Lipoic acid inhibits expression of ICAM-1 and VCAM-1 by CNS endothelial cells and T cell migration into the spinal cord in experimental autoimmune encephalomyelitis

2006 ◽  
Vol 175 (1-2) ◽  
pp. 87-96 ◽  
Author(s):  
Priya Chaudhary ◽  
Gail H. Marracci ◽  
Dennis N. Bourdette
Keyword(s):  
Spinal Cord ◽  
Endothelial Cells ◽  
Cell Migration ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Lipoic Acid ◽  
Autoimmune Encephalomyelitis ◽  
T Cell Migration ◽  
Experimental Autoimmune

scholarly journals LRCH1 interferes with DOCK8-Cdc42–induced T cell migration and ameliorates experimental autoimmune encephalomyelitis

2016 ◽  
Vol 214 (1) ◽  
pp. 209-226 ◽  
Author(s):  
Xiaoyan Xu ◽  
Lei Han ◽  
Guixian Zhao ◽  
Shengjie Xue ◽  
Yunzhen Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cell Migration ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Critical Role ◽  
Point Mutations ◽  
Nucleotide Exchange ◽  
Autoimmune Encephalomyelitis ◽  
T Cell Migration ◽  
Experimental Autoimmune

Directional autoreactive CD4+ T cell migration into the central nervous system plays a critical role in multiple sclerosis. Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation. Little is known about whether DOCK8 is related to multiple sclerosis (MS) and how to restrict its GEF activity. Using two screening systems, we found that LRCH1 competes with Cdc42 for interaction with DOCK8 and restrains T cell migration. In response to chemokine stimulation, PKCα phosphorylates DOCK8 at its three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration. Point mutations at the DOCK8 serine sites block chemokine- and PKCα-induced T cell migration. Importantly, Dock8 mutant mice or Lrch1 transgenic mice were protected from MOG (35–55) peptide–induced experimental autoimmune encephalomyelitis (EAE), whereas Lrch1-deficient mice displayed a more severe phenotype. Notably, DOCK8 expression was markedly increased in PBMCs from the acute phase of MS patients. Together, our study demonstrates LRCH1 as a novel effector to restrain PKCα–DOCK8–Cdc42 module–induced T cell migration and ameliorate EAE.

scholarly journals Aged hind-limb clasping experimental autoimmune encephalomyelitis models aspects of the neurodegenerative process seen in multiple sclerosis

2019 ◽  
Vol 116 (45) ◽  
pp. 22710-22720
Author(s):  
Lindsay S. Cahill ◽  
Monan Angela Zhang ◽  
Valeria Ramaglia ◽  
Heather Whetstone ◽  
Melika Pahlevan Sabbagh ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Hind Limb ◽  
Histopathological Analysis ◽  
Autoimmune Encephalomyelitis ◽  
Axon Injury ◽  
Relapsing Remitting ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2+ mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS.

scholarly journals Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis

2017 ◽  
Vol 114 (30) ◽  
pp. E6107-E6116 ◽  
Author(s):  
Stephen Blackmore ◽  
Jessica Hernandez ◽  
Michal Juda ◽  
Emily Ryder ◽  
Gregory G. Freund ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Glial Activation ◽  
Partial Recovery ◽  
Autoimmune Encephalomyelitis ◽  
Peripheral Infection ◽  
Upper Respiratory ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Most MS patients experience periods of symptom exacerbation (relapses) followed by periods of partial recovery (remission). Interestingly, upper-respiratory viral infections increase the risk for relapse. Here, we used an autoimmune-prone T-cell receptor transgenic mouse (2D2) and a mouse-adapted human influenza virus to test the hypothesis that upper-respiratory viral infection can cause glial activation, promote immune cell trafficking to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice with influenza A virus (Puerto Rico/8/34; PR8) and then monitored them for symptoms of inflammatory demyelination. Clinical and histological experimental autoimmune encephalomyelitis was observed in ∼29% of infected 2D2 mice. To further understand how peripheral infection could contribute to disease onset, we inoculated wild-type C57BL/6 mice and measured transcriptomic alterations occurring in the cerebellum and spinal cord and monitored immune cell surveillance of the CNS by flow cytometry. Infection caused temporal alterations in the transcriptome of both the cerebellum and spinal cord that was consistent with glial activation and increased T-cell, monocyte, and neutrophil trafficking to the brain at day 8 post infection. Finally,Cxcl5expression was up-regulated in the brains of influenza-infected mice and was elevated in cerebrospinal fluid of MS patients during relapse compared with specimens acquired during remission. Collectively, these data identify a mechanism by which peripheral infection may exacerbate MS as well as other neurological diseases.

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