Translational Neuroimmunology, Volume 8: Multiple Sclerosis

By Nima Rezaei and Niloufar Yazdanpanah

Translational Neuroimmunology: Multiple Sclerosis provides an update on bench to bedside studies on Multiple Sclerosis as an autoimmune disease. Divided into twelve chapters, the book begins with an in-depth introduction to the neuroimmunology and immunopathology of multiple sclerosis. Sections also provide content on genetics and epigenetics, the microbiome, diagnosis, and treatment of multiple sclerosis. Finally, various precision treatments are covered. All information is presented in an accessible, practical format, making this volume a valuable resource for immunologists, neurologists and researchers in translational biomedical research.

• Provides an introduction on multiple sclerosis as an autoimmune disease, from bench to bedside
• Encourages the development of immunologic approaches to analyze the interaction and specific properties of nervous tissue elements during development and disease
• Focuses on understanding and therapeutically manipulating immunological responses to injury, degeneration and autoimmunity in the central nervous system
• Shows the changes in relevant immune and inflammatory reactions at the cellular and molecular level during the development of nervous system diseases

• Language: English
• Publisher: Academic Press
• Release date: Jun 16, 2023
• ISBN: 9780443185793

Book preview

Chapter 1: Introduction to the neuroimmunology of multiple sclerosis

Niloufar Yazdanpanaha,b,d; Nima Rezaeib,c,d,⁎    a School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

b Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

c Department of Immunology, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran

d Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

* Corresponding author

Abstract

Multiple sclerosis (MS), known as the most common demyelinating disease in high-income regions, is a chronic disabling disease with an autoimmune pathology, mainly affecting the central nervous system (CNS). In 1868, for the first time, Jean-Martin Charcot described the features of MS as la sclérose en plaques. MS physiopathology is a complex picture of interactions between various environmental and genetic factors. Therefore, it is necessary to reap the benefits of interdisciplinary approaches both in basic science studies and in the clinic. Translational research is of utmost importance in complex diseases like MS to help apply preclinical and laboratory findings in clinical practice.

Keywords

Multiple Sclerosis; MS; Neuroimmunology; Translational research; Treatment; Diagnosis

1: Introduction

Multiple sclerosis (MS), known as the most common demyelinating disease in high-income regions, is a chronic disabling disease with an autoimmune pathology, mainly affecting the central nervous system (CNS). According to the MS International Federation (MSIF), around 2.8 million people are living with MS worldwide [1]. The highest and lowest prevalence of MS has been reported in North America and sub-Saharan Africa, respectively. The considerable difference in the reported prevalence of MS in different regions could be attributed to multiple factors, including the lack of proper registries or reporting systems in some regions, and to the fact that in countries with undeveloped health-care facilities, patients might die due to various etiologies, infections in particular, before manifesting MS symptoms [2]. Currently, the available statistics report a median age of 23–24 years as the onset of initial symptoms. MS is more common in women, with a female-to-male prevalence ratio of 3:2 [1,2].

MS physiopathology presents a complex picture of the interactions between various environmental and genetic factors. Different environmental factors have been known to have established links with MS, including vitamin D levels, obesity, ultraviolet B (UVB) radiation, smoking, and some infections such as Epstein–Barr virus infection [3]. On the other hand, a variety of genetic factors, including MHC alleles (HLA-DRB1*15:01) and non-MHC genes, have strong associations with MS susceptibility and physiopathology; well-known non-MHC genes include TNFRSF6B, RPS6KB1, SOX8, CXCR5, and NFKB1[4,5]. Genome-wide association studies (GWASs) have been conducted in an attempt to elucidate the role of genetics in MS susceptibility [6]. Many of the identified single nucleotide polymorphisms (SNPs) were located close to the genes with an identified immune function but in dominantly regulatory regions than in coding regions. Functional variants were reported within regions such as IL7R, IL2RA, TNFR1, BAFF, and CYP2R1 [7–10].

In 1868, for the first time, Jean-Martin Charcot described the features of MS as la sclérose en plaques. His main achievement was distinguishing between the tremor seen in paralysis agitans (which was later known as Parkinson’s disease) and the tremor in MS [11]. Thereafter, the three well-known fundamental indicators of MS (intention tremor, nystagmus, and scanning or staccato speech) are named Charcot’s triad.

