Pınar Şengül

Department of Neuroscience, Health Sciences Institute, Acibadem University,

Istanbul, Türkiye

Correspondence: neuroscientistpinar@gmail.com

*Corresponding Author:  Pınar Şengül, Department of Neuroscience, Health Sciences Institute, Acibadem University,

Istanbul, Türkiye

Received: December 28, 2024 Accepted:  January 25, 2025 Published: January 30, 2025

Citation: Pınar Şengül. DECODING  MULTIPLE SCLEROSIS : HISTORY, EPIDEMIOLOGY, MECHANISMS, THERAPY AND VEGAN DIET  (2025). OLCIAS 2025 (1)

ABSTRACT

This comprehensive review attempts to comprehensively elucidate the complex interactions between demyelination, epigenetic regulation, and the influence of diet on microglia and macrophage polarisation in Multiple sclerosis background. Through meticulous exploration of the mechanistic underpinnings, including autoimmune processes, oxidative stress, and immune cell orchestration in the central nervous system, we aim to provide an understanding Comprehensive coverage of MS pathogenesis. Furthermore, this review discusses therapeutic implications and integrative approaches, providing insights for the management of this multifaceted neurological disorder. A dedicated section is included to delve into the role of Sphingosine-1-phosphate and its significance in the context of MS. Navigating the Complexities of Multiple Sclerosis

Embarking on an adventure through the complex field of multiple sclerosis, this review endeavours to unravel the layers of complexity surrounding a neurological challenge that remains still terrible. At its core, MS manifests as an immune-mediated attack on the integrity of myelin in the Central Nervous System,  This section serves as a gateway to a comprehensive exploration of MS, incorporating its historical journey, epidemiological complexities, and the ever-evolving tapestry of our understanding of its mechanisms. its pathogenesis.

Key words: MS pathogenesis, Central Nervous System, mechanisms.

Historical Context: Revealing the Story Through Time

To truly appreciate the contemporary context of Multiple Sclerosis, a journey into its historical origins reveals a fascinating story, characterised by developments in diagnostic paradigms, treatment efforts, and the  resilience of scientific research have shaped our quest for understanding.

Early observations

Centuries old medical manuscripts, such as the works of Jean-Martin Charcot in the 19th century, offer some of the earliest systematic observations of MS-like symptoms, (Charcot, J., 1877). The identification and understanding of multiple sclerosis as a distinct neurological disorder developed later, with contributions from Charcot's students andcontemporaries, such as Jean-Antoine Villemin, Pierre Marie, and others, (Pesapane, F., Marcelli, S., Nazzaro, G. Hieronymi Fracastorii, 2015 ; Murray T. J., 2009). They played key roles in defining the clinical and pathological characteristics of MS in the late 19th and early 20th centuries.

These early records describe the clinical manifestations and attempts to classify the disorder, laying the foundation for subsequent research.

Diagnostic Evolution

The 20th century saw significant advances in diagnostics, with the advent of technologies such as lumbar puncture to analyse cerebrospinal fluid,(Gomes H. R., 2022).

The advent of magnetic resonance imaging in the 1980s revolutionised MS diagnosis, allowing visualisation of demyelinating lesions in the central nervous system with unprecedented clarity, (Chung et al, 2020).

Treatment milestones

Historical treatment interventions have been primarily palliative, with limited impact on the course of the disease. The late 20th century marked a paradigm shift with the development of the first disease- modifying therapy, interferon beta-1b, which offered a new approach to modulating the immune response and slowing progression of disease, (Gonzalez-Lorenzo et al., 2024).

Scientific Research And Breakthroughs Pioneering

The research in the mid-20th century identified the autoimmune nature of MS, implicating T cells in pathogenesis, (Scolding et al, 2017).

Recent breakthroughs underscore the significance of B cells, paving the way for targeted therapies like rituximab and ocrelizumab, (Dubey et al.2017). These advancements showcase the dynamic evolution of scientific understanding in the realm of multiple sclerosis. Ocrelizumab, an effective medication for MS, reduces the likelihood of relapses by 46%and disability worsening by 40% when compared to an alternative treatment known as interferon beta 1a. In certain cases, rituximab, a comparable medication, may be employed as an alternative to ocrelizumab, (Negron et al, 2019; Roos et al., 2023).

