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