Immune Wars: The Past, Present, and Future of Multiple Sclerosis Research
Daniel Wunschel
Illustrations by Abigail Schoenecker
Episode I: The Phantom Disorder
For most, hopping out of bed and brushing your teeth are tasks done with ease. Once you decide to get up, your muscles spring into action and you find yourself standing in no time. In the bathroom, you quickly squeeze toothpaste on your brush and get to cleaning your teeth. Now imagine yourself back in bed: despite your best efforts, your muscles can not enact what your brain asks them to do. Once you finally make it to the bathroom, your shaking hands struggle to remove the cap and squeeze the tube before the paste misses the brush and falls into the sink. No matter how hard you try, the movements of your muscles never match what your brain is dictating. For people living with multiple sclerosis (MS), daily tasks — such as getting out of bed and brushing your teeth — can become overwhelmingly difficult. Multiple sclerosis is the most common neurological disease in people of ages 20 to 40, and the disease typically presents through muscle weakness, visual impairment, and a loss of coordination and control over bodily movements [1, 2]. MS can vary over a person’s lifetime, causing those affected to experience phases of relapse and recovery [1]. While we know how MS manifests, the disorder remains a neurological puzzle with many missing pieces [3]. Many of these missing pieces rely on understanding the biology behind the cause of the disease and its progression [3]. Although the specific cause of MS is unknown, some associated factors have been identified, including low levels of vitamin D, tobacco smoking, and certain viruses [2, 4, 5]. Of these potential causes, the Epstein-Barr virus (EBV) has drawn significant interest amongst researchers [6, 7]. EBV is the most common cause of mononucleosis — commonly known as ‘mono’ — and is associated with a 32-fold increased risk of developing MS [6, 7]. While nearly everyone with MS is infected with EBV, there are many more individuals infected with EBV that do not develop MS, creating a cloud of uncertainty surrounding the relationship between EBV and MS [7]. Nonetheless, belief in the connection between EBV and MS has guided research for decades [8, 9].
Episode II: Attack of the T-Cells
Despite the uncertainty surrounding the causes of MS, we know MS is an autoimmune disease in which the immune system attacks its own body’s tissues [10, 11, 12]. Normally, the immune system targets disease-causing bacteria or viruses called pathogens, but a malfunctioning immune system may also mistakenly attack healthy cells or tissues like myelin [13, 14, 15]. Dysfunctional immune activation sometimes causes immune cells to migrate into the brain and inadvertently target oligodendrocytes — cells that produce insulation called myelin — as well as myelin itself [14, 16]. Myelin is a fat and protein-rich insulation that wraps around the axons of neurons in the brain, forming a layer called the myelin sheath [17, 18]. Like the coating on electrical wires protecting the transmission of electric current, myelin helps to transmit signals between neurons [17, 19]. The loss of myelin, called demyelination, is followed by axon degradation, which diminishes the ability of neurons to transmit crucial signals [17]. In addition, the destruction of oligodendrocytes reduces the brain’s ability to produce new insulation [17]. While the cause of the initial immune response in MS which damages oligodendrocytes and myelin is unknown, demyelination is believed to be perpetuated by the dysfunctional activation of the immune system, leading to neuroinflammation [20, 21].
Neuroinflammation is the activation of the brain’s immune system in response to infection or injuries [22]. In MS, neuroinflammation becomes harmful to the body when T-cells — a type of immune cell that normally kills infected cells — go into overdrive and attack healthy tissue [23, 24, 25]. In conjunction with neuroinflammation, immune attacks on oligodendrocytes and myelin result in the formation of lesions, or localized damage to the brain or spinal cord [26, 27]. Depending on the site and severity of lesions, people with MS experience different symptoms [1]. Lesions along the optic nerve cause visual impairment, a common symptom of early-stage MS. [1, 17, 28]. Lesions on muscle-stimulating nerve fibers may cause difficulty walking by preventing muscles from receiving signals from the central nervous system, leading to reduced control over body movements [29, 30, 31].
Episode III: Revenge of the Statistics
Research into EBV as a potential causal factor of MS stems from a seemingly monumental statistic: almost everyone diagnosed with MS tests positive for EBV [1, 7, 32]. The overlap in EBV and MS has fueled research into the potential causal link between MS and EBV, in which EBV possibly triggers the dysfunctional immune response and associated neuroinflammation in MS [33, 34]. Active EBV infections are thought to be characterized by an increase in the number and reactivity of EBV-attacking T-cells, which contributes to neuroinflammation [33, 35]. Another way EBV may trigger neuroinflammation is by mimicking myelin proteins, which hold together the layers of myelin sheaths [34, 36, 37]. When EBV infects the body, the immune system responds by sending T-cells to attack foreign pathogens [34, 36]. When attempting to kill EBV, the virus’s structural resemblance to myelin may cause the immune system to attack myelin proteins instead, leading to further neuroinflammation [6, 34, 38]. Additionally, the risk of MS increases with the degree of EBV infection, suggesting a connection between severity of EBV and MS symptoms [34, 35, 39].
