At the end of each topic we have added a "Bottom Line" to summarize for you!
Melatonin contributes to seasonality of MS relapses. MS is a complex disease caused by a combination of environmental and genetic factors. Several environmental factors that affect MS have been identified, including smoking, increased salt intake, vitamin D levels and certain infections. Researchers have recently found that melatonin levels are associated with relapse rate in people with relapse remitting MS. Melatonin is a hormone that controls circadian (daily) rhythms. Levels of melatonin are controlled by seasonal changes in day length, and reach their peak in the autumn and winter. It was found that melatonin levels measured in 139 people with MS showed an inverse relationship (correlation) with disease activity, meaning that higher levels of melatonin correlated with lower relapse rates. Using a mouse model of MS, the authors then found that melatonin prevented development of disease. Finally, again using the mouse model, the authors showed that melatonin acts directly to limit the development of a kind of inflammatory T cell, called Th17 cells. These cells are implicated in MS. They also found that melatonin also increases the development of regulatory T cells, another kind of immune cell, that are thought to protect against disease. This study is important because it identifies a new environmental factor that may contribute to MS. However, based on their studies in the mouse model it should be made clear that the exact effects of melatonin in humans are not clear.
Bottom line: Melatonin, a hormone involved in light and dark cycles, was found to correlate with the seasonality of MS relapses and was found to be protective in a mouse model of disease. Future work should aim to confirm these results in human T cells and assess melatonin as a potential biomarker of disease activity.
How MS therapies affect T cells in patients. Often there is a disconnect between molecular and cellular research and the therapies that ultimately are informed by this research. This review aims to bridge that gap by discussing what is known about the features of T cells that are implicated in causing and propagating MS disease and how current therapies affect these cells. Overall, many therapies cause non-specific effects on T cells, ranging from limiting migration in the body to non-specifically blocking their ability to grow. For example, the first line treatments IFN-beta and glatiramer acetate partly target T cell inflammation, where the former lowers activation of T cells and the latter leads to a shift in the nature of the T cell response. Other therapies like Natalizumab block T cells from getting into the central nervous system (CNS), where demyelination occurs, through blocking a specific protein interaction. In essence, this limits all T cells from getting into the CNS which can have negative side effects for some patients. Similarly Fingolimod blocks T cells from leaving specialized immune organs, thus, similar to Natalizumab, blocks whole pools of cells from entering circulation. Newer treatments that target how T cells specifically get activated (and ultimately lead to inflammation) may offer a more specific alternative to currently approved drugs.
Bottom line: Current therapies have a range of effects on all T cells, including those cells that cause MS. Because these therapies are not specific, there are often other less wanted side effects. Future work is needed to understand what is required to activate the T cells that actually cause disease, and how this can be specifically blocked.
Promoting re-myelination. In addition to targeting the cause of MS, drugs are needed to promote repair of damage to myelin, the coating around the neurons, in the central nervous system (CNS) to help patient recovery. Researchers have found that an oral drug, called GANT61, that was originally a cancer therapy may be effective in repairing CNS tissue. The authors identified cells in the brains of mice, called neural stem cells (NSCs), that move to areas of demyelination (loss of the myelin sheath around axons) and neuronal (nerve) damage, a hallmark of MS. The activity of these cells is controlled by a signaling pathway called sonic hedgehog (Shh). This pathway leads to the production of a protein called Gli1. When Gli1 is present it means that the Shh pathway is active. The authors found that stopping activation of this pathway let NSCs turn into cells that work better to remyelinate (help myelin grow around) neurons in damaged parts of the CNS. Using a mouse model of MS, they then showed that mice treated with GANT61, which stops Shh, had less severe relapses and higher levels of myelin. This suggests that stopping Shh signaling is important in promoting remyelination, and identification of specific pathways that lead to demyelination can help with recovery.
Bottom line: GANT61, a drug that inhibits (stops) a specific pathway in neural stem cells, was shown to lower the severity of relapses in a mouse model of MS. Whether it will do the same in humans still needs to be studied.
