put them back in to let Mother Nature go back to work."
Source: Medical News Today © MediLexicon International Ltd 2004-2012 (17/10/12)
Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, has achieved a positive Proof of Concept for its lead metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator (PAM) compound series in a validated rodent model for multiple sclerosis (MS).
MS is a chronic inflammatory demyelinating auto-immune disease that affects the central nervous system (CNS), leading to serious disability.
"We are very excited that this promising Addex mGluR4 PAM series may offer a differentiated approach to treating MS," said Professor Ursula Grohmann, of University of Perugia, Italy, in whose laboratories one of these studies was performed. "These data confirm our previous observations, using an mGluR4 PAM tool compound called PHCCC, which demonstrated efficacy in the industry standard neuroinflammation model of MS, the Relapsing-Remitting Experimental Allergic Encephalomyelitis (RR-EAE) model. In this study, the mGluR4 PAM worked by promoting regulatory T-cell (Treg) formation and reversing pro-inflammatory T-cell release. Therefore, we believe that positive modulation of mGluR4 could potentially stop the destruction of myelin in MS in a robust and durable manner."
Addex lead chemical series is a highly selective orally available mGluR4 PAM and shows good pharmacokinetic properties for potential once-daily dosing. When administered once a day for 3 weeks at 10, 30 and 60 mg/kg sc, Addex mGluR4 PAM demonstrated a dose-dependent, statistically significant reduction in paralysis (clinical score) and the relapse rate in the RR-EAE model of MS in mice. The presentation of these data is being planned for a major international conference.
"Current MS therapies are primarily focused on reinstating motor function after an inflammatory attack, preventing new attacks, and preventing or treating disability and symptoms, such as spasticity. In addition, most of these therapies are primarily based on immunomodulatory strategies, and have serious compliance-limiting side effects", noted Graham Dixon, CSO of Addex Therapeutics. "We believe a well-tolerated, oral mGluR4 PAM would represent a major advance in the treatment of MS because of the novel and potentially broader mechanism; having the potential to not only treat symptoms, but slow disease progression and offer neuroprotection. We are now rapidly advancing this lead series towards a clinical candidate and conducting experiments to further elucidate the biological role of mGluR4 PAM in MS."
"Moving the lead compound from this series into full development in 2012 clearly illustrates our strategy of advancing innovative novel selective oral small molecule drug candidates against previously "undruggable" targets" said Bharatt Chowrira, CEO of Addex Therapeutics. "These data along with the recently announced data on the role of the mGluR4 PAMs in Parkinson's disease, the positive Phase 2 data for dipraglurant in Parkinson's disease levodopa-induced dyskinesia, the two Phase 2 clinical trials being conducted by our partner Janssen, and our GABABR PAM program advancing towards an IND filing later this year, demonstrate the power of Addex platform that continues to generate multiple, novel high value product opportunities."
High levels of glutamate are detected in patients with relapsing remitting multiple sclerosis. It has been suggested that glutamate may affect neuroinflammation via modulation of immune cells and/or neuroprotection through mGluR4 signaling. Therefore, pharmacological activation of mGluR4 may represent a novel therapeutic avenue addressing multiple aspects of MS pathology.
The mGluR4 belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gαi/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in neurotransmitter release from presynaptic terminals.
The mGluR4 have unique distribution in key brain regions involved in multiple CNS disorders. In particular, mGluR4 is abundant in striato-pallidal synapses within the basal ganglia circuitry a key area implicated in movement disorders, like Parkinson's disease. In the immune system mGluR4 has been found on dendritic cells (DCs). Emerging data implicate mGluR4 in multiple indications such as multiple sclerosis, Parkinson's disease, anxiety, neuropathic and inflammatory pain, schizophrenia and diabetes.
Source: Pharmabiz.com © 2012 Saffron Media Pvt. Ltd (25/09/12)
Wayne State University School of Medicine researchers, working with colleagues in Canada, have found that one or more substances produced by a type of immune cell in people with multiple sclerosis (MS) may play a role in the disease's progression. The finding could lead to new targeted therapies for MS treatment.
B cells, said Robert Lisak, M.D., professor of neurology at Wayne State and lead author of the study, are a subset of lymphocytes (a type of circulating white blood cell) that mature to become plasma cells and produce immunoglobulins, proteins that serve as antibodies. The B cells appear to have other functions, including helping to regulate other lymphocytes, particularly T cells, and helping maintain normal immune function when healthy.
