Insights into the immunopathogenesis of multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Significant progress has been made in our understanding of the etiology of MS. MS is widely believed to be an autoimmune disease that results from aberrant immune responses to CNS antigens. T cells are considered to be crucial in orchestrating an immunopathological cascade that results in damage to the myelin sheath. This review summarizes the currently available data supporting the idea that myelin reactive T cells are actively involved in the immunopathogenesis of MS. Some of the therapeutic strategies for MS are discussed with a focus on immunotherapies that aim to specifically target the myelin reactive T cells.     

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

Immunoregulatory T cells of (CD4+)CD25+ phenotype suppress T cell function and protect rodents from organ-specific autoimmune disease. The human counterpart of this subset of T cells expresses high levels of CD25 and its role in human autoimmune disorders is currently under intense investigation. In multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), the activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event. Here, we investigated whether MS is associated with an altered ability of (CD4+)CD25high regulatory T cells (Treg) to confer suppression of myelin-specific immune responses. Whereas Treg frequencies were equally distributed in blood and cerebrospinal fluid of MS patients and did not differ compared to healthy controls, the suppressive potency of patient-derived (CD4+)CD25high T lymphocytes was impaired. Their inhibitory effect on antigen-specific T cell proliferation induced by human recombinant myelin oligodendrocyte protein as well as on immune responses elicited by polyclonal and allogeneic stimuli was significantly reduced compared to healthy individuals. The effect was persistent and not due to responder cell resistance or altered survival of Treg, suggesting that a defective immunoregulation of peripheral T cells mediated by (CD4+)CD25high T lymphocytes promotes CNS autoimmunity in MS.     

Impacts of microbiome metabolites on immune regulation and autoimmunity

A vast number of studies have demonstrated a remarkable role for the gut microbiota and their metabolites in the pathogenesis of inflammatory diseases, including multiple sclerosis (MS). Recent studies in experimental autoimmune encephalomyelitis, an animal model of MS, have revealed that modifying certain intestinal bacterial populations may influence immune cell priming in the periphery, resulting in dysregulation of immune responses and neuroinflammatory processes in the central nervous system (CNS). Conversely, some commensal bacteria and their antigenic products can protect against inflammation within the CNS. Specific components of the gut microbiome have been implicated in the production of pro‐inflammatory cytokines and subsequent generation of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of regulatory T‐cells (Treg), contributing to immune suppression. Short‐chain fatty acids may induce Treg either by G‐protein‐coupled receptors or inhibition of histone deacetylases. Tryptophan metabolites may suppress inflammatory responses by acting on the aryl hydrocarbon receptor in T‐cells or astrocytes. Interestingly, secretion of these metabolites can be impaired by excess consumption of dietary components, such as long‐chain fatty acids or salt, indicating that the diet represents an environmental factor affecting the complex crosstalk between the gut microbiota and the immune system. This review discusses new aspects of host–microbiota interaction and the immune system with a special focus on MS as a prototype T‐cell‐mediated autoimmune disease of the CNS.     

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked. Authors JDL and LAB share senior authorship. The authors have no conflict of interest.     

IL‐12‐polarized Th1 cells produce GM‐CSF and induce EAE independent of IL‐23

CD4⁺ T‐helper (Th) cells reactive against myelin antigens mediate the mouse model experimental autoimmune encephalomyelitis (EAE) and have been implicated in the pathogenesis of multiple sclerosis (MS). It is currently debated whether encephalitogenic Th cells are heterogeneous or arise from a single lineage. In the current study, we challenge the dogma that stimulation with the monokine IL‐23 is universally required for the acquisition of pathogenic properties by myelin‐reactive T cells. We show that IL‐12‐modulated Th1 cells readily produce IFN‐γ and GM‐CSF in the CNS of mice and induce a severe form of EAE via an IL‐23‐independent pathway. Th1‐mediated EAE is characterized by monocyte‐rich CNS infiltrates, elicits a strong proinflammatory cytokine response in the CNS, and is partially CCR2 dependent. Conversely, IL‐23‐modulated, stable Th17 cells induce EAE with a relatively mild course via an IL‐12‐independent pathway. These data provide definitive evidence that autoimmune disease can be driven by distinct CD4⁺ T‐helper‐cell subsets and polarizing factors.     