Procedures for cerebrospinal fluid (CSF) biobanking will ensure higher powered biomarker discovery studies. Biomakers are molecules or cell types that can be measured in a patient and have value in predicting, diagnosing, and treating disease. In MS, as well as other diseases of the nervous system, identifying biomarkers in the CSF could be incredibly valuable since the CSF is closer to where disease occurs in the central nervous system (CNS) as compared to blood. One aspect of making sure that studies have enough samples from patients to allow for meaningful analysis is to ensure that when CSF is collected it is handled and stored appropriately for research use. CSF is typically collected during initial diagnosis, and currently, is used to test for two biomarkers: oligoclonal IgG and typically cell count. Currently, no other markers are routinely used in clinical practice for diagnosis or monitoring disease. This article covers the basics of how to biobank CSF the right way so that it can be included in larger studies. This is important to minimize (make less) artificial errors in data due to sample handling and allow for inclusion of as many samples as possible in studies. Centers that are currently collecting CSF or are proposing to start collecting CSF should read through this review as a guide for proper collection, storage, and metadata to include in their data bases.
Bottom line: The study of CSF samples can be incredibly valuable to identify new biomarkers of MS, and to ensure inclusion in studies, it is important to follow standard guidelines when collecting, storing, and handling these samples from patients.
B cells reach a critical threshold. T cells, the cells that cause inflammation in MS, become activated by antigen presenting cells (APCs). It is believed that two kinds of cells, dendritic cells (DCs) and B cells, activate these antigen-specific T cells, where the contribution from the latter has been less well characterized. Using a model of MS disease, researchers sought to characterize the relative importance of these two kinds of APCs. They found that B cells in combination with DCs induce severe disease, and that increasing the number of antigen-specific B cells also led to increased disease. They also found, as was previously reported, that antigen presentation by B cells alone was not enough to cause disease unless a critical number of B cells was reached. This is important because this demonstrates a key role for both cell types, where B cells may be more important in sustaining inflammation during chronic disease and DCs are important in initiating disease. Rituximab, an antibody that depletes B cells, has shown success for treatment in some patients. The results of this study might suggest that B cell targeted treatment may be beneficial to patients who are at later disease stages, and DC targeting treatments could be explored for earlier phases of disease. Future work should aim to address more clearly the role of these APCs in humans, as well as better characterize their relative importance at different disease stages.
STAT4 regulates GM-CSF production in mouse model of MS. GM-CSF is a cytokine produced by T cells that is thought to mediate MS disease. These T cells also produce the cytokines IFNγ and IL-17, where all three cytokines are implicated in causing and propagating disease to varying degrees. The authors of this study sought to determine, using a mouse model of MS, what transcription factor controls the production of GM-CSF. A transcription factor is a protein that controls the production of other proteins, therefore it is important in controlling what a cell does by controlling the proteins it makes. Identifying transcription factors that ultimately lead to the production of inflammatory molecules that cause disease can ultimately lead to a better understanding of how these cells operate and lead to very specific drug or therapeutic targets. The authors found that one transcription factor, called STAT4, controls the production of GM-CSF. Mice that could not make STAT4 did not get disease, their T cells were unable to make GM-CSF, and the number of T cells that produce all three cytokines was lower. STAT4 has previously been identified as a susceptibility loci in genome-wide association studies (GWAS) for people with MS. Taken together, this indicates that STAT4 may play a key role in MS through promoting cytokine production in T cells. Future studies should determine how STAT4 levels could be controlled and if these results are reproducible in human T cells.
TLR2 stimulation reduces effectiveness of Tregs, effect enhanced in Tregs from MS donors. Regulatory T cells are crucial for controlling and limiting immune responses and the balance between these cells and inflammatory T cells is key to immune balance. It has been shown that Tregs from persons with MS are less suppressive, meaning that they are unable to control T cell proliferation as well as their counterparts from healthy donors. The reasons why this occurs are not clearly understood. In this study, the authors show that stimulation of a surface protein called TLR2 is involved in reducing Treg function, both in MS and healthy donors. TLR2 is part of a group of proteins, called Toll-like receptors, involved in alerting the immune system that invading microbial pathogens are present. They found that Tregs from MS patients express higher levels of TLR2 and that stimulating TLR2 led Tregs to be less functional and produce more inflammatory cytokines, like IL-17 and IL-6. The authors suggest that this may provide a link between certain microbial infections and relapses in MS patients. Through their experiments, they also suggest that therapies that target IL-6 could be effective. This, coupled with previous reports showing that T cells expressing the receptor for IL-6 are less capable of being suppressed, indicate that anti-IL-6 therapy might help maintain the correct balance of Th17 to Tregs.
