scholarly journals T Cell–Transfer Experimental Autoimmune Encephalomyelitis: Pillar of Multiple Sclerosis and Autoimmunity

2017 ◽  
Vol 198 (9) ◽  
pp. 3381-3383 ◽  
Author(s):  
Reinhard Hohlfeld ◽  
Lawrence Steinman
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Cell Transfer ◽  
Autoimmune Encephalomyelitis ◽  
T Cell Transfer ◽  
Experimental Autoimmune

scholarly journals The Innate Immune Receptor CD14 Mediates Lymphocyte Migration in EAE

2015 ◽  
Vol 37 (1) ◽  
pp. 269-275 ◽  
Author(s):  
Ramona Halmer ◽  
Laura Davies ◽  
Yang Liu ◽  
Klaus Fassbender ◽  
Silke Walter
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Innate Immune ◽  
Autoimmune Encephalomyelitis ◽  
Immune Receptors ◽  
Experimental Autoimmune

Background: Multiple sclerosis is the most common autoimmune disease of the central nervous system in young adults and histopathologically characterized by inflammation, demyelination and gliosis. It is considered as a CD4+ T cell-mediated disease, but also a disease-promoting role of the innate immune system has been proposed, based e.g. on the observation that innate immune receptors modulate disease severity of experimental autoimmune encephalomyelitis. Recent studies of our group provided first evidence for a key role of the innate immune LPS receptor (CD14) in pathophysiology of experimental autoimmune encephalomyelitis. CD14-deficient experimental autoimmune encephalomyelitis mice showed increased clinical symptoms and enhanced infiltration of monocytes and neutrophils in brain and spinal cord. Methods: In the current study, we further investigated the causes of the disease aggravation by CD14-deficiency and examined T cell activation, also focusing on the costimulatory molecules CTLA-4 and CD28, and T cell migration capacity over the blood brain barrier by FACS analysis, in vitro adhesion and transmigration assays. Results: In the results, we observed a significantly increased migration of CD14-deficient lymphocytes across an endothelial monolayer. In contrast, we did not see any differences in expression levels of TCR/CTLA-4 or TCR/CD28 and lymphocyte adhesion to endothelial cells from CD14-deficient compared to wildtype mice. Conclusion: The results demonstrate an important role of CD14 in migration of lymphocytes, and strengthen the importance of innate immune receptors in adaptive immune disorders, such as multiple sclerosis.

scholarly journals Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II

2022 ◽  
Vol 12 ◽  
Author(s):  
Lili Tang ◽  
Ge Li ◽  
Yang Zheng ◽  
Chunmei Hou ◽  
Yang Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
T Cell Activation ◽  
Immune Tolerance ◽  
Cell Activation ◽  
Autoimmune Encephalomyelitis ◽  
Mhc Ii ◽  
Experimental Autoimmune

Tim-3, an immune checkpoint inhibitor, is widely expressed on the immune cells and contributes to immune tolerance. However, the mechanisms by which Tim-3 induces immune tolerance remain to be determined. Major histocompatibility complex II (MHC-II) plays a key role in antigen presentation and CD4+T cell activation. Dysregulated expressions of Tim-3 and MHC-II are associated with the pathogenesis of many autoimmune diseases including multiple sclerosis. Here we demonstrated that, by suppressing MHC-II expression in macrophages via the STAT1/CIITA pathway, Tim-3 inhibits MHC-II-mediated autoantigen presentation and CD4+T cell activation. As a result, overexpression or blockade of Tim-3 signaling in mice with experimental autoimmune encephalomyelitis (EAE) inhibited or increased MHC-II expression respectively and finally altered clinical outcomes. We thus identified a new mechanism by which Tim-3 induces immune tolerance in vivo and regulating the Tim-3-MHC-II signaling pathway is expected to provide a new solution for multiple sclerosis treatment.

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 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 The Use of Myeloid Suppressor Cells to  Inhibit Experimental Autoimmune  Encephalomyelitis: a Potential  Immunotherapy for Multiple Sclerosis

2021 ◽  
Author(s):  
◽  
Clare Yan Slaney
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Specific Immunotherapy ◽  
Suppressor Cells ◽  
Experimental Results ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

