Our understanding of the pathogenesis of MS has expanded considerably in recent decades. We have seen a shift towards a more complex picture of MS, as a disease involving a variety of immunopathogenic mechanisms with pathology affecting both white and gray matter in the brain. Current basic research in MS continues to clarify the complex pathobiology of the disease, with the goal of improved diagnosis, treatment, and prevention.
Despite advances in our understanding of MS, gaps in understanding pose major challenges to improved treatment of MS. We still do not understand the cause(s) of MS nor have a complete picture of the pathogenesis of the disease. The effectiveness of currently available disease-modifying treatments is limited to 35% to 40% and we do not understand the reasons behind treatment failure in patients who fail to respond or lose response to available medications. Additionally, progressive MS remains resistant to currently available treatment strategies.
Goals of basic research in MS
The two main goals of basic research in MS are (1) to clarify the string of events that results in CNS lesion formation and disease onset and (2) to determine to what extent various factors, including immune and CNS dysfunction, the environment, genetics, and gender contribute to disease expression and outcomes.
A variety of tools are used in MS research. These include high-throughput genetic screening techniques, animal modules of MS, methods for molecular analysis, flow cytometry methods for examining functional and surface features of neural and immune cells, cell culture methods for modeling interactions between neural and immune cells, techniques for measuring and assessing soluble factors including neurotransmitters, cytokines, chemokines, hormones, and growth factors, neuroimaging techniques, and histopathological and microscopic methods.
Key Research Tools Descriptions and Examples in MS
- Genomics and gene screening
- Gene and protein expression arrays
- Tools in bioinformatics, statistics, and data mining allow integration of multiple research tools to identify molecular signatures of disease activity
- Experimental autoimmune encephalomyelitis (EAE) model useful in examining MS autoimmune components and neurodegeneration and demyelination
- Cuprizone model useful for examining cellular and molecular interactions involved in demyelination
- Other animal modules include virus-induced demyelinating diseases, myelin-deficient or transgenic mice, and humanized mice
- Allows identification of molecular signature of disease activity
- Allow assessment of functional and surface features of neural and immune cells
- Useful for modeling interactions between neural and immune cells
Assessment soluble factors:
- Allow measurement of changes in factors including neurotransmitters, cytokines, chemokines, hormones, and growth factors
- Advanced magnetic resonance imaging (MRI) techniques are effective in measuring damage to nerves and correlating this damage to disability
- Optical coherence tomography (OCT) under development to evaluate retinal nerve fiber damage
- Positron emission tomography (PET) allows imaging of CNS inflammation in real time
Key research questions in MS
The pathology of MS affects two systems in the body, the CNS (including the brain, optic nerves, and spine) and the immune system. Each of these is subject to a number of influencing factors that may contribute to dysfunction, including genetics, the environment, and gender. Basic research in MS tends to focus on the two systems where the pathology of MS appears and looks at different factors that may contribute to and influence that pathology. The research questions below represent some of the main areas of ongoing research in MS.
Where does the primary injury in MS occur, in the CNS or elsewhere?
This question seeks to determine whether MS stems from a defect in myelin or its precursors in the CNS, followed by secondary damage from a dysfunctional immune system. Since it is very difficult to examine tissues affected by MS at its earliest stages of development, obtaining an answer to this question poses a difficult challenge.
What structural of functional defects in myelin or its precursors contribute to MS?
This question seeks to determine the nature of the defects in myelin that allow MS to develop. There is a growing body of research investigating structural and functional characteristics of myelin in patients with MS. Studies have suggested that myelin in individuals with MS may be less mature than in non-MS individuals and that this lack of maturity may increase susceptibility for MS. Studies have also focused on the structure of the proteins that make up myelin (eg, myelin-specific protein) in MS patients and how structural changes may interact with immune system cells in MS. Other studies have examined how defects in oligodendrocytes, the CNS cells that create myelin, may play a role in inducing immune responses in MS.
If MS is associated with defects in myelin, what extrinsic exposure triggers the immune response in MS?
This question addresses possible factors outside of the body that may trigger the autoimmune response in MS, including viruses and other environmental factors. To date research in this area has implicated multiple environmental factors that appear to increase susceptibility to MS. However, no single factor has emerged as the primary factor in disease susceptibility.
What causes axonal damage and neuronal death in MS?
Research has examined a variety of molecular mechanisms that may contribute to axonal dysfunction, eventually leading to nerve death in MS. These include intrinsic myelin dysfunction that increases susceptibility for demyelination, immune processes causing inflammation following demyelination, and damage to mitochondria. This is a particularly important area of research, because increased understanding of the molecular mechanisms behind axonal damage may lead to new treatment strategies for protecting against nerve damage in MS.
How is myelin repair limited in MS?
A number of ongoing research efforts seek to determine why normal myelin formation and repair (via oligodendrocytes) fails to occur in MS. Studies have examined deficits in signaling between damaged axons and oligodendrocytes, defects in cells that develop into oligodendrocytes, and defects in regulatory molecules that guide oligodendrocyte development and function. Other studies have examined the effect of the pro-inflammatory environment in MS on oligodendrocyte myelin repair function.
What is the nature of immune dysfunction in MS?
A large body of research has examined the process of immune dysfunction in MS and has identified a number of different immune cell types that play a role in promoting inflammation in MS, including interleukin-17–producing T-cells, myelin-specific CD8+ T-cells, and natural killer (NKT) T-cells. Other studies have focused on the role of a range of regulatory T-cells (Tregs) in the dysfunctional regulatory environment that characterize autoimmune diseases like MS.
What role do factors including genes, environment, and gender have on immune dysfunction in MS?
Although the etiology of MS remains unclear, a large ongoing research effort seeks to determine the role of factors including genes, environmental triggers, and gender in MS. Evidence from twin studies strongly suggests a genetic component to MS and results from genome-wide studies have linked multiple genetic abnormalities to increased MS susceptibility. Studies of possible environmental triggers for MS have implicated low levels of vitamin D and decreased sunlight exposure in development of MS. A number of studies have examined potential viral triggers in MS (eg, Epstein-Barr virus). However, there have been no definitive results to date from this line of research.