In patients with MS, the B cells appear to attack the brain and spinal cord, possibly because there are substances produced in the nervous system and the meninges -- the covering of the brain and spinal cord -- that attract them. Once within the meninges or central nervous system, Lisak said, the activated B cells secrete one or more substances that do not seem to be immunoglobulins but that damage oligodendrocytes, the cells that produce a protective substance called myelin.
The B cells appear to be more active in patients with MS, which may explain why they produce these toxic substances and, in part, why they are attracted to the meninges and the nervous system. The brain, for the most part, can be divided into gray and white areas. Neurons are located in the gray area, and the white parts are where neurons send their axons -- similar to electrical cables carrying messages -- to communicate with other neurons and bring messages from the brain to the muscles. The white parts of the brain are white because oligodendrocytes make myelin, a cholesterol-rich membrane that coats the axons. The myelin's function is to insulate the axons, akin to the plastic coating on an electrical cable. In addition, the myelin speeds communication along axons and makes that communication more reliable. When the myelin coating is attacked and degraded, impulses -- messages from the brain to other parts of the body -- can "leak" and be derailed from their target. Oligodendrocytes also seem to engage in other activities important to nerve cells and their axons.
The researchers took B cells from the blood of seven patients with relapsing-remitting MS and from four healthy patients. They grew the cells in a medium, and after removing the cells from the culture collected material produced by the cells. After adding the material produced by the B cells, including the cells that produce myelin, to the brain cells of animal models, the scientists found significantly more oligodendrocytes from the MS group died when compared to material produced by the B cells from the healthy control group. The team also found differences in other brain cells that interact with oligodendrocytes in the brain.
"We think this is a very significant finding, particularly for the damage to the cerebral cortex seen in patients with MS, because those areas seem to be damaged by material spreading into the brain from the meninges, which are rich in B cells adjacent to the areas of brain damage," Lisak said.
The team is now applying for grants from several sources to conduct further studies to identify the toxic factor or factors produced by B cells responsible for killing oligodendrocytes. Identification of the substance could lead to new therapeutic methods that could switch off the oligodendrocyte-killing capabilities of B cells, which, in turn, would help protect myelin from attacks.
Source: Science Daily Copyright © 1995-2011 ScienceDaily LLC (06/08/12)
Researchers have identified an antibody found in the blood of about half of patients with multiple sclerosis that is not found in people without the autoimmune disease.
The implications of the antibody's presence aren't fully understood. But in rodents, the antibody binds to and damages brain cells that are known to be important to neurological function, according to the study.
Although the research is preliminary, experts say the findings may open the door for a blood test that could more easily diagnosis multiple sclerosis (MS) patients. The results also suggest a new target for MS treatments that would prevent the antibody from binding to brain cells.
"We have known for a long time that antibodies were involved in the destruction of nervous system tissue in MS, but we have not had a good handle on what the target was for these antibodies," said Timothy Coetzee, chief research officer for the National Multiple Sclerosis Society, who was not involved in the study. "What this research has identified is what might be a potential trigger or target in MS."
The study is published in the July 12 issue of the New England Journal of Medicine.
In multiple sclerosis, the body's own immune system attacks myelin, the substance that insulates nerve fibers of the central nervous system. The damage disrupts nerve signals traveling to and from the brain, which can lead to symptoms such as numbness, movement difficulties, blurred vision, fatigue and eventually cognitive problems.
What isn't known, however, is precisely which components of the immune system go awry, which cell proteins the immune system specifically targets and to what extent this varies from patient to patient.
In this study, researchers screened the blood serum of two sets of patients with MS and compared it to the serum of people without MS. About 47 percent of the nearly 400 people with MS had high levels of KIR4.1 antibodies, while none of the non-MS control participants did.
In addition, only three of the nearly 330 people with other neurological diseases had high levels of KIR4.1, indicating that the antibody researchers are homing in on is specific to MS and not more general neurological problems.
Researchers then injected KIR4.1 antibodies into the brains of rodents and found the antibody damaged the brain tissue and altered immune response in the region. It should be noted, however, that results found in animals often do not translate to humans.
"If this is truly the target of the immune response, this could pave the way to other therapies for MS," said senior study author Dr. Bernhard Hemmer, professor of neurology at Technische Universitat in Munich.
Dr. Emmanuelle Waubant, professor of neurology at the University of California, San Francisco, and director of the UCSF Multiple Sclerosis Center, called the results exciting yet preliminary.
Prior research has found "lots of changes in the immune response that we think relates to the disease," she said. But pinpointing specific antibodies has been difficult, with some studies showing relevance but others failing to repeat the finding.