T cells from patients with MS differ functionally from those found in healthy donors. MS is thought to be caused by auto-reactive T cells that recognize antigens in the central nervous system (CNS). Strikingly, these T cells are found in healthy donors and MS patients, but these cells do not cause disease in healthy individuals. A key question in MS research to date has been how are these cells different? This has been a difficult question to study because these cells are very rare and technically challenging to isolate in humans. Using a novel assay to identify these auto-reactive T cells from patients, researchers have found that cells isolated from MS patients are functionally different as compared to those from healthy donors. T cells from MS patients produce the inflammatory cytokines GM-CSF, IFN-γ, and IL-17. These cytokines are thought to be important in disease based on studies in the mouse model used to study MS. Contrary to cells from MS patients, those from healthy donors produce IL-10, an immunosuppressive cytokine that is important for lowering immune responses. The researchers also found that these cells have a different transcriptome, or molecular profile of DNA expression, suggesting possible targets for intervention and pathways that may explain why these cells cause disease in MS patients. Understanding these differences is critical to help identify new targeted therapies and to better understand how these cells are controlled effectively in healthy individuals. Future work should look to identify which molecules are key to controlling this response.
A link between metabolism and immune signaling in the brain of MS patients. A hallmark of MS is the formation of lesions in the brain and CNS. These lesions, which represent areas of demyelination, are often found in parts of the brain called white and grey matter. Damage in gray matter has also been associated with the symptoms, such as cognitive impairments, of MS patients. One outstanding question is what factors might influence formation of lesions in what is called non-lesional normal appearing gray matter (NAGM) in MS patients. This is important because it would help to understand what at the molecular level can lead to lesion formation and contribute to disease and symptoms. The authors of this study profiled NAGM from patients with MS and control patients. By profiling the transcriptome, the authors found several molecular targets, immune inflammatory pathways, and metabolic pathways that are different between MS and control patients. The authors found that the link between lower metabolism and inflammation in the NAGM may be through astrocytes, a kind of highly frequent cell in gray matter in the brain. This lower metabolism could cause mental fatigue in MS patients, suggesting that targeting inflammation through IL-1β could alleviate symptoms.
B cells balance may be altered in patients with MS. B cells are a kind of immune cell that produce antibodies to recognize antigens. These cells can also activate and regulate the function of T cells, which are known to be important in MS. The success of B cell targeted treatments, like Rituximab, has revealed a potential role for these B cells in mediating disease. To date a clear understanding of the role of B cells has not been well characterized in patients. The authors of this study sought to quantify the proportions of different kinds of B cells in the blood of MS and healthy donors to determine if there was a difference in certain types. They found an increase in total number of B cells in blood of MS patients, however they did not find that there was a decrease in regulatory B cells. These regulatory cells are thought to minimize immune responses through production of IL-10, an anti-inflammatory cytokine. This study supports the idea that altered blood B cell state in MS patients might be important in disease, and future studies should aim to study the functional differences of these cells, such as ability to stimulate T cells, what cytokines they produce, and potentially if they’re different from those in the central nervous system (CNS).
CSF sampling of IgG alone may not predict MS disease course. The identification of biomarkers that can help physicians make predictions about disease is important because this would allow for control over the course of therapy. One source of predictive biomarkers is the cerebrospinal fluid (CSF) of MS patients. CSF is usually used to identify levels of IgG, or antibody protein, and oligoclonal bands that indicate IgG in the CSF. This study sought to determine if biomarkers measured in the CSF of MS patients at diagnosis, such as protein level and number of cells, was correlated with timing of disease. They found that they could not, using their models, establish a link between these CSF measurements and disease course. They did find that higher protein level in the CSF was associated with disease severity. According to their study design, they started with information from a group of ~4,000 patients, and due to lack of established MRI, complete biological, 5-year follow-up data and a lack of CSF sampling, they could only include ~400 patients in their study. It is striking that the number of patients included in their study was limited due to non-uniform patient data collection, and highlights the need for more complete patient data in MS databases. Future work should seek to determine if there are other biomarkers in the blood and CSF that could help predict disease, where a combination of markers might give more predictive power.