<p>The ideal treatments for multiple sclerosis (MS) are ones that specifically target the disease causing autoreactive T cells without compromising the immune system's ability to respond to pathogens and infections. However, the current treatments for MS are antigen non-specific and there is a need for the development of antigen-specific therapies that do not induce global immunosuppression. Thus, this thesis aims to investigate the potential of using the body's own suppressor cells to develop an antigen-specific immunotherapy to inhibit experimental autoimmune encephalomyelitis (EAE), the murine model for MS. In our laboratory, there are two versions of mutated superantigens, SMEZ-2-M1 (SM) and double mutant SMEZ-2 (DM). SM is defective at its TCR binding site, but retains its ability to bind to MHCII molecules. Based on previous findings from our laboratory that administration of a SM conjugate with myelin oligodendrocyte glycoprotein (MOG35-55) peptide in incomplete Freund's adjuvant (IFA) suppressed EAE in a CD25+ regulatory T cell (Treg)-dependent manner, it was hypothesised that the administration of SM-MOG35-55/IFA expanded and/or activated MOG35-55 specific Tregs in vivo. In the first part of this thesis, I tested this hypothesis. The experimental results showed that neither the Foxp3+ nor CD25+ Tregs primed in vivo by SM-MOG35-55/IFA could inhibit EAE and surprisingly, treating mice with SM-MOG35-55/IFA did not significantly suppress EAE as previously described. Nevertheless, the administration of SM-MOG35-55 into mice using various methods repeatedly showed minor suppression of EAE, suggesting an in vivo suppressive capability of SM-MOG35-55. Interestingly, after being injected into mice intravenously, SM was captured by a blood MHCII-CD11b+F4/80+Gr-1+ cell population in an MHCII-independent manner. Cells expressing the same surface markers have been reported in the literature to be myeloid derived suppressor cells (MDSCs), suggesting that the SM+MHCII-CD11b+F4/80+Gr-1+ cells may be suppressor cells, i.e. a subpopulation of MDSCs, and play a role in SM-MOG35-55 mediated EAE suppression. In the second part of this thesis, I went on to test the blood MHCII-CD11b+F4/80+Gr-1+ cells' suppressive potential using DM. Unlike SM, DM is defective at both MHCII and TCR binding sites, and possessed an enhanced binding capability to the blood MHCIICD11b+ F4/80+Gr-1+ cells. The experimental results demonstrated that the blood MHCII-CD11b+F4/80+Gr-1+cells are potent suppressors of T cell responses, and were subsequently named as blood MDSCs (bMDSCs). bMDSCs suppressed T cell proliferation in vitro in a cell contact-dependant manner, and nitric oxide played an important role in this suppression. In the third part of this thesis, I investigated the potential of using DM for EAE suppression via bMDSCs. When DM was conjugated to MOG35-55 and administered subcutaneously into mice, EAE was suppressed in a MOG35-55-specific manner. Moreover, the adoptive transfer of bMDSCs from the DM-MOG35-55 treated mice transferred EAE suppression, confirming that bMDSCs play an important role in this suppression. Taken together, these results reveal a previously unknown role of bMDSCs in limiting immune responses. Moreover, the use of DM to direct the activity of bMDSC may prove to be a unique antigen-specific immunotherapy for EAE, which has great potential to be developed into a treatment of MS and other autoimmune diseases.</p>

On the role of cytokines and route of antigen delivery on the modulation of experimental autoimmune encephalomyelitis

2012 ◽  
Author(s):  
◽  
Jason Allen Cascio
Keyword(s):  
Multiple Sclerosis ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Cell Activity ◽  
Therapeutic Effects ◽  
Th2 Cytokines ◽  
Autoimmune Encephalomyelitis ◽  
Cns Inflammation ◽  
Tolerogenic Function ◽  
Experimental Autoimmune

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Experimental autoimmune encephalomyelitis (EAE) is a mouse model of the human autoimmune disease multiple sclerosis and is caused by myelin-reactive T lymphocytes that recognize antigens embedded within the myelin sheath in the central nervous system. Herein, we describe two aspects of immune modulation that can be utilized to suppress self-reactive T cell activity and reverse the disease. Oral tolerance to protein antigens is a well-established phenomenon that has received recent attention for its potential to induce non-reactivity to self-antigens. We have previously shown that intra-peritoneal injection of myelin oligodendrocyte glycoprotein (MOG) in the context of an immunoglobulin chimera (Ig-MOG) is effective for modulation of myelin-reactive T cells and reversal of EAE. In this study, we sought to determine whether Ig-MOG could reverse EAE when administered as an orally fed regimen. The results show that oral Ig-MOG is able to suppress both MOG peptide and CNS homogenate induced EAE, and does so by down-regulating both Th1 and Th17 responses. The therapeutic effects of Ig-MOG were found to be mediated by antigen presenting cells of the lamina propria, which acquired Ig-MOG induced tolerogenic function that was dependent on antigen-driven T cell contact. This tolerogenic function was mostly mediated by the up-regulation of the suppressive molecule PD-L1, and inhibition of PD-L1 abrogated the ability of oral IgMOG to induce tolerance. In sum, this study provides a novel oral treatment regimen for EAE that offers insight for improved treatments for human multiple sclerosis. It has long been known that Th2 cytokines, such as IL-4 and IL-13, can suppress inflammation and modulate EAE. However, the mechanisms by which these cytokines exert their suppressive functions are poorly understood. To better elucidate how Th2 cytokines regulate CNS inflammation, we generated IL-13R[alpha]1[superscript -/-] mice and induced EAE. Intriguingly, IL-13R[alpha]1[superscript -/-] mice developed early onset and more severe EAE compared to their WT counterparts. The exacerbated disease was characterized by enhanced Th17 and Th1 responses in the lymph nodes and CNS, respectively. The enhanced T cell activity was mediated by IL-13R[alpha]1-deficient APCs that secreted greater amounts of the pro-inflammatory cytokine IL-6 and induced enhanced T cell proliferation. Bone marrow chimera experiments revealed that the sole APCs responsible for disease exacerbation were the CNS-resident microglia, which displayed enhanced MHC II and CD86 expression upon EAE induction. In sum, this study reveals a novel mechanism for the control of CNS inflammation, in which microglia utilize IL-13R[alpha]1 to modulate inflammation and control EAE.

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