SunText Review of Biotechnology Open Access Review Article Volume 1:1 Role of CD4 + T Helper Cells as Mediators of Inflammation in the Pathophysiology of Multiple Sclerosis-A Systematic Review (original) (raw)
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T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis
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Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood–brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytok...
Update on Inflammation, Neurodegeneration, and Immunoregulation in Multiple Sclerosis
Clinical Neuropharmacology, 2009
Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system of uncertain etiology. There is consensus that a dysregulated immune system plays a critical role in the pathogenesis of MS; therefore, we aim to summarize current hypotheses concerning the complex cellular and molecular interactions involved in the immunopathology of MS. Although CD4 + T lymphocytes have long been implicated in the immunopathology of MS, the role of other T-cell subtypes has been recognized. CD4 + and CD8 + cells have been isolated from different locations within MS lesions and F/C T cells have been isolated from early MS lesions. The prevalent dogma has been that CD4 + T H 1 cells release cytokines and mediators of inflammation that may cause tissue damage, although CD4 + T H 2 cells may be involved in modulation of these effects. Recent evidence, however, suggests that additional T-cell subsets play a prominent role in MS immunopathology: T H 17 cells, CD8 + effector T cells, and CD4 + CD25 + regulatory T cells. In addition, laboratory and clinical data are accumulating on the prominent role of B lymphocytes and antigenpresenting cells in MS pathogenesis. On the basis of these observations, new therapeutic approaches for MS will need to focus on resetting multiple components of the immune system.
European Journal of Inflammation
Multiple Sclerosis (MS) presents in a variety of clinical forms associated with a diverse grade of neurological impairment, different prognosis and, possibly, multiple pathogenic mechanisms. Thus, whereas relapsing-remitting (RR) MS appears to be largely driven by inflammatory processes, neurodegeneration, partially independent from inflammation, drives primary progressive (PP) and secondary progressive (SP) MS. An extensive analysis of neuroinflammation in the different forms of MS was performed by evaluating immunophenotypic and functional parameters in MBP-stimulated T lymphocytes of 103 MS patients (26 benign (BE) MS, 30 RRMS, 33 SPMS and 14 PPMS) and 40 healthy controls (HC). Results showed that: i) IL-17-producing and RORC/yt-expressing CD4+ T cells (THI7 lymphocytes), as well as IL-6 expressing CDI4+ cell were augmented in all patients; ii) IL-22expressing cells were increased in all forms of MS with the exception of PPMS; iii) TGF-p-expressing B cells were increased only in RRMS; and iv) GATA3-, NFATc-l, IL-13-, and IL-25-expressing cells (TH2 lymphocytes) were augmented in RRMS and BEMS patients alone. Data herein indicate a pivotal pathogenic role of THl7-driven inflammation in all clinical forms of MS and suggest that control over disease (RRMS and BEMS) is associated not with lack of inflammation per se, but rather with the activation of immune-mediated anti-inflammatory mechanisms. These results could help the design of novel diagnostic and therapeutic approaches. Multiple sclerosis (MS), a demyelinating autoimmune disease ofthe central nervous system, is triggered by molecular mimicry with cross-reacting and yet undefined epitopes and is associated with the activation of CD4+ TH I and TH I7 lymphocytes, CD8+ T lymphocytes, and B lymphocytes, as well as myeloid dendritic cells. The activation of these cells drives the neuroinflammation that plays an important role in damaging the myelin sheath (I, 2). The most common clinical phenotype ofMS is the relapsing-remitting (RR) form, which is characterized by an acute onset of symptoms and signs suggestive of neurological dysfunction, followed by complete or partial recovery. The long-term prognosis of RRMS is usually unfavorable, since patients enter the so-called secondary progressive (SP) phase of
Neuron, 2003
Neurological 3-to 4-fold risk for MS. Other genes within the HLA Sciences complex, including tumor necrosis factor (TNF)-␣, com-Beckman Center for Molecular Medicine ponents of the complement cascade, and myelin oligo-Stanford University dendrocyte glycoprotein (MOG), are also involved in MS Stanford, California 94305 pathogenesis. However, genes outside the HLA complex also contribute to MS pathogenesis. In fact, genome-based studies of multiplex MS families (more than Multiple sclerosis (MS) is an autoimmune central nerone family member affected) indicate that 10 to 15 chovous system (CNS) demyelinating disease that causes mosomal loci contribute to MS susceptibility. Multiple relapsing and chronic neurologic impairment. Recent genes acting in concert may elevate the risk for MS. observations have altered certain traditional concepts Myelin-Specific CD4 ؉ T Cells Initiate regarding MS pathogenesis. A greater diversity of cell CNS Inflammation types and molecules involved in MS is now evident.
