scholarly journals SerpinB1 controls encephalitogenic T helper cells in neuroinflammation

2019 ◽  
Vol 116 (41) ◽  
pp. 20635-20643 ◽  
Author(s):  
Lifei Hou ◽  
Deepak A. Rao ◽  
Koichi Yuki ◽  
Jessica Cooley ◽  
Lauren A. Henderson ◽  
...  
Keyword(s):  
T Cells ◽  
T Helper ◽  
Cd4 Cells ◽  
Autoimmune Encephalomyelitis ◽  
Antibody Treatment ◽  
Surface Receptors ◽  
Gm Csf ◽  
Cytolytic Granule ◽  
Neutrophil Survival ◽  
Experimental Autoimmune

SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17–expressing T cells. Here, we show that serpinB1 (Sb1) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, Sb1−/− mice are resistant to EAE with a paucity of T helper (TH) cells that produce two or more of the cytokines, IFNγ, GM-CSF, and IL-17. These multiple cytokine-producing CD4 cells proliferate extremely rapidly; highly express the cytolytic granule proteins perforin-A, granzyme C (GzmC), and GzmA and surface receptors IL-23R, IL-7Rα, and IL-1R1; and can be identified by the surface marker CXCR6. In Sb1−/− mice, CXCR6+ TH cells are generated but fail to expand due to enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death. Finally, anti-CXCR6 antibody treatment, like Sb1 deletion, dramatically reverts EAE, strongly indicating that the CXCR6+ T cells are the drivers of encephalitis.

scholarly journals Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis

Brain ◽  
2010 ◽  
Vol 133 (4) ◽  
pp. 1067-1081 ◽  
Author(s):  
Ingo Kleiter ◽  
Jian Song ◽  
Dominika Lukas ◽  
Maruf Hasan ◽  
Bernhard Neumann ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
T Helper ◽  
T Helper 1 ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment

2004 ◽  
Vol 10 (5) ◽  
pp. 540-548 ◽  
Author(s):  
Mathilde SA Deloire ◽  
Tarik Touil ◽  
Bruno Brochet ◽  
Vincent Dousset ◽  
Jean-Marie Caillé ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
T Cells ◽  
T Cell ◽  
Magnetic Resonance ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Process ◽  
Resonance Imaging ◽  
Autoimmune Encephalomyelitis ◽  
Antibody Treatment ◽  
Experimental Autoimmune

Large inflammatory infiltrates of T cells, macrophages and B cells in the central nervous system (CNS) contribute to the pathogenesis of multiple sclerosis (MS). The passage of T cells through the blood-brain barrier can be suppressed with antibodies directed against alpha-4 integrins (VLA-4) that mediate T-cell adherence. This treatment, in phase III of clinical trial evaluation, reduces lesion development in MS patients. In the ongoing inflammatory disease process the consequences of T-cell inhibitory anti-VLA-4 antibodies on inflammatory compounds are still poorly investigated. We show that anti-VLA-4 antibody treatment during the late preclinical phase of the acute experimental autoimmune encephalomyelitis (EAE) MS rat model interrupts T-cell egress out of the vascular compartment and suppresses clinical disease and histological alterations but macrophage recruitment in the CNS is not fully compromised. Among the treated EAE animals not developing disease, none presented foci of T-cell infiltration in CNS. However, in 75% of the treated EAE rats monocyte ingress in CNS was observedin vivo by magnetic resonance imaging with the ultrasmall superparamagnetic iron oxide contrast agent. Our data shed new light on the role of remaining macrophage brain infiltration in an induced but interrupted T-cell-mediated EAE disease process.

scholarly journals Absence of Monocyte Chemoattractant Protein 1 in Mice Leads to Decreased Local Macrophage Recruitment and Antigen-Specific T Helper Cell Type 1 Immune Response in Experimental Autoimmune Encephalomyelitis

2001 ◽  
Vol 193 (6) ◽  
pp. 713-726 ◽  
Author(s):  
DeRen Huang ◽  
Jintang Wang ◽  
Pia Kivisakk ◽  
Barrett J. Rollins ◽  
Richard M. Ransohoff
Keyword(s):  
T Cells ◽  
Active Immunization ◽  
T Helper Cell ◽  
Wild Type ◽  
Cell Type ◽  
T Helper ◽  
Autoimmune Encephalomyelitis ◽  
Monocyte Chemoattractant ◽  
Helper Cell Type ◽  
Experimental Autoimmune