MS presents with different symptoms, including fatigue, mood instabilities and depression, cognitive problems, loss of sensation, vision problems, limb weakness or incoordination, abnormalities in gait, impaired cranial nerve function, and, in some cases, bowel, bladder, and sexual dysfunction [12–16].

2: Neuroimmunopathology

MS has been known to have a complicated pathophysiology, in which different immunological and neurological components are involved. Although MS pathophysiology cannot be attributed to a single component, T-helper type 1 (Th1) cells are recognized as the main instigator, to some extent. Different findings support the prominent role of Th1 cells in MS, for instance, a considerably elevated proportion of T cells that express the characteristic Th1 chemokine receptor pattern (CXCR3/CCR5) in MS patients, besides reports about the increased expression of the related chemokines ligand for CXCR3/CCR5 by MS plaques [17,18]. In addition, a bias toward Th1-related cytokines that resulted from the CSF analysis of cytokine mRNA in MS patients and the detection of proinflammatory cytokines, including TNF-α and IL-12, in MS plaques, further support the effect of Th1 [18–20]. Moreover, observations indicating that, in MS patients, secretion of cytokines was more similar to a Th1-mediated response also strengthen the role of Th1 cells [21,22]. Th17 cells that are activated in the periphery bind to the adhesion molecules and chemokine receptors expressed by the choroid plexus cells [23], therefore passing the blood–brain barrier (BBB) and stimulating a proinflammatory response [23,24]. It should be noted that by secreting IL-17 and IL-22, Th17 is capable of increasing the permeability of the BBB, which, in turn, enables the infiltration of autoreactive Th17, IFN-γ-secreting Th1, cytotoxic CD8+ cells, B cells, and plasma cells [25].

B cells are also involved in the neuroimmunopathology of MS. A considerable body of evidence supports the role of B cells in MS. Enhanced intrathecal synthesis of immunoglobulin G (IgG) and the presence of oligoclonal bands in the cerebrospinal fluid (CSF) samples of MS patients point to the contribution of B cells to MS physiopathology [26]. Besides, the role of EBV infection in susceptibility to MS, the detection of B cells infiltrating the meninges, and the formation of ectopic lymphoid follicles further strengthen the role of B cells [27]. In addition, reports indicating the secretion of proinflammatory cytokines, including interleukin-6 (IL-6) by B cells in experimental autoimmune encephalomyelitis (EAE), underpin the effect of B cells in MS physiopathology [26–28].

Infiltration and clonal expansion of B cells have been observed in the meningeal tissue, brain parenchyma, and the CSF of MS patients in different stages of the disease. In SPMS, due to the prolonged inflammatory status, tertiary lymphoid structures are formed in the meningeal tissue, which contains B and T lymphocytes, plasma cells, and follicular dendritic cells [29–31]. In PPMS, there is no organized lymphoid structure and only diffuse meningeal infiltration is evident in its pathology [30,31].

Unlike many antibody-mediated neuroimmunological diseases, such as myasthenia gravis (MG) and neuromyelitis optica spectrum disorder (NMOSD), in which patients who are positive for a specific autoantibody manifest a similar phenotype, in MS, the hypothesis of the presence of specific autoantigens recognized by B cells requires further support, as patients who are positive for a specific antibody do not present with clinical/phenotypic uniformity [32,33]. As the presence of specific autoantigens in MS remains ambiguous, the potential mechanism triggering and regulating B cell activation and maturation remains to be clarified. Further research on the diversity of B cell receptors has revealed that activation and maturation of B cells occur in the cervical lymph nodes; then, the B cells migrate to the CNS [34,35].

On the other hand, it is suggested that the suppressive function of regulatory T cells (Tregs), including FOXP3-expressing CD4+ Tregs and IL-10-producing type 1 Tregs [36,37], is compromised in MS patients; therefore, the overactivity and autoreactivity of immune cells cannot be properly controlled, leading to tissue damage and disease pathology [38]. In the CNS, there is no large repertoire of Tregs; however, variants of HLA-II that are associated with MS are capable of skewing the thymic selection toward such a direction that more Tregs enter the periphery and compromise the autoreactive T cells [37]. In addition, non-HLA genetic factors associated with MS, such as BACH2, could also contribute to impaired Treg function [39,40]. Nevertheless, patients with FOXP3 deficiency (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; IPEX) do not experience CNS-directed autoimmune complications, and, so, it is hypothesized that Treg dysfunction in MS patients could be an acquired process rather than a genetic or primary one [41].