Mosaic of Knowledge

The Genetics Society continues to shed light on the genetic underpinnings of MS, (Cooper et al., 1998), adding to our new understanding. As we leaf through the historical tapestry of Multiple Sclerosis, it becomes clear that the combination of centuries of observations, diagnostic breakthroughs, treatment innovations and tireless scientific research have created a complex mosaic that informs our current understanding of this complex disorder.

Epidemiology: Decoding Geographic and Demographic Patterns

A comprehensive understanding of multiple sclerosis requires an in-depth exploration of its epidemiological context. Beyond mere statistics, we scrutinise real-world data to elucidate the geographic and demographic patterns that contribute to the complex formation of MS prevalence and incidence . These patterns, which include regional nuances, age-specific vulnerabilities, and gender disparities, form indispensable threads in the fabric of our understanding, providing a nuanced portrait of the global impact of this neurological conundrum.

Geographic Variations

High Incidence Areas: MS exhibits notable geographic variations, with higher prevalence observed in certain areas, such as Northern Europe, North America and some parts of Australia. These common patterns have prompted investigations into specific environmental factors and genetic predispositions in these regions. The International Multiple Sclerosis Federation reports that about 2.8 million people worldwide have MS, and the numbers have been increasing since 2013. This affects young adults aged 20 to 40 and puts a strain on society due to lost productivity, along with costs for medications, caregivers, and healthcare, (Wallin et al., 2016; Qian et al., 2023).

Latitudinal gradient: The latitudinal gradient hypothesis posits a correlation between the prevalence of multiple sclerosis and the distancefrom the equator, with a higher incidence observed in populations residing farther from the equator, implicating environmental factors such as exposure to sunlight and subsequent variations in vitamin D levels. This underscores the significance of the Vitamin D hypothesis, which suggests that the latitudinal gradient of MS risk is predominantly influenced by early-life environmental exposures, emphasising the importance ofsufficient vitamin D production, starting from in utero and birth     and continuing throughout life, especially in females, as a key factor in mitigating MS risk, (Sabel et al., 2021; Simpson et al., 2019).

Vulnerability by age: MS typically manifests in young adulthood, peak onset between ages 20 and 40, (Habbestad et al. 2023).

Demographic Dynamics

MS is recognised as a distinct demographic entity. Gender disparity: Notably, MS exhibits a clear gender bias, with a higher incidence in women. The reasons for this sex disparity are still being investigated, implicating hormonal, genetic and immunological factors in the complex interplay of MS pathogenesis.

Environmental and genetic factors

Environmental triggers: Studies explore environmental factors, including viral infections, vitamin D levels and smoking, as potential triggers or triggers causes MS risk. These factors, interacting with genetic susceptibility, add complexity to the understanding of MS epidemiology.

Genetic predisposition: Genome-wide association studies have identified atr number of genetic variants associated with MS susceptibility, (Hittle et al.,2023; Al-Abdullah & Siddiqui, 2018).

In unpacking the epidemiological tapestry of MS, integrating real-world data on geographic and demographic patterns will enrich our understanding. This nuanced approach allows for more precise delineation of risk factors, contributes to targeted interventions, improves patient care, and advances our collective understanding of this neurological mystery.

Economic and Social Impact: Beyond the Clinical Manifestations Going beyond the statistical manifestations, a closer examination reveals the profound social and economic consequences of Multiple Sclerosis. The economic burden, health care challenges, and widespread impact on quality of life serve as a profound reminder of the urgent need to decipher the complexity of demyelinating, epigenetic modifications and the influence of diet on modulating immune responses in MS.

Economic burden

Direct and indirect costs: MS imposes a significant economic burden on individuals, the health care system, and society at large. Direct costs include medical costs, including diagnostic procedures, medications, and rehabilitation, (Khakban et al., 2023). Indirect costs arise from reduced productivity due to disability, early retirement and the need for careassistance, (Bebo et al. 2022). Treatment costs: The evolving landscape of MS therapies, including disease-modifying drugs and rehabilitation interventions, contribute significantly on health care costs, (Kobelt et al.,2006). Access to these treatments and their applicability are important considerations in addressing MS- related healthcare challenges, (Edinger & Habibi, 2024; Sippel et al., 2021).

