Multiple Perspectives in Multiple Sclerosis: May 28, 2015

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.

http://stm.sciencemag.org/content/7/287/287ra74

 
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.

http://www.sciencedirect.com/science/article/pii/S0889159115001208

 
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). 

http://omicsgroup.org/journals/blood-b-cell-and-regulatory-subset-content-in-multiple-sclerosis-patients-2376-0389-1000139.pdf

 
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. 

http://www.biomedcentral.com/content/pdf/s12883-015-0330-4.pdf