The role of immune semaphorins in multiple sclerosis

Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
FEBS letters (Impact Factor: 3.34). 03/2011; 585(23):3829-35. DOI: 10.1016/j.febslet.2011.03.033
Source: PubMed

ABSTRACT The nervous and immune systems have similar functional characteristics. Both have an intricate network of synaptic connections and an exquisite communication system that enable intercellular signal transduction. Although semaphorins were originally identified as guidance cues in neural development, accumulating evidence indicates that several semaphorins called 'immune semaphorins', such as Sema3A, 4A, 4D, 6D and 7A, are critically involved in various phases of the immune response by regulating immune cell-cell contacts or cell migration. In this review, we present recent knowledge on the functions of semaphorins and their receptors in the immune system and their potential roles in the pathogenesis of multiple sclerosis (MS), a representative CNS autoimmune disease, and its animal model, experimental autoimmune encephalomyelitis (EAE).

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    ABSTRACT: Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood¿brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.
    07/2014; 2(1):84. DOI:10.1186/PREACCEPT-1363293028126438
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    ABSTRACT: Objective: To investigate the role of the multifunctional protein Semaphorin 5A (Sema5A) in modulating cellular immune responses and as a biomarker in rheumatoid arthritis (RA). Methods: Soluble recombinant Sema5A was used to assess its effect on the functions of primary T and NK cells isolated from the peripheral blood of healthy donors. Cell proliferation and expression of transcription factors was determined by flow cytometry. Cytokine secretion was analysed by Luminex technology. Sera of 145 RA patients and control sera from healthy individuals or patients with non-RA rheumatic diseases were analysed for the presence of secreted Sema5A by ELISA and immunoblotting. Results: Soluble Sema5A strongly increased T- and NK-cell proliferation and induced the secretion of proinflammatory Th1/Th17 cytokines. Accordingly, Sema5A stimulation caused a significant upregulation of T-bet and RORγt levels in T cells. In addition, significantly elevated levels of secreted Sema5A were detected in the sera of RA patients compared to healthy controls. Sema5A levels were highest in RA patients positive for the RA biomarker anti-cyclic citrullinated peptide (p<0.001, compared to systemic lupus erythematosus and Sjögren syndrome patients) and correlated with levels of rheumatoid factor as a prototypical RA marker. Conclusion: Soluble Sema5A is a potent activator of T and NK cells in vitro and high Sema5A serum levels are associated with RA. Taken together, the results indicate that Sema5A contributes to the pathogenesis of RA through antigen-independent T- and NK-cell activation. Hence, Sema5A is a promising complementary biomarker for the diagnosis of RA. © 2014 American College of Rheumatology.
    06/2014; 66(6). DOI:10.1002/art.38425
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    ABSTRACT: Objectives Hypoxia, a hallmark feature of chronic inflammation, plays a key role in the development of inflammatory demyelinating lesions of multiple sclerosis (MS). Periplaque demyelinated lesions (PDL) of MS represent incompletely demyelinated lesions surrounding fully demyelinated plaques, characterized by low-grade inflammation and tissue remodeling. At present, the precise molecular pathology of PDL remains unknown.Methods To study the role of hypoxia in the pathophysiology of PDL, we identified a comprehensive set of chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq)-based hypoxia-inducible factor-1α (HIF-1α) direct target genes in human umbilical vein endothelial cells by in silico next-generation sequencing data analysis. We characterized HIF-1α target signature in PDL of secondary progressive MS by analyzing a microarray dataset.ResultsWe identified a total of 2291 hypoxia-restricted HIF-1α target genes. The set of 80 genes (15%) out of 549 upregulated genes in PDL, compared with normal appearing white matter, corresponded to ChIP-Seq-based HIF-1α target genes. They showed a significant relationship with the molecular network composed of the semaphorin Sema6D, a key molecule involved in activation of antigen-specific T cells by dendritic cells.Conclusions These results suggest a possible involvement of hypoxia in periplaque lesion formation in MS.
    02/2015; DOI:10.1111/cen3.12195

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