The need for multidisciplinary care: The multifaceted nature of MS requires comprehensive and multidisciplinary care. This includes neurologists, physical therapists, occupational therapists, and mental health specialists, contributing to the complexity of healthcare management and resource allocation, (Feys et al., 2016 ; Wallin et al., 2015).

Quality of life implications

Physical and psychological impacts: MS substantially impacts both physical and psychological well-being, contributing to fatigue, compromised mobility, and cognitive dysfunction. Psychiatric manifestations, including depression, anxiety, bipolar disorder, and psychotic symptoms, further complicate the illness and diminish the overall quality of life. Cognitive changes, affecting processing speed, attention, memory, and language, are prevalent in MS patients, (Chwastiak & Ehde, 2007; Silveira et al., 2019). Social participation: Challenges related to MS can limit socialparticipation, contributing to feelings of isolation. Social structures and supportive communities play an important role in mitigating these impacts and promoting a more inclusive environment, (Hosseini & Etemadifar, 2022; Latinsky- Ortiz & Strober, 2022).

Research Focus Areas

Myelination: Investigation of the mechanisms of demyelination is central to understanding the progression of MS. Research efforts are focused on identifying targets for neuroprotective therapies that preserve myelin integrity. These interventions encompass immunomodulation, promoting cell viability, preserving neuron quantity and integrity, protecting myelin, reducing oxidative stress, and stimulating regenerative processes. The methodology involves a meticulous search of biomedical databases, screening criteria, and assessing the risk of bias in included studies. The results reveal a predominance of preclinical animal studies, notably using cuprizone for demyelination induction. Most clinical trials are in phase II, emphasising the ongoing need for research in regenerative therapies for MS, (Allanach et al., 2022; Harlow et al., 2015; Villoslada, 2016). Epigenetic Modifications: Epigenetic modifications, in influencing gene expression without altering the underlying DNA sequence, are emerging as key factors in MS pathogenesis. Elucidating these adjustments holds promise for developing targeted interventions. Epigenetic modifications, including DNA methylation and miRNA profiles, play a pivotal role in multiple sclerosis pathogenesis. These changes, observed in various tissues such as blood, cerebrospinal fluid, and brain, offer insights into disease susceptibility, progression, and potential biomarkers, paving the way for targeted therapeutic interventions and a deeper understanding of the complex interplay between genetics and the environment in MS, (Gacias & Casaccia, 2014; Hasan & Afzal, 2019; Zhou et al., 2014).

Influence of diet on immune response: The complex interaction between dietary influence and immune response is an active area of research. Exploring the role of nutrition in regulating the immune system providesinsight into potential lifestyle interventions for MS. The immune system, comprising innate and adaptive responses, involves various cell types, including phagocytes, dendritic cells, eosinophils, neutrophils, mast cells, cytotoxic T cells (T8), and T4 helper cells (T4). T cells, specifically Th1, Th2, and Th17 subtypes, play distinct roles in responding to pathogens, producing cytokines such as Interferon γ (IFNγ) and interleukins (ILs).

Regulatory T cells contribute to immune response modulation, while B lymphocytes synthesis antibodies to counter antigens. The inflammatory response, mediated by cytokines, prostaglandins, and complements, is influenced by specific nutrients, including vitamins (A, B1, B2, B3, B12, C, D), minerals (Zinc, Selenium), amino acids (arginine, tryptophan), and fatty acids. Understanding the impact of these nutrients on immuneprocesses opens avenues for potential dietary interventions in immune- related conditions like multiple sclerosis, (Noor et al., 2021; Munteanu & Schwartz, 2022).