T cells in multiple sclerosis and experimental autoimmune encephalomyelitis
Clinical & Experimental Immunology, 2010
Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4 + T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting gd T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, gd, CD8 + and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.
Autoreactive lymphocytes in multiple sclerosis: Pathogenesis and treatment target
Frontiers in Immunology
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by destruction of the myelin sheath structure. The loss of myelin leads to damage of a neuron’s axon and cell body, which is identified as brain lesions on magnetic resonance image (MRI). The pathogenesis of MS remains largely unknown. However, immune mechanisms, especially those linked to the aberrant lymphocyte activity, are mainly responsible for neuronal damage. Th1 and Th17 populations of lymphocytes were primarily associated with MS pathogenesis. These lymphocytes are essential for differentiation of encephalitogenic CD8+ T cell and Th17 lymphocyte crossing the blood brain barrier and targeting myelin sheath in the CNS. B-lymphocytes could also contribute to MS pathogenesis by producing anti-myelin basic protein antibodies. In later studies, aberrant function of Treg and Th9 cells was identified as contributing to MS. This review summarizes the aberrant function and coun...
A basic overview of multiple sclerosis immunopathology
European Journal of Neurology, 2015
Multiple sclerosis (MS) is a multi-component disease characterized by inflammation, neurodegeneration and failure of central nervous system (CNS) repair mechanisms. Immune dysregulation appears to originate with dendritic cells (antigen-presenting cells) which have an activated phenotype in individuals with MS. Dendritic cells migrate across the blood-brain barrier and induce differentiation of memory T cells into pro-inflammatory T helper 1 (Th1) and Th17 lymphocytes. In turn, induction of macrophage and microglial activation produces other proinflammatory cytokines and oxygen and nitric oxide radicals responsible for the demyelination and axonal loss. Other known mediators of MS pathology include CD8+ T cells and memory B cells within the CNS. Some pathological hallmarks of MS are early axonal degeneration and progressive decline of brain volume in patients with clinically isolated syndromes who progress to clinically definite MS. Many new options to interfere with the course of MS have become available in recent years. To limit inflammatory demyelinating processes and delay disease progression, intervention to control inflammation must begin as early as possible. Each distinct type of immunotherapy (immunomodulation, immunosuppression and immune-selective interventionblockade type, sequestering type or depleting type) corresponds to a specific underlying immunopathology of MS.
Immunology, 2008
Autoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex-matched and age-matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose-dependent release of interferon-c (IFN-c), tumour necrosis factor-a (TNF-a) and interleukin-10 (IL-10) by patient-derived MNCs. The patients' cells produced higher amounts of IFN-c and TNF-a, and lower amounts of IL-10, than cells from healthy controls (P < 0Á03 to P < 0Á04). Five patients with MS and no controls, displayed MBP-induced CD4 + T-cell proliferation. These high-responders exhibited enhanced production of IL-17, IFN-c, IL-5 and IL-4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P < 0Á002 to P < 0Á01). A strong correlation was found between the MBP-induced CD4 + T-cell proliferation and production of IL-17, IFN-c, IL-5 and IL-4 (P < 0Á0001 to P < 0Á01) within the patient group, and the production of IL-17 and IL-5 correlated with the number of active plaques on magnetic resonance images (P = 0Á04 and P = 0Á007). These data suggest that autoantigendriven CD4 + T-cell proliferation and release of IL-17 and IL-5 may be associated with disease activity. Larger studies are needed to confirm this.