"In this case, researchers had a large number of participants," she said. "Nearly half of them had the antibody, and the protein in the brain identified as a target for this antibody is known to be important for nerve functioning."
"The antibodies are like Velcro. They bind to proteins or antigens in different tissues," she added. "Many antibodies don't bind in the brain, so they are unlikely to have relevance in MS. But this antibody did."
Still, Hemmer said, not everyone with MS had high levels of KIR4.1 antibodies, meaning there are almost certainly other aspects of the immune system involved.
And MS can vary significantly from person to person. Future research should seek to determine if MS patients with the antibodies fare better or more poorly than others, Coetzee said, as well as what other antibodies and elements of the immune system might be involved.
Source: HealthDay Copyright © 2012 HealthDay.(12/07/12)
Breakthrough in understanding human immune response has potential for the development of new drug therapies
A team of researchers at Trinity College Dublin’s School of Medicine has gained new insights into a protein in the human immune system that plays a key role in the protective response to infection and inflammation. The research findings have just been published in the internationally renowned peer-reviewed Journal of Biological Chemistry.
The TCD researchers investigated whether signalling via a protein known as the ‘LFA-1 integrin’ influences gene expression in immune cells called ‘T-cells’. In doing so, they discovered what is called “ a genetic signature”, that is a group of genes responding to the signal that make T-cells fail to respond to a controlling molecule called transforming growth factor-β (TGF-β).
“This is a bit like removing the handbrake and setting the immune system into action,” says Professor of Medicine, Dermot Kelleher who led the research.
The research may also have implications for treating inflammatory diseases where drugs targeting LFA-1 have had unacceptable and serious side effects such as progressive multi-focal leukoencephalopathy (PML) in the brain. “If we more fully understand the signalling mechanism leading to downstream gene regulation by LFA-1, we may be able to devise selective therapies to better treat various autoimmune diseases without major side effects such as PML,” according to Professor Kelleher.
Scientists have known for decades that LFA-1 is responsible for the majority of T-cell migratory behaviours associated with the immune response. Central to the success of immune responses that restrain inflammation are regulatory molecules, including a multifunctional cytokine TGF-β, which is essential for the development and function of an immune cell type, called the regulatory T-cells.
In the current study, Trinity College Dublin scientists conducted a genome wide analysis and detected that the expression of several genes were altered when T-cells were triggered to migrate to a site of inflammation through the interaction of LFA-1 with another protein called ICAM-1. This research was performed in collaboration with the Immunology Research Group at the National Children’s Research Centre at Our Lady’s Children’s Hospital, Crumlin led by SFI Stokes Professor of Translational Immunology, Padraic Fallon.
“There is still much to learn about the genetic changes induced by the LFA-1 signal, but our studies are the first to show that a regulatory T-cells associated signal is influenced,” says TCD research fellow in clinical medicine, Dr. Navin Kumar Verma, a lead author on the study. “The findings are novel and significantly contribute to the understanding of how the organism mounts an immune response. Several other genes identified here offer a general framework for future research in order to identify excellent targets for novel therapies for immune-mediated human diseases such as rheumatoid arthritis or inflammatory bowel disease.”
More information: The full citation of the paper is: Verma NK, Dempsey E, Long A, Davies A, Barry SP, Fallon PG, Volkov Y, and Kelleher D (2012) Leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction induces a novel genetic signature resulting in T-cells refractory to transforming growth factor-β signalling. Journal of Biological Chemistry.
Source: Medical Xpress © Medical Xpress 2011-2012 (09/07/12)
A novel study at Queen's University Belfast which could eventually lead to new treatments for Multiple Sclerosis (MS) has been awarded £425K by the Biotechnology and Biological Sciences Research Council (BBSRC).
Currently some 100,000 people in the United Kingdom have MS which affects the ability of nerve cells in the brain, spinal cord and eye, to communicate with each other effectively.
The new study, based in Queen's Centre for Infection and Immunity, will investigate how parts of the immune system can help repair the damage caused by MS attacks.
The project is being led by Dr Denise Fitzgerald, who herself experienced a condition similar to MS, called Transverse Myelitis when she was 21. As a result of inflammation in her spinal cord, she was paralysed in less than two hours.
Dr Fitzgerald had to learn to walk again as the damage in her spinal cord repaired itself over the following months and years. It is this natural repair process that often becomes inefficient in MS, a chronic life-long condition, and this failure of repair can lead to permanent disability. Boosting this natural repair process in the brain and spinal cord is the next frontier in treating MS, as currently there are no drugs that are proven to do so.
