Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN- Therapy in Multiple Sclerosis (original) (raw)
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The Journal of Immunology, 2012
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the CNS and a leading cause of lasting neurologic disabilities in young adults. Although the precise mechanism remains incompletely understood, Ag presentation and subsequent myelin-reactive CD4+ T cell activation/differentiation are essential for the pathogenesis of MS. Although semaphorins were initially identified as axon guidance cues during neural development, several semaphorins are crucially involved in various phases of immune responses. Sema4A is one of the membrane-type class IV semaphorins, which we originally identified from the cDNA library of dendritic cell (DC). Sema4A plays critical roles in T cell activation and Th1 differentiation during the course of experimental autoimmune encephalomyelitis, an animal model of MS; however, its pathological involvement in human MS has not been determined. In this study, we report that Sema4A is increased in the sera of patients with MS. The expression of Sema4A is in...
Roles of Sema4A in multiple sclerosis and interferon-β therapy efficacy
Clinical and Experimental Neuroimmunology, 2013
The early initiation of appropriate treatment is important for a better prognosis for patients with multiple sclerosis (MS). Although interferon (IFN-b) has been the most prescribed therapy for MS, some patients are poor responders to this therapy. Therefore, finding biomarkers to predict treatment responsiveness is required. Some patients with MS have high serum Sema4A and concurrently have characteristics of Th17-skewing conditions, and do not respond well to IFN-b therapy. In the present review, we discuss Sema4A and responsiveness to IFN-b therapy. In addition, we review biomarkers relevant to IFN-b therapy responsiveness. (Clin. Exp. Neuroimmunol
Journal of Neuroinflammation, 2020
Background Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS. Methods We adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-β (n = 38) in all of...
Decreased expression of Sema3A, an immune modulator, in blood sample of multiple sclerosis patients
Gene, 2017
Semaphorin 3A (sema3A) as an immune modulator could participate in the pathogenesis of autoimmune diseases. In the current study, we aimed to investigate Sema3A expression in peripheral blood mononuclear cells (PBMCs) and its serum level in relapsing-remitting multiple sclerosis (RRMS) patients. Fifteen newly determined and untreated RRMS patients were chosen and assessed in relapsing and remitting phases in compare with fifteen healthy individuals. In consistent with previous findings in other autoimmune diseases, our results revealed that serum level of Sema3A and its expression in PBMCs of RRMS patients were significantly lower than in normal subjects. We also evaluated this down regulation predictive value with ROC analysis. According to our data, we suggest that Sema3A could be involved in pathogenesis of MS and might be a potential diagnostic biomarker for the disease.
Neurobiology of disease, 2014
Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmun...
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.
Role of CD4+T Helper Cells as Mediators of Inflammation in the Pathophysiology of Multiple Sclerosis- A Systematic Review., 2020
Multiple Sclerosis (MS) represents a chronic inflammatory autoimmune condition like other autoimmune ones such as rheumatoid arthritis (RA), Psoariasis, Endometriosis, etc. MS results in continuous depletion of axonal myelin in various regions of the central nervous System (CNS) & influences the occurrence of a variety of clinical symptoms like muscle spasms, optic neuritis as well as paralysis. Over a decade advances made in research conducted in animal models of MS to get better insight of pathophysiology of MS disease corroborated that MS is an autoimmune inflammatory disorder secondary to recruitment of self-reactive lymphocytes, basically CD4+T cells in the CNS. Actually high concentrations of T helper cells (Th) cell subsets as well as associated cytokines as well as chemokines have been observed in the CNS lesions as well as cerebrospinal; fluid (CSF) of MS patients ,along with breakdown of blood brain barrier (BBB), as well as consequent activation of resident astrocytes as well as microglia and ultimately neuroinflammation. Thus we decided to do a systematic review utilizing the Pubmed Engine, Google Scholar Web of Science utilizing the MeSH terms like Th cell kinds like Th1; Th 17; Th22; Th9 and others from 1980 till date on 31st July 2020. We found over 25,000 articles out of which we selected 154 articles for this review to study the influence of the variety of Th like cells involved in the aetiopathogenesis. No meta-analysis was conducted. Till date various kinds of Th cells have been discovered and named as per the liberated lineage defining cytokines. Significantly Th 1, Th17, Th22, Th9 as well as Th1 like Th17 have been correlated with MS. Thus we have detailed the crosstalk of various Th cell subpopulations as well as their lineage defining cytokines in manipulating the inflammatory responses in MS along with how the innovative drugs that have received FDA approval interact which target T lymphocytes for the therapy of the disease.