MicroRNA signature of central nervous system‐infiltrating dendritic cells in an animal model of multiple sclerosis

Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c⁺ antigen‐presenting cells that are critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c⁺ DCs in the CNS is that microglia can upregulate CD11c during inflammation, making it challenging to distinguish bone marrow‐derived DCs (BMDCs) from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells and regulate their function within the CNS during neuro‐inflammation. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c⁺ cells using a non‐biased murine array. Several miRNAs, including miR‐31, were enriched in CD11c⁺ cells within the CNS during EAE, but not LysM⁺ microglia. Moreover, to distinguish CD11c⁺ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR‐31 expression was specific to BMDCs. Interestingly, miR‐31‐binding sites were enriched in mRNAs downregulated in BMDCs that migrated into the CNS, and a subset was confirmed to be regulated by miR‐31. Finally, miR‐31 was elevated in DCs migrating through an in vitro blood–brain barrier. Our findings suggest miRNAs, including miR‐31, may regulate entry of DCs into the CNS during EAE, and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS.     

Cell‐based interventions to halt autoimmunity in type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) results from death of insulin‐secreting β cells mediated by self‐immune cells, and the consequent inability of the body to maintain insulin levels for appropriate glucose homeostasis. Probably initiated by environmental factors, this disease takes place in genetically predisposed individuals. Given the autoimmune nature of T1DM, therapeutics targeting immune cells involved in disease progress have been explored over the last decade. Several high‐cost trials have been attempted to prevent and/or reverse T1DM. Although a definitive solution to cure T1DM is not yet available, a large amount of information about its nature and development has contributed greatly to both the improvement of patient's health care and design of new treatments. In this study, we discuss the role of different types of immune cells involved in T1DM pathogenesis and their therapeutic potential as targets and/or modified tools to treat patients. Recently, encouraging results and new approaches to sustain remnant β cell mass and to increase β cell proliferation by different cell‐based means have emerged. Results coming from ongoing clinical trials employing cell therapy designed to arrest T1DM will probably proliferate in the next few years. Strategies under consideration include infusion of several types of stem cells, dendritic cells and regulatory T cells, either manipulated genetically ex vivo or non‐manipulated. Their use in combination approaches is another therapeutic alternative. Cell‐based interventions, without undesirable side effects, directed to block the uncontrollable autoimmune response may become a clinical reality in the next few years for the treatment of patients with T1DM.     

Methyl Butyrate Alleviates Experimental Autoimmune Encephalomyelitis and Regulates the Balance of Effector T Cells and Regulatory T Cells

Inflammation - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by demyelinating neuropathy. The etiology of MS is not yet clear and its treatment...     

The increasing incidence and prevalence of female multiple sclerosis--a critical analysis of potential environmental factors

Multiple sclerosis (MS) is the most common acquired inflammatory demyelinating disorder of the central nervous system (CNS). Not unlike many inflammatory diseases with a presumed autoimmune pathogenesis, it has been established that there is a female preponderance in prevalence. While in the past it was shown that there are two women for every man with a diagnosis of MS, recent serial cross-sectional assessments provide compelling evidence for an increase of the female to male sex ratio in patients with relapsing-remitting MS over the last decades. An understanding of this phenomenon might provide key insights into the pathogenesis of the disease but also may have implications for health-care strategies and further research efforts. We review possible etiologies for the gender disparity in MS, and we discuss possible underlying causes. We determined that the biologically most plausible explanations for a disproportional increase of MS among women in some population may be the role of vitamin D in MS pathogenesis. Decreased sun exposure may be a critical factor in diminished vitamin D levels in many recent cohort studies. Vitamin D insufficiency or deficiency has been shown to affect T cell differentiation and regulation, which may affect cellular immune responses against autoantigens and pathogens that have been associated with the etiology of MS. Vitamin D also appears to impact B cell activation and differentiation, another cell type that has been implicated in the inflammatory cascade underlying CNS autoimmune disease.     

多发性硬化免疫机制研究新进展

多发性硬化（MS）是一种以中枢神经系统白质神经变性为特征的自身免疫性疾病,其确切的病因发病机制尚不清楚。目前认为是在易感基因的基础上,受环境因素的触发由CD4^＋T细胞介导的中枢神经系统的自身免疫性疾病,但其他免疫细胞（包括B细胞、CD8^＋T细胞等）也能通过诱导或调控MS患者中枢神经系统内的免疫应答过程而可能参与MS的发病。以往认为Th1／Th2型反应失衡是其关键致病因素,近年来随着对其研究的深入,提出许多新的观点,为多发性硬化的免疫机制及治疗策略研究提供了新方向。     