Speaking about the importance of the new study, Dr Fitzgerald said: "The central goal of our research is to identify new strategies to treat MS and other inflammatory and demyelinating disorders.
"Nerve cells communicate by sending signals along nerve fibres which are contained within a fatty, insulating, protective substance, known as Myelin. In MS, Myelin is attacked and damaged (demyelination) which can lead to either faulty signalling by nerves, or death of the nerve cells. As a result, patients experience loss of nerve function in the area of the brain/spinal cord that has been damaged. This research project centres around understanding Myelination, a process of insulating the nerve fibres with Myelin, and Remyelination, a natural regenerative process that replaces damaged Myelin.
"We already know that the immune system is implicated as a potential culprit in MS, as the damage is thought to be caused by inflammation in the central nervous system (CNS; brain, spinal cord and optic nerve). But in recent years we have learned a great deal about how the immune system also supports tissue repair in the CNS.
"In particular, there is a group of immune cells called T cells which have recently been shown to support remyelination. There are different subsets of T cells, however, and little is still known about which subsets are beneficial in this process. In our study we aim to discover if these different T cell subsets influence remyelination of the CNS, and if ageing of the T cells impairs remyelination in older individuals.
"The outcomes of this study will include new knowledge of how the immune system, and T cells in particular, influence remyelination in the Central Nervous System. We will also learn a great deal about how ageing affects the ability of T cells to help tissue repair.
"Given the profound neurological impairments that can accompany ageing, and our growing aged population, is it imperative that we understand how normal CNS repair can become impaired with age.
"By understanding this process of CNS repair in detail. we will also gain an insight into other inflammatory and demyelinating disorders."
Source: Phys Org © Phys.Org™ 2003-2012 (31/05/12)
Scientists have discovered a molecular mechanism that could help explain how multiple sclerosis (MS) and other autoimmune diseases can be exacerbated by the onset of an infection.
MS is an autoimmune disease of the central nervous system which affects approximately 100,000 people in the UK.
The research, directed by Dr Bruno Gran at The University of Nottingham, focused on a population of cells of the immune system known as regulatory T cells, which control and regulate the behaviour of other immune cells. The results of this study have been published in the Journal of Immunology.
Dr Bruno Gran, from the School of Clinical Sciences, said: "The connection between infections and MS is complex. We have known for many years that in some cases, infections can promote disease exacerbations (also known as "MS relapses"). Our study sheds light on a new mechanism that could explain how infections can trigger such relapses. This might have relevance to other autoimmune diseases as well"
When the immune system is functioning properly Regulatory T cells — also known as Tregs — keep in check the tendency of other cells of the immune system to over react and cause inflammation when the body is under attack from infectious agents such as bacteria or viruses.
The battle of the immune cells
In the battle that follows the research group discovered that bacteria and viruses activate certain receptors of the innate immune system — known as Toll-like receptors (TLRs), making the Tregs less inhibitory. The positive consequence is that inflammatory immune cells are more able to react against infectious agents and eliminate them. The problem is that such increased activity of inflammatory immune cells could also increase the occurrence of autoimmune reactions against organs such as the central nervous system.
Research led by award winning PhD student
Most of the experimental work was conducted in the laboratory by award winning PhD student Mukanthu Nyirenda under the supervision of Dr Gran in the Division of Clinical Neurology. The research was funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland.
Last year Mukanthu received the University Endowed Postgraduate Prize in recognition of the progress he has made with his research. He is also a previous recipient of a Jacqueline Du Pre' Award of the Multiple Sclerosis International Federation.
Mukanthu said: "This publication is a very important part of the work leading to my doctoral dissertation, planned for 2012. I am grateful for the recognition and support given to me by the University with the Endowed Postgraduate Prize."
The study was carried out in collaboration with Professor Cris Constantinescu and other researchers at The University of Nottingham and experts at McGill University in Montreal.
Flirting with the enemy
The research team also found that when stimulated by molecules that activate TLRs, regulatory T cells become themselves functionally more similar to inflammatory T cells, another reason why autoimmune reactions could occur in relation to infections.
Although this part of the study focussed on healthy subjects, ongoing studies in Dr Gran's laboratory are comparing the properties of regulatory T cells in these people with those obtained from patients with MS. Other researchers have previously found that Tregs may in fact be defective in MS patients, and this study contributes to our understanding of how episodes of infections, known to influence the clinical course of MS, could in certain circumstances promote the occurrence of autoimmunity.
Source: Science Codex (20/02/12)