Multiple Perspectives in Multiple Sclerosis: October 2015

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. 
http://www.cell.com/abstract/S0092-8674(15)01038-7
 
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.
http://austinpublishinggroup.com/multiple-sclerosis/fulltext/ajmsn-v2-id1009.php
 
 
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.
http://www.sciencedaily.com/releases/2015/09/150930140621.htm 
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14957.html
 
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. 
http://www.neurology.org/content/73/22/1914.short
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