T-cell-based immunotherapy in multiple sclerosis: induction of regulatory immune networks by T-cell vaccination

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with presumed autoimmune origin. Pathogenic autoimmune responses in MS are thought to be the result of a breakdown of self tolerance. Several mechanisms account for the natural state of immunological tolerance to self antigens, including clonal deletion of self-reactive T cells in the thymus. However, autoimmune T cells are also part of the normal T-cell repertoire, supporting the existence of peripheral regulatory mechanisms that keep these potentially pathogenic T cells under control. One such mechanism involves active suppression by regulatory T cells. It has been indicated that regulatory T cells do not function properly in autoimmune disease. Immunization with attenuated autoreactive T cells, T-cell vaccination, may enhance or restore the regulatory immune networks to specifically suppress autoreactive T cells, as shown in experimental autoimmune encephalomyelitis, an animal model for MS. In the past decade, T-cell vaccination has been tested for MS in several clinical trials. This review summarizes these clinical trials and updates our current knowledge on the induction of regulatory immune networks by T cell vaccination.     

Activation of CD4⁺ Foxp3⁺ regulatory T cells proceeds normally in the absence of B cells during EAE

B cells and regulatory T (Treg) cells can both facilitate remission from experimental auto immune encephalomyelitis (EAE), a disease of the central nervous system (CNS) used as a model for multiple sclerosis (MS). Considering that B-cell-depletion therapy (BCDT) is used to treat MS patients, we asked whether Treg-cell activation depended on B cells during EAE. Treg-cell proliferation, accumulation in CNS, and augmentation of suppressive activity in the CNS were normal in B-cell-deficient mice, indicating that B cells are not essential for activation of the protective Treg-cell response and thus provide an independent layer of regulation. This function of B cells involved early suppression of the encephalitogenic CD4(+) T-cell response, which was enhanced in B-cell-deficient mice. CD4(+) T-cell depletion was sufficient to intercept the transition from acute-to-chronic EAE when applied to B-cell-deficient animals that just reached the peak of disease severity. Intriguingly, this treatment did not improve disease when applied later, implying that chronic disability was ultimately maintained independently of pathogenic CD4(+) T cells. Collectively, our data indicate that BCDT is unlikely to impair Treg-cell function, yet it might produce undesirable effects on T-cell-mediated autoimmune pathogenesis.     

The potential role of iNKT cells in experimental allergic encephalitis and multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disorder associated with neurological signs and chronic inflammatory demyelination of the central nervous system (CNS). MS has been thought as Th1 (T helper) and Th17 cells mediated disease, but cells of the innate immune system play an important role both in the initiation and progression of MS. The invariant Natural Killer T (iNKT) cells are the unique innate lymphocytes subtype involved in inflammation and autoimmune disorders and secretes cytokines such as interferon gamma (IFN-γ), Interleukin (IL)-10, IL-4 and IL-13. A reduction in number or defect in function of iNKT cells has been associated with an increased prevalence of autoimmune disorders indicating that iNKT cells have an immune-regulatory role in autoimmune disorders. Also, the protective role of iNKT cells has been extensively studied in EAE and the results of these studies show that iNKT cells might be a target for therapeutic purposes, but needs more extensive studies of their biology. In this review, we will attempt to show the protective role of iNKT cells in the pathogenesis of EAE and human disease.     

Interleukin-7: Fuel for the autoimmune attack

Interleukin-7 (IL-7) is a critical survival factor for lymphocytes and recent studies suggest targeting the IL-7/IL-7Rα pathway holds promise for the treatment of autoimmune diseases. Several lines of evidence, genetic as well as functional, indicate an important role for this cytokine in autoimmune inflammation: polymorphisms in the IL-7Rα have been associated with increased risk for autoimmune disease and blocking IL-7/IL-7Rα with antibodies showed therapeutic efficacy in several autoimmune mouse models. Insights are starting to emerge about the mechanisms underlying IL-7's role in autoimmunity and tolerance, revealing surprising novel functions beyond its traditional activity as a T cell survival factor. In the first part of this review, the functions of IL-7 in the immune system are concisely described, providing a basis for understanding their potential role in promoting autoimmune responses. In the second part, current knowledge about the role of IL-7 in various autoimmune conditions is reviewed.     

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD4⁺Foxp3⁺ regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non‐Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non‐Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing‐remitting MS show significantly impaired migratory capacity under non‐inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood–brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.     