Vegan Influence

A vegan diet, characterised by the exclusion of all animal-derived products and an emphasis on plant-based foods such as fruits, vegetables, grains, legumes, nuts, and seeds, has gained attention for its potential benefits on multiple fronts, (Appleby & Key, 2015). People choose veganism for various reasons, including ethical concerns about animal welfare, (Singer, 2020), health considerations for reducing the risk of chronic diseases like heart disease, (Dybvik et al., 2023) and certain cancers (Huang et al., 2012) and environmental worries related to reducing greenhouse gas emissions, land and water use, and deforestation associated with animal agriculture.

Studies have shown that vegan diets offer a rich array of nutrients, including vitamins, minerals, phytochemicals, and fiber, which contribute to potential health benefits and impact immune regulation. Vitamins play critical roles in immune cell differentiation, proliferation, and cytokine production, influencing the balance between pro-inflammatory and anti- inflammatory responses. For example, vitamin D deficiency has been linked to increased susceptibility to autoimmune diseases like MS, while antioxidants like vitamin C help mitigate oxidative stress, dampening inflammatory cascades implicated in MS pathogenesis. Weikert et al. (2020) support the fact that vegans have higher amounts of vitamin C intake compared to omnivores, Despite prevailing assumptions regarding the risk of vitamin D deficiency in vegan diets, recent research challenges this notion. Chan et al. (2019) conducted a comprehensive study examining serum 25- hydroxyvitamin D [s25(OH)D] concentrations across different dietary groups, including vegans, partial vegetarians, and nonvegetarians. Contrary to popular belief, their findings revealed no significant difference in s25(OH)D levels based on dietary habits. This study, drawing from a diverse sample of participants from the Adventist Health Study-2, underscores the importance of revisiting preconceived notions about veganism and vitamin D status. Moreover, it highlights the multifaceted factors influencing s25(OH)D concentrations, such as vitamin D supplementation, skin pigmentation, and sun exposure intensity. Thus, while the global discourse often perpetuates concerns about vitamin Dadequacy in vegan diets, empirical evidence suggests a more nuanced understanding, where dietary factors alone may not dictate vitamin D status.

Moreover, plant-derived phytochemicals exhibit various immunomodulatory effects, from anti- inflammatory and antioxidant properties to the modulation of intracellular signalling pathways.

Flavonoids, for instance, have been shown to inhibit pro-inflammatory mediators, attenuating neuroinflammation in conditions like MS, (Rodríguez-Negrete,et al., 2024).

Furthermore, Sengul (2022) and Sengul & Kasten (2018) asserted that vegan diet adherents have been associated with better verbal learning memory capacities and higher life satisfaction compared to omnivorous diet adherents.This suggests that the benefits of veganism extend beyond health and environmental considerations to potential cognitive and psychological advantages.

Overall, the benefits of veganism suggest a holistic approach to well-being through dietary choices.

Emphasising Urgency: Decoding Molecular Symphonies

In the intricate landscape of multiple sclerosis, the urgency to unravel the complex interplay among demyelination, epigenetic modifications, and nutritional factors intensifies alongside burgeoning scientific evidence. This urgency is underscored by the diverse clinical manifestations of MS, including sensory loss, motor symptoms, autonomic dysfunction, and cognitive difficulties. MS, a leading cause of neurological disabilities, exhibits various clinical courses, such as relapsing– remitting, secondary progressive, primary progressive, and clinically isolated syndrome. Both genetic and environmental factors contribute to MS, involving major histocompatibility complex (MHC) haplotypes, cytokine alleles, infections, sunlight exposure, and smoking. Notably, intricate interactions between genetic variants and environmental factors modulate the risk of MS, particularly through pathways like N-glycosylation and vitamin D metabolism. Despite ongoing research, MS lacks curative medications, emphasising the crucial role of redox processes in its initiation and progression. Autoreactive T cells, integral to MS pathogenesis, orchestrate autoimmune responses against the central nervous system (CNS), highlighting the need for a comprehensive understanding of the molecularsymphony directing MS pathogenesis. (Miljković & Spasojević, 2013; Mansilla et al., 2021).

Oligodendrocytes and Myelin Dynamics: Delve deeper into the molecular complexities involved in understanding the role of oligodendrocytes, the primary producers of myelin.

Research is shedding light on the mechanisms that govern myelin maintenance and repair, factors that are important in understanding the impact of demyelination in MS, (Lucchinetti et al., 1996).