Monocyte chemoattractant protein (MCP)-1 plays a critical role in innate immunity by directing the migration of monocytes into inflammatory sites. Recent data indicated a function for this chemokine in adaptive immunity as a regulator of T cell commitment to T helper cell type 2 (Th2) effector function. Studies in a Th1-dependent animal model, experimental autoimmune encephalomyelitis (EAE), showed that MCP-1 was highly expressed in the central nervous system (CNS) of affected rodents, and MCP-1 antibodies could block relapses of the disease. Mice deficient for the major MCP-1 receptor, CC chemokine receptor (CCR)2, did not develop EAE after active immunization but generated effector cells that could transfer the disease to naive wild-type recipients. We analyzed EAE in mice deficient for MCP-1 to define the relevant ligand for CCR2, which responds to murine MCP-1, MCP-2, MCP-3, and MCP-5. We found that C57BL/6 MCP-1–null mice were markedly resistant to EAE after active immunization, with drastically impaired recruitment of macrophages to the CNS, yet able to generate effector T cells that transferred severe disease to naive wild-type recipients. By contrast, adoptive transfer of primed T cells from wild-type mice into naive MCP-1–null recipients did not mediate clinical EAE. On the SJL background, disruption of the MCP-1 gene produced a milder EAE phenotype with diminished relapses that mimicked previous findings using anti–MCP-1 antibodies. There was no compensatory upregulation of MCP-2, MCP-3, or MCP-5 in MCP-1–null mice with EAE. These results indicated that MCP-1 is the major CCR2 ligand in mice with EAE, and provided an opportunity to define the role of MCP-1 in EAE. Compared with wild-type littermates, MCP-1−/− mice exhibited reduced expression of interferon γ in draining lymph node and CNS and increased antigen-specific immunoglobulin G1 antibody production. Taken together, these data demonstrate that MCP-1 is crucial for Th1 immune responses in EAE induction and that macrophage recruitment to the inflamed CNS target organ is required for primed T cells to execute a Th1 effector program in EAE.

scholarly journals Hyperbaric Oxygen Therapy Alleviates the Autoimmune Encephalomyelitis via the Reduction of IL-17a and GM-Csf Production of Autoreactive T Cells as Well as Boosting the Immunosuppressive IL-10 in the Central Nervous System Tissue Lesions

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 943
Author(s):  
Hsin-Ying Clair Chiou ◽  
Shu-Hung Huang ◽  
Chih-Hsing Hung ◽  
Su-Min Tsai ◽  
Hui-Ru Kuo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Oxygen Therapy ◽  
T Cell Subsets ◽  
T Helper ◽  
Autoimmune Encephalomyelitis ◽  
Autoreactive T Cells ◽  
Gm Csf ◽  
The Central Nervous System ◽  
Cns Lesions

Multiple sclerosis (MS) is a chronic autoimmune disease mainly caused by autoreactive T cells, followed by neuronal demyelination and disabling paralysis. Hyperbaric oxygen therapy (HBOT) is usually an adjunct to therapy for the treatment of neurological disorders. However, it remains still controversial whether HBOT is an effective option for the treatment of MS. Experimental autoimmune encephalomyelitis (EAE) is a well-studied mouse model investigated for the MS pathogenesis and the efficacy of the therapeutic intervention. Both encephalitogenic Th1 and Th17 are pivotal T cell subsets immunopathogenically producing several disease-initiating/modifying cytokines in the central nervous system (CNS) lesions to further exacerbate/ameliorate the progression of EAE or MS. However, it remains unclear whether HBOT modulates the context of T helper cell subsets in CNS lesions. We employed EAE in the presence of HBOT to assess whether disease amelioration is attributed to alterations of CNS-infiltrating T cell subsets. Our results demonstrated that semi-therapeutic HBOT significantly alleviated the progression of EAE, at least, via the suppression of Th17 response, the downregulation of CD4 T helper cells expressing GM-CSF or TNF-α, and the boosting of immunomodulatory IL-4 or IL-10-expressed CD4 T cells in the CNS lesions. Conclusively, HBOT attenuated EAE through the modulation of T cell responses in an earlier stage.

scholarly journals A T cell-intrinsic function for NF-κB RelB in experimental autoimmune encephalomyelitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Guilhem Lalle ◽  
Raphaëlle Lautraite ◽  
Allison Voisin ◽  
Julie Twardowski ◽  
Pierre Stéphan ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Severity ◽  
Autoimmune Encephalomyelitis ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Nf Kappab ◽  
And Function ◽  
Experimental Autoimmune

AbstractNF-kappaB (NF-κB) is a family of transcription factors with pleiotropic functions in immune responses. The alternative NF-κB pathway that leads to the activation of RelB and NF-κB2, was previously associated with the activation and function of T cells, though the exact contribution of these NF-κB subunits remains unclear. Here, using mice carrying conditional ablation of RelB in T cells, we evaluated its role in the development of conventional CD4+ T (Tconv) cells and their function in autoimmune diseases. RelB was largely dispensable for Tconv cell homeostasis, activation and proliferation, and for their polarization toward different flavors of Thelper cells in vitro. Moreover, ablation of RelB had no impact on the capacity of Tconv cells to induce autoimmune colitis. Conversely, clinical severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) was significantly reduced in mice with RelB-deficient T cells. This was associated with impaired expression of granulocyte–macrophage colony-stimulating factor (GM-CSF) specifically in the central nervous system. Our data reveal a discrete role for RelB in the pathogenic function of Tconv cells during EAE, and highlight this transcription factor as a putative therapeutic target in MS.

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