Linkage analysis of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the rat identifies a locus controlling demyelination on chromosome 18.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) with a complex etiology comprising a genetically determined predisposition and a suspected auto- immune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS, which can be used to define susceptibility loci for autoimmune neuroinflammation. We have recently established a chronic relapsing EAE model characterized by inflammation and focal demyelination in the CNS by immunizing a variety of rat strains with the CNS-specific myelin oligodendrocyte glycoprotein (MOG). This model is more MS-like than any other rodent EAE model described up to now. Here we present the first systematic genome search for chromosomal regions linked to phenotypes of MOG-induced EAE in a (DA x ACI) F(2)intercross. A genome-wide significant susceptibility locus linked to demyelination was identified on chromosome 18. This region has not been described in inflammatory diseases affecting other organs and the responsible gene or genes may thus be nervous system specific. Other chromosomal regions showing suggestive linkage to phenotypes of MOG-induced EAE were identified on chromosomes 10, 12 and 13. The chromosome 10 and 12 regions have previously been linked to arthritis in DA rats, suggesting that they harbour immunoregulatory genes controlling general susceptibility to autoimmune diseases. We conclude that identification of susceptibility genes for MOG-induced EAE on rat chromosomes 10, 12, 13 and 18 may disclose important disease pathways for chronic inflammatory demyelinating diseases of the CNS such as MS.     

Epitope spreading and molecular mimicry as triggers of autoimmunity in the Theiler's virus-induced demyelinating disease model of multiple sclerosis

The pathogenesis of multiple sclerosis (MS), a human demyelinating disease of the central nervous system (CNS), is currently unknown. It is widely thought that MS is an autoimmune disease which is supported by animal studies showing that myelin-specific CD4+ T cells can induce similar clinical disease in mice as observed in MS. However, the mechanism(s) of activation of these autoreactive CD4+ T cells are unknown. Although genetic susceptibility is important, other factors may be involved. Viral infections have long thought to be involved in the pathogenesis of MS although there exists little or no direct evidence implicating a role for a specific virus in MS pathogenesis. This review will discuss two models of virus-induced CNS autoimmunity, molecular mimicry and epitope spreading. These two mechanisms of activation of autoreactive T cells are presented in the context of MS.     

Multiple sclerosis animal models: a clinical and histopathological perspective

There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, that is, damage to axons, synapses and nerve cell bodies. While we are equipped with appropriate therapeutic options to prevent immune‐cell driven relapses, effective therapeutic options to prevent the progressing neurodegeneration are still missing. In this review article, we will discuss to what extent pathology of the progressive disease stage can be modeled in MS animal models. While acute and relapsing–remitting forms of experimental autoimmune encephalomyelitis (EAE), which are T cell dependent, are aptly suited to model relapsing‐remitting phases of MS, other EAE models, especially the secondary progressive EAE stage in Biozzi ABH mice is better representing the secondary progressive phase of MS, which is refractory to many immune therapies. Besides EAE, the cuprizone model is rapidly gaining popularity to study the formation and progression of demyelinating CNS lesions without T cell involvement. Here, we discuss these two non‐popular MS models. It is our aim to point out the pathological hallmarks of MS, and discuss which pathological aspects of the disease can be best studied in the various animal models available.     

The blood–brain-barrier in multiple sclerosis: Functional roles and therapeutic targeting

In most regions of the central nervous system (CNS), the composition of the neuronal microenvironment is maintained by virtue of particular blood–brain-barrier (BBB) characteristics, to which vascular endothelial cells (ECs) contribute an important role. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS, characterized at tissue level by multifocal perivascular infiltrates, predominantly of lymphocytes and macrophages. Thus, lymphocyte recruitment into the brain across ECs of the BBB represents a critical event in disease pathogenesis, which is highly restricted and carefully regulated. In recent years, different investigations have identified the crucial components involved in leukocyte migration, providing new insights into mechanisms modulating neuroinflammatory reactions. In this review, several topics relating to these events are discussed, namely: (1) cellular and molecular characteristics of the BBB regulating permeability, as well as signals inducing EC differentiation in the brain and specific cell properties; (2) pathogenic mechanisms guiding the migration of different leukocyte populations through the BBB in MS; and (3) current knowledge on how different MS therapies targeting leukocytes migration across the BBB function. Furthermore, because the BBB has proven to be an important retaining wall preventing drug passage into the CNS, novel strategies directed at successful delivery of large molecules for effective treatment of various inflammatory conditions of the brain, both currently available or still under development, are discussed.