In the early stages of the disease, axons and neurons are protected; nevertheless, as the disease progresses, along with the propagation of demyelinating lesions, edema, neuroinflammation, gliosis, and neuroaxonal loss occur, which are associated with the patient’s disability. The spatiotemporal dissemination of lesions correlates with disease manifestation and type of patient’s disability [42]. For example, a concentration of lesions in the spinothalamic tract or posterior column fibers can lead to an altered sensation, whereas the involvement of the corticospinal tracts is followed by limb weakness and spasticity. Affected spinocerebellar fibers and cerebellar pathways can result in tremor development, gait problems, and incoordination of limbs [43]. Impairment of the cranial nerves occurs following brainstem lesions, whereas bowel and sexual dysfunction and bladder problems, such as neurogenic bladder, occur following the involvement of spinal cord pathways [44]. MS patients may also experience visual loss due to optic neuritis, some neuropsychiatric conditions, and degrees of cognitive problems [42–48]. Brain atrophy and ventricular enlargement are other pathological findings, more common in the advanced stages of the disease.

In brief, different cells and factors contribute to MS pathology and it is not a simple mechanism attributed to a single factor. As the disease develops, the composition of T cell repertoires in the infiltrates remains relatively constant; observations indicate an increase in the proportion of B cells and plasma cells. During the disease course, microglia and macrophages stay chronically activated.

3: Diagnosis

An MS diagnosis is based on objective evidence about inflammatory damage within the CNS, the signs of which are expected to be disseminated across both space and time. Duration of symptoms that last for more than 24 h and at least a 1-month interval between the disease attacks are important features for suspecting MS. Different phenotypes are considered to be the subtypes of multiple sclerosis. The term radiologically isolated syndrome (RIS) is used to describe incidental findings on magnetic resonance imaging (MRI) studies although the patient manifests no signs or symptoms [49]. The term clinically isolated syndrome (CIS) is used when the patient experiences the first episodes of demyelination, which manifest as optic neuritis and cerebellar or brainstem symptoms; this condition is more common in young adults. In CIS, symptoms start by manifesting from a few hours to days and then remain for 24 h (at least) to several weeks (at longest) and gradually disappear; it should be noted that the duration between two attacks is no longer than 30 days [49,50]. The condition in which the patient experiences multiple episodes of the disease flare of symptoms (relapse), followed by a full resolution of the symptoms (remission) in the earlier stages of the disease and an incomplete recovery from the relapses in the advanced stages of the disease, is named relapsing–remitting MS (RRMS) [51]. As the disease progresses, if left untreated, the patient will no longer experience relapses and remissions but will start to develop a progressive neurodegenerative disease, which is strongly linked to prolonged chronic neuroinflammation; this condition is known as secondary progressive MS (SPMS). SPMS is associated with considerably fewer enhanced brain lesions and decreased brain parenchymal volume [51]. Primary progressive MS (PPMS) is a condition in which acute attacks are absent at the onset and in the initial stages of the disease; the patient experiences progressive myelopathy that does not show a proper response to immunotherapeutic interventions [52].

MRI and examination of the patient’s CSF sample are the two main tests for an MS diagnosis. In MRI, due to the impaired function of the BBB, the IV gadolinium contrast enters the CNS, which is indicative of acute inflammation, and is detectable in the early steps of MS lesion formation. Later, the lesions will still be visible as focal areas with hyperenhancement, which are located in periventricular, juxtacortical, infratentorial, and spinal cord lesions. A periventricular dominant distribution of lesions is characteristic of MS. In CSF analysis, mononuclear cell pleocytosis and the presence of oligoclonal bands direct the diagnosis toward MS. Oligoclonal bands and enhanced production of intrathecal IgGs represent the activity of B cells within the CNS. However, this phenomenon is not exclusive to MS and can also occur in some types of CNS infections.