Despite a multitude of discoveries suggesting an EBV-MS connection, we cannot conclude that EBV alone causes the development of the autoimmune disorder [6, 33, 40]. As is the case with many other viruses, EBV may remain in the body in a latent state even after an infected individual has recovered from their initial symptoms [41, 42]. Since nearly everyone with MS has EBV, one might think that EBV causes MS, however, this connection has not been established [44, 45]. People who are diagnosed with MS also test positive for hundreds of other viruses, suggesting that viral presence in individuals with MS is not unique to EBV [46]. Many people with MS present with general autoimmune dysfunction and receive autoimmune diagnoses outside of MS [47, 48, 49]. For example, a number of people who test positive for MS and EBV are also diagnosed with inflammatory bowel disease — an autoimmune disorder affecting the digestive tract — or Hashimoto’s disease — an autoimmune disease that affects the thyroid [50, 51, 52]. While EBV is not a definitive cause of MS, research into EBV’s connection to MS has helped expand our understanding of the role of neuroinflammation in people living with MS [6, 34].
Episode IV: A Neurological Hope
While the connections between EBV and MS are unclear, investigations continue to explore the relationship between the immune and nervous systems, primarily focusing on the role of neuroinflammation in the immune system’s response [8, 53, 54]. By improving our understanding of the connection between MS and neuroimmunology — the combined study of neuroscience and the immune system — personalized treatments can be built for people living with MS [55]. In order to improve the efficacy of MS treatments and construct individualized treatment plans, it’s crucial to map gene activity and examine what proteins are implicated in the development of MS [56, 57, 58]. Mapping genes and proteins involved in MS can reveal characteristics unique to each person living with the disease and be used to develop individualized drug therapy treatments [59, 60, 61, 62]. One leading MS treatment strategy involves modifying genes involved in the immune response of people with MS, in order to dampen autoimmune effects experienced by people living with the disease [62]. Novel techniques, such as RNA sequencing, provide a detailed picture of the biological processes altered by MS, allowing us to further understand the contributing factors to disease development by locating and targeting related genes and proteins in treatment [63, 64, 65].
In recent years, additional treatment methods for MS that directly target components of neuroinflammation have improved the quality of life for people with the disease [9, 66]. Novel methods include disease-modifying treatments (DMTs), which reduce the immune response in the brain and aim to limit demyelination and disease progression as a whole [67]. Currently, 20 DMTs are approved for MS in the United States, each one targeting a different component of the overactive immune system [42, 68]. For example, one type of DMT, Fingolimod, reduces the ability of immune cells to engage with the CNS by preventing the circulation of lymphocytes: immune cells made in bone marrow, including T-cells [68, 69, 70]. Fingolimod is also suspected to lessen attacks on myelin, which in turn decreases neuroinflammation by reducing the amount of inflammation-promoting molecules [42, 68, 71]. In clinical trials, Fingolimod has successfully reduced relapse rates and significantly decreased disability progression, lesion activity, and brain volume loss in people with MS [72].
In addition to DMTs, medications that encourage remyelination — the process of forming new myelin sheaths around axons — are promising [73, 74, 75]. Some of these medications enhance the differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes [76]. One way medications do this is by altering the local environment to become more hospitable to OPCs created within the brain [76]. OPCs are prevalent in MS lesions, but the microenvironments of lesions prevent OPCs from becoming oligodendrocytes [42, 77]. Medications that encourage the transformation of OPCs into oligodendrocytes aid in the formation of new myelin, which prevents axon degradation and improves MS symptoms [76, 78]. Two FDA-approved drugs that have improved remyelination are miconazole and clobetasol [79]. Miconazole, an antifungal medication, encourages the development of oligodendrocytes by promoting OPC differentiation into oligodendrocytes, aiding remyelination without causing damage to the immune system [79, 80]. Clobetasol, a widely-used eczema medication, is an immunosuppressant that also helps with remyelination. [79, 80]. Clobetasol increases the differentiation of oligodendrocytes in lesions and promotes the signaling of anti-inflammatory molecules, reducing inflammation and promoting remyelination [81]. Drugs with both similar and different mechanisms of action are being developed today [82].
Episode V: The Clinical Trials Strike Back
While it may seem that time spent looking into a connection between EBV and MS was wasted due to no definitive links between the virus and the disease being uncovered, the treatments of today and tomorrow are founded on information uncovered due to this research [9, 55, 56]. Neuroinflammation in MS may not originate from EBV, but EBV is still thought to play an important role in the disease [7, 8, 9]. As we continue to search for the missing pieces of the MS puzzle, several ongoing clinical trials that focus on neuroinflammatory correlates of MS hold promise [82]. Clinical trials that target dysfunction in myelination and immune suppression may improve the quality of life for people with MS. Over the next few years, several clinical trials are expected to reach completion, adding to the arsenal of treatments against MS [82]. By aiming to slow down disease progression and improve shortcomings of current treatments, clinical trials can make common tasks like brushing your teeth and getting out of bed more achievable for people with multiple sclerosis.
Episode VI: Return of the References
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