Too big to fail: a call for neurologists to speak up against rising cost of disease modifying treatments (DMTs). There are currently 12 FDA approved DMTs for the treatment of MS. The first DMT was introduced in 1993 (IFNβ-1b, Betaseron). Usually, an increase in the number of drugs available, in this case DMTs, would mean that the cost of these drugs should go down. However, this study has found that the cost of DMTs has increased significantly, on average increasing in cost by 21-36% over the past 20 years. For example, glatiramer acetate (Copaxone), increased from an estimated annual cost of $8,292 in 1993 to $59,158 in 2013. Compared to another drug, TNF inhibitor, this rate of change is significantly higher and is faster than inflation for other prescription drugs. This study is important because it carefully records this unexplainable increase in cost of DMTs for MS. The findings suggest that this may be due to a lack of control of drug prices and a lack of generic (no brand) drugs to drive prices down in the market for MS drugs. Although it is not clear why these prices are increasing so much, it is clear that this price raise may make it difficult for some people to get the treatment they need.
Link to article: http://www.neurology.org/content/early/2015/04/24/WNL.0000000000001608.short?rss=1
Expression of GM-CSF in T cells suppressed by IFNβ therapy. T cells, a kind of immune cell, play an important role in MS. Understanding what makes these cells different between patients with MS and healthy people is important for understanding MS and finding key targets for therapy. The role of T cells that produce an inflammatory cytokine, or protein, called GM-CSF has been defined in mice with MS but little has been studied in humans. This study sought to determine if T cells that produce GM-CSF are increased in patients with MS. They found that the numbers of T cells that produce GM-CSF are increased in patients with MS as compared to healthy donors, and these cells can also be found in lesions (areas of myelin loss) in the CNS of patients. This means these cells may play an important role at the site of disease. They also found that untreated patients had less of these cells than those treated with IFNβ, a prominent DMT. The authors show that IFNβ directly reduces the production of this cytokine, indicating a potential mechanism for how this drug works. All of these points are important because they support a key role of GM-CSF in MS. Also, understanding how IFNβ treatment works will help us understand the causes of MS and other ways to treat it.
Link to article: http://www.jimmunol.org/content/early/2015/04/25/jimmunol.1403243.abstract
Pools of T cells are similar between the central nervous system (CNS), cerebrospinal fluid (CSF) and the blood in patients with MS. Myelin specific T cells react to myelin antigens from the central nervous system, or the brain and the spinal cord. An antigen is a substance that causes the body to form antibodies against it, and when T cells find an antigen they recognize they grow and produce cytokines. It is thought that T cells that react to myelin antigens drive MS disease and lead to destruction of the myelin that insulates neurons. It is important that we identify what makes these cells different from cells that are not antigen reactive, and to understand if there is a difference between these cells in the blood and the CNS. One method for finding and tracking these antigen-specific T cells is through T cell receptor (TCR) repertoire analysis. When an antigen-specific T cell becomes activated, it will grow (this is called clonal expansion) and there will be more of its TCR in a given pool of cells. The goal of this study was to determine if this TCR repertoire was different between lesions in the CNS, the CSF, and the blood of MS patients. The authors found that there were clones of CD8 T cells in the CSF, CNS, and blood. There was also an overlap between the CSF and CNS. This means that the CD8 T cells may play a role in the processes that cause MS. More importantly, it is possible that taking a sample of the CSF may show what is happening in MS lesions. They also found a specific kind of CD8 T cell with certain markers on the surface (CCR5, LFA-1) that should be studied in more detail since these may be involved in causing the disease.