Evaluation of the function of CNS pathways by assessing nerve conduction by evoked potentials and optical coherence tomography (OCT) to examine the patient’s vision are the other tests that could be used for an MS diagnosis.

In addition, it is important to consider the differential diagnoses when performing a workup for MS, particularly in regions with low MS prevalence; neurosarcoidosis, NMOSD, and some infections such as tuberculosis could be more probable. A correct diagnosis is vital as some disease-modifying therapies that are specifically designed for MS may exacerbate the disease. In cases with the onset of the disease’s first manifestation at an older age, it is important to consider vascular diseases that are more prevalent in the elderlies. In patients with systemic signs and symptoms, it is crucial to consider systemic autoimmune/autoinflammatory diseases such as systemic lupus erythematosus (SLE), Behçet’s syndrome, Sjögren’s syndrome, Susac syndrome, and some types of vasculitides. Besides, MS may also occur along with some autoimmune diseases; so, careful examination and consideration of the whole course of the disease and the clinical picture are crucial to making the right diagnosis.

It should be noted that an MS diagnosis is clinical; nevertheless, paraclinical assessments help exclude treatable conditions in differential diagnoses. Antinuclear factor, thyroid function test, and vitamin B12 are necessary for the initial workup. In addition, serology for syphilis and HIV-1 is strongly recommended.

4: Treatment

MS treatment consists of two main parts, namely, symptomatic therapies and disease-modifying therapies. Disease-modifying therapies are specifically designed for MS, whereas symptomatic therapies are not and are useful in alleviating neurological symptoms.

The first approved drugs for MS, which are referred to as disease-modifying therapies, were fingolimod (Gilenya, which influences the migration of immune cells from the lymph nodes by affecting the S1P1 receptor) [53], natalizumab (Tysabri, which targets VLA-4 [α4β7 integrin] on T cells and monocytes that binds to the VCAMs in the endothelial cells in the CNS) [54], and ocrelizumab (Ocrevus, which influences CD20+ B cells) [55,56], which were immunosuppressive agents. Shortly afterward, immunomodulatory agents were introduced, including interferon-beta (IFN-β, which impedes T-lymphocyte adhesion to endothelial cells by engagement to VLA-1 on T cells, inhibits the production of MMPs, interferes with T cell activation, and affects Tregs) [57], glatiramer acetate (Copaxone, which affects cytokine production) [58], and teriflunomide (Aubagio, which is an active derivative of leflunomide that interferes with the proliferation of immune cells by hampering the de novo synthesis of pyrimidine nucleotides) [59]. Later on, immune reconstitution therapies emerged, which have shown great promise for MS treatment as they have led to long-term sustainable remission in the treatment-free periods during the course of the disease. Alemtuzumab (Lemtrada, which targets CD52+ cells) and cladribine (Mavenclad, which is useful for the highly active forms of RRMS) are examples of immune reconstitution therapies [60,61].

MS patients experience a variety of neurological complications. Hence, the importance of symptomatic treatment in the treatment strategy is undeniable, although such treatments might also expose the patients to different adverse effects [62,63]. Anticholinergic drugs ameliorate neurological bladder, and tricyclic antidepressants (TCA) and gabapentin alleviate neuropathic pain. These are examples of symptomatic treatments that could be used in the treatment plan for different diseases. Meanwhile, some symptomatic therapies are exclusively designed and approved for MS, for instance, Sativex for spasticity relief and Fampridine that is useful for improving walking in patients [62,63].

5: Conclusion

Regardless of the remarkable advances made in its diagnosis and treatment, MS remains an unsolved problem for human health. Identification of new biomarkers useful for disease diagnosis, risk stratification, and disease prediction before the onset of symptoms is the main goal of many ongoing studies. Studying the immune-related, neurological, biochemical, and many other factors/cells involved in MS pathophysiology would be useful in designing new treatment strategies. On the other hand, studying rehabilitation methods to help MS patients cope with their disease and perform better functions in their daily lives has undeniable importance.

MS is a multifactorial disease with a complicated pathophysiology that requires interdisciplinary approaches both in basic science studies and in the clinic. Translational research is of utmost importance in complex diseases like MS to help apply preclinical and laboratory findings in clinical practice.

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