Progression of MS

Dietary Influences and Immune Responses

Gut-Brain Axis: Scientific attention has focused on the Gut-Brain axis, where dietary influences intersect with immune responses. Understanding  how the microbiome regulates the immune system will shed light on potential treatments. Probiotics, prebiotics and dietary interventions are emerging as focal points in this complex relationship. In the intricate realm of Major Depressive Disorder (MDD), the interplay between dietary influences and immune responses aligns with the emerging significance of the Gut-Brain axis. As scientific focus intensifies on how the microbiome modulates the immune system, potential treatments for MDD come into view. The bidirectional communication between the gut microbiome, immune system, and brain forms a complex axis sensitive to stress, crucial in understanding stress-related disorders like MDD. Exploring this axis reveals promising avenues, including the potential benefits of probiotics and prebiotics in alleviating depressive symptoms, highlighting the multifaceted nature of MDD pathogenesis and the promising role of dietary interventions in mental health, (Foster et al., 2021).

Immunometabolism: Diving into immunometabolism, we explore how dietary components impact immune cell function. Elucidation of the metabolic pathways in the generation of immune responses will further our understanding, paving the way for targeted dietary interventions in the management of MS. In the realm of immunometabolism, the integration of nutritional metabolomics becomes a pivotal tool for unraveling the impact of dietary components on immune cell function. Advanced technologies and computational tools, including high-throughput metabolomics techniques, allow the identification of diverse biomarkers reflecting nutritional intake. Metabolomics, with its capacity to measure small molecule metabolites in biological samples, offers a real-time snapshot of an individual's metabolic status, influenced by age, diseases, environment,lifestyle, and nutrition. This precision nutrition approach, integrating -omics techniques, particularly metabolomics, aligns with the emerging era of systems epidemiology.

The comprehensive profiling of the endogenous and food metabolome not only helps identify dietary biomarkersobjectively but also unravels the molecular mechanisms linking diet to health and disease. As we delve into the metabolic pathways shaping immune responses, the marriage of immunometabolism and nutritional metabolomics lays the foundation for targeted dietary interventions, offering a nuanced approach in the management of conditions likeMultiple Sclerosis, (Guasch-Ferré et al., 2018).

Therapeutic Innovations Neuroprotective Strategies: Urgency in MS research is driving the discovery of neuroprotective strategies. From recombinant therapies to new approaches targeting the amyotrophic pathway, the search for advanced treatments aims to halt diseaseprogression and enhance neurological recovery, (Talanki Manjunatha et al. 2022; Maghzi,et al., 2013). Neuroprotective approaches encompass a spectrum of interventions, ranging from mimicking essential CNS processes (e.g., trophic factor signaling, myelin formation) to regenerativetherapies such as stem cells, which release trophic factors, suppress local inflammation, and create a supportive microenvironment for neuronal survival. Additionally, secondary neuroprotection involves reducing insults, like restoring blood supply in ischemia or employing immunomodulatory drugs (e.g., glatiramer acetate, fingolimod, dimethyl- fumarate, or laquinimod) to decrease CNS inflammation in MS. Thetrophic factor strategy, rooted in evolutionary development, activates signaling pathways (e.g., PI3K, MAPKK, NFKB) that halt apoptosis, promote cell survival, and induce beneficial effects such as reducing oxidative stress. While past trials with trophic factors faced challenges, including pharmacological limitations and trial design issues, the core role of trophic factor pathways in promoting neuronal and oligodendrocyte survival highlights their potential as therapeutic targets for preventing permanent CNS damage in MS, (Villoslada, 2016).

Precision medicine:

Advances in gene and biomarker discovery contribute to the emergence of precision medicine. Tailoring therapeutic interventions based on the genetic and molecular characteristics of each individual represents a paradigm shift in MS management, consistent with the urgency of delivering effective treatments. Recent studies emphasise the potential ofbiomarkers in Multiple Sclerosis, including CSF chitinase 3-like 1 and neurofilament light subunit for prognosis in clinically isolated syndrome,and CD62L and CSF IgM oligoclonal bands as candidates for risk stratification in MS patients treated with natalizumab. These biomarkers, alongside evolving MRI techniques, contribute to the ongoingadvancement of precision medicine in the diagnosis, prognosis, and treatment response of MS. (Chitnis & Prat, 2020; Comabella et al., 2016).