Link to article: http://onlinelibrary.wiley.com/doi/10.1002/acn3.199/full
New factors predict risk of disability accumulation over time. A clinically isolated syndrome (CIS) is defined as an episode that suggests inflammatory demyelination in the brain or spinal cord. Many patients who have a CIS can develop MS. A key question is what factors can predict whether a patient with CIS will develop MS? Knowing this is very important since it would allow for early treatment with disease modifying therapies (DMTs), and early treatment has been shown to significantly impact disease progress. The goal of this paper was to find out what factors, including clinical and radiological, can predict development of MS and how the disease progresses. They found that the presence of oligoclonal bands (proteins called immunoglobulins) in the cerebrospinal fluid (CSF) and the number of lesions (areas of demyelination) on brain imaging with magnetic resonance imaging (MRI) could predict whether or not a CIS will become MS. This study is important because it highlights clinical information that might help determine if someone with CIS is likely to develop MS. However, the number of patients in this study, or the sample size, was small (1,058 patient's data was included). This makes it hard to know if this information represents people with MS as a whole and future study is needed to confirm their findings.
Link to article: http://brain.oxfordjournals.org/content/early/2015/04/21/brain.awv105
Bacteria in your gut aid in more than digestion. The gut microbiome is made up of all the bacteria and other microorganisms that live in a persons gut. A persons microbiome can be affected by many things, ranging from diet to smoking or drinking, and antibiotic use. A whole new area of research is showing how important the microbiome is for maintaining overall health and the immune system, and studies have linked certain species of bacteria with obesity and inflammatory bowel disease. Studies in animal models of MS suggest that the gut microbiome may play a role in disease since certain species of bacteria have been linked with protection from disease in these animal models. Studies with small groups of MS patients have revealed promising results, but these are limited due to their size. Most of the data in humans is currently descriptive and show some differences in broad groups of bacteria between MS patients and healthy people. Larger scale studies, like those being conducted by the MS Microbiome Consortium, should reveal a clearer role for the microbiome in MS. For complex diseases like MS, an integrative approach to therapy that factors in lifestyle choices that clearly affect the microbiome could be hugely beneficial. READ MORE. Here is a link for open enrollment in MS Microbiome Consortium study: http://msgenetics.ucsf.edu/cr_Guts.html
Anti-LINGO Phase II trial data released by Biogen indicates success in repair. There is no available therapy for MS that aims to repair myelin that has been destroyed in the CNS. BIIB033 is a new antibody from Biogen that targets LINGO, a protein expressed by neurons and myelin-producing oligodendrocyte cells in the CNS. This anti-LINGO antibody promotes CNS repair, or remyelination, in animal models of MS, which highlights its potential for repair in humans. Phase I clinical trials were completed in August 2014, and a current Phase II trial is underway for treatment of relapse remitting MS. Biogen recently announced clinical trial data showing the success of BIIB033 in the treatment of acute optic neuritis (AON). AON is caused by inflammation of the optic nerve and is a common symptom of MS. This new data is important because it shows safety and success of the first drug whose goal is to promote repair of damage in the CNS. Here is a link to the ongoing Phase II clinical trial for MS: https://clinicaltrials.gov/show/NCT01864148
Linking imaging data with clinical data in patients with primary progressive MS (PPMS). A key challenge in understanding MS is linking imaging information, usually obtained through MRI, to clinical data, such as physical disabilities in patients. The ability to link this image data with clinical data is key for two key reasons: 1) to improve understanding of disease mechanisms that lead to injury and disability and 2) develop image-based markers of disease that might help predict disease course. This study used a combination of two imaging methods, called MRS and QSI, to determine if changes in the images of the cervical cord (the area of the CNS behind the throat) predict degeneration in the spinal chord region of the CNS. They also determined if imaging could be associated with disability in patients with PPMS. Several clinical measurements were found to be associated with imaging data. For example, a higher concentration of myo-inositol, a molecule that can be quantified through this imaging, was associated with poor postural stability. This study provides an excellent framework for developing imaging and clinical correlations, and should be extended to study larger groups of patients over time.
Rescue and repurpose: new insights from existing drugs. There is a huge unmet clinical need for drugs to treat PPMS. One proposed approach to find new drugs is to use already approved drugs, or those that are far along in their development, since most of these have undergone the costly process of clinical trials to show safety. This study developed a formal system to find these drug candidates based on their potential to be relevant to PPMS disease, their ability to be taken orally, and good safety data. Starting from 19,092 publications, they developed a candidate list of 52 drugs, of which 7 are recommended for further study in clinical trials for PPMS. This is important because this study provides a systematic method for this “drug rescue” approach, and has identified 7 candidate oral drugs for testing. READ MORE