Mechanism of myelin destruction

In this important section, our exploration into the complex landscape of myelin breakdown unfolds with meticulous scrutiny, aimed at unraveling the enigmatic mechanisms that orchestrate this complex phenomenon.

Delving into the microcosm of the Central Nervous System, we explore a fascinating trio of factors: autoimmune processes, oxidative stress, and the activity of immune cells.

Autoimmune Processes: Revealing the Molecular Ballet The intricate dance of autoimmune processes is unveiled as we decipher the molecular ballet behind myelin breakdown. This exploration extends beyond mere recognition, delving into the complexities of molecular mimicry, epitope spreading, and the immune domino effect, ultimately leading to a misdirected attack on myelin by the immune system.

Autoimmunity can manifest following infections with viruses, bacteria, or parasites, with reported autoantibodies and persistent cell-mediatedimmune reactions. In conditions like disseminated postinfectious encephalomyelitis and measles encephalitis, cell-mediated immune reactions against autoantigens have been documented, suggesting potentialparallels to the induction of experimental autoimmune encephalomyelitis(EAE) in rodents. Viral infections, such as measles or Semliki Forest virus, may enhance susceptibility to EAE, possibly by priming myelin-reactive T  cells through virus-induced damage to CNS tissue, exposure of cellular antigens, and changes in the blood-brain barrier integrity, allowing entry ofantigen-specific CD4+ T cells into the CNS, (Welsh & Young, 2008).

Molecular Mimicry

Recent studies illuminate the concept of molecular mimicry, where structural resemblances between myelin proteins and foreign antigens prompt misguided immune responses. This occurrence breaches immune tolerance, creating a scenario conducive to an autoimmune assault on myelin. The term "molecular mimicry" was coined by Damian in 1964, describing shared antigens between host and parasite. If an infectiousagent exhibits an antigenic determinant akin to a host molecule, it may trigger an immune response that inadvertently attacks the host antigen due to the degeneracy of the T-cell repertoire. Several instances of molecular mimicry in autoimmune diseases of the CNS include T cells reacting to viral proteins that cross-react with corneal antigens, antibodies raised against Campylobacter jejuni in Guillian–Barre syndrome cross-reacting with human gangliosides, and T cells from multiple sclerosis patientsrecognising myelin basic protein (MBP) and reacting with peptides from Epstein Barr virus, influenza type A, and human papillomavirus, (Welsh & Young, 2008 ; Levin et al., 2002).

Epitope spreading

The immune system's step-by-step expansion of its attack to involve more myelin targets, known as epitope spreading, adds complexity to autoimmune diseases. This continuous broadening of the immune response over time worsens demyelination. Recent studies, especially in multiple sclerosis and its experimental model (EAE), suggest that chronicprogression in autoimmune diseases is closely linked to epitope spreading.

This involves a constant acquisition of new self-recognition events, resulting in a cascade of inflammatory T cell reactions targeting sequential self-antigens. Notably, as epitope spreading occurs, the original immune response linked to disease onset regresses. This suggests a changing T cell response during autoimmune disease progression. This evolving perspective highlights the ongoing nature of self-recognition in autoimmune diseases, viewed as a "daily changing target, (Miller et al.,2001; Tuohy & Kinkel, 2000).

CONCLUSION

In summary, this review explores the complex connections between demyelination, epigenetics, and diet in influencing microglia and macrophage polarisation in multiple sclerosis. It covers mechanistic aspects, including autoimmune processes and immune cell orchestration, providing a comprehensive understanding of MS pathogenesis. The reviewdiscusses therapeutic implications, integrative approaches, historical developments, epidemiological patterns, and the economic impact of MS, emphasising the urgency to unravel its complexity. It highlights the need todecode the molecular intricacies and the dance causing myelin breakdown, marking a pivotal chapter in ongoing MS research.

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