scholarly journals Age related susceptibility to grey matter demyelination and neurodegeneration is associated with meningeal neutrophil accumulation in an animal model of Multiple Sclerosis

2021 ◽  
Author(s):  
Michelle Zuo ◽  
Naomi Fettig ◽  
Louis-Philippe Bernier ◽  
Elisabeth Possnecker ◽  
Shoshana Spring ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Th17 Cells ◽  
Grey Matter ◽  
Clinical Symptoms ◽  
White Matter Lesions ◽  
Neutrophil Accumulation ◽  
Cns Inflammation ◽  
Age Related ◽  
Meningeal Inflammation

People living with multiple sclerosis (MS) experience episodic central nervous system (CNS) white matter lesions instigated by autoreactive T cells. With age, MS patients show evidence of grey matter demyelination and experience devastating non-remitting symptomology. What drives progression is unclear and has been hampered by the lack of suitable animal models. Here we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induces a non-remitting clinical phenotype that is associated with persistent meningeal inflammation and cortical pathology in old, but not young SJL/J mice. While the quantity and quality of T cells did not differ in the brains of old vs young EAE mice, an increase in neutrophils and a decrease in B cells was observed in the brains of old mice. Neutrophils were also found in the meninges of a subset of progressive MS patient brains that showed evidence of meningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and grey matter pathology are dictated by age and associated with other immune cells such as neutrophils.

Author response for "White matter lesions in multiple sclerosis are enriched for CD20 dim CD8 + tissue‐resident memory T cells"

2020 ◽  
Author(s):  
Cheng‐Chih Hsiao ◽  
Nina L. Fransen ◽  
Aletta M.R. den Bosch ◽  
Kim I.M. Brandwijk ◽  
Inge Huitinga ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
White Matter ◽  
Memory T Cells ◽  
White Matter Lesions ◽  
Author Response ◽  
Resident Memory T Cells

scholarly journals Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

2021 ◽  
Vol 141 (4) ◽  
pp. 585-604 ◽  
Author(s):  
Carmen Picon ◽  
Anusha Jayaraman ◽  
Rachel James ◽  
Catriona Beck ◽  
Patricia Gallego ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Signaling Pathway ◽  
Cortical Neurons ◽  
Grey Matter ◽  
Molecular Mechanisms ◽  
Fold Increase ◽  
Cell Types ◽  
Meningeal Inflammation ◽  
Cortical Grey Matter

AbstractSustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

scholarly journals Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients

2017 ◽  
Vol 134 (3) ◽  
pp. 383-401 ◽  
Author(s):  
Gijsbert P. van Nierop ◽  
Marvin M. van Luijn ◽  
Samira S. Michels ◽  
Marie-Jose Melief ◽  
Malou Janssen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
White Matter ◽  
Functional Characterization ◽  
White Matter Lesions ◽  
Multiple Sclerosis Patients

White matter lesions in multiple sclerosis are enriched for CD20 dim CD8 + tissue‐resident memory T cells

2020 ◽  
Author(s):  
Cheng‐Chih Hsiao ◽  
Nina L. Fransen ◽  
Aletta M.R. van den Bosch ◽  
Kim I.M. Brandwijk ◽  
Inge Huitinga ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
White Matter ◽  
Memory T Cells ◽  
White Matter Lesions ◽  
Resident Memory T Cells

Fingolimod Treatment Reduces Circulating CD4+ Regulatory T Cells and Th17 Cells in Blood of Patients with Multiple Sclerosis (P02.112)

Neurology ◽  
2012 ◽  
Vol 78 (Meeting Abstracts 1) ◽  
pp. P02.112-P02.112 ◽  
Author(s):  
V. Brinkmann ◽  
F. Raulf ◽  
C. Vedrine ◽  
C. Allard
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Th17 Cells

scholarly journals A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis

2001 ◽  
Vol 194 (5) ◽  
pp. 669-676 ◽  
Author(s):  
Eric S. Huseby ◽  
Denny Liggitt ◽  
Thea Brabb ◽  
Bryan Schnabel ◽  
Claes Öhlén ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Autoimmune Encephalomyelitis ◽  
Effector Cells ◽  
Cns Autoimmunity ◽  
The Central Nervous System

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4+ and CD8+ T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4+ myelin-specific T cells. The role of CD8+ myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8+ T cell–mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4+ T cell–mediated EAE. These data suggest that myelin-specific CD8+ T cells could function as effector cells in the pathogenesis of MS.

scholarly journals The direct deleterious effect of Th17 cells in the nervous system compartment in multiple sclerosis and experimental autoimmune encephalomyelitis: one possible link between neuroinflammation and neurodegeneration

2020 ◽  
Vol 28 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Rodica Balasa ◽  
Smaranda Maier ◽  
Laura Barcutean ◽  
Adina Stoian ◽  
Anca Motataianu
Keyword(s):  
Multiple Sclerosis ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Th17 Cells ◽  
Direct Interaction ◽  
Autoimmune Encephalomyelitis ◽  
Cns Inflammation ◽  
Direct Role ◽  
Autoimmune Attack ◽  
Experimental Autoimmune

AbstractThe processes of demyelination and neurodegeneration in the central nervous system (CNS) of multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) are secondary to numerous pathophysiological mechanisms. One of the main cellular players is the Th17 lymphocyte. One of the major functions described for Th17 cells is the upregulation of pro-inflammatory cytokines, such as IL-17 at the level of peripheral and CNS inflammation. This review will focus on the newly described and unexpected, direct role played by the Th17 cells in the CNS of MS patients and EAE models. Th17 and their main cytokine, IL-17, are actively involved in the onset and maintenance of the immune cascade in the CNS compartment as Th17 were found to achieve brain-homing potential. Direct interaction of myelin oligodendrocyte glycoprotein - specific Th17 with the neuronal cells firstly induces demyelination and secondly, extensive axonal damage. The Th17 cells promote an inflammatory B cell response beyond the BBB through the presence of infiltrating Th follicles. Due to their role in preventing remyelination and direct neurotoxic effect, Th17 cells might stand for an important connection between neuroinflammation and neurodegeneration in a devastating disease like MS. The Th17 cell populations have different mechanisms of provoking an autoimmune attack not only in the periphery but also in the CNS of MS patients.

scholarly journals T-cell responses to acute cardiorespiratory or resistance exercise in cohorts of physically active or physically inactive older adults: A randomized complete crossover

2021 ◽  
Author(s):  
Rachel M. Graff ◽  
Kristofer Jennings ◽  
Emily C. LaVoy ◽  
Victoria E. Warren ◽  
Brad W. Macdonald ◽  
...  
Keyword(s):  
Older Adults ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Th17 Cells ◽  
T Cell Response ◽  
Moderate Intensity ◽  
Physically Active ◽  
Post Exercise ◽  
Age Related

AbstractAging is associated with many chronic diseases that are maintained and perpetuated by immune dysregulation and chronic systemic inflammation. T-cells often undergo age-related changes, including an accumulation of memory cells, which places individuals at increased risk for novel infections and may predispose them to increased inflammation. Regular exercise training has been suggested to offset age-related changes in T-cells, but the majority of literature is derived from cardiorespiratory exercise (CRE) studies. Much less is understood about the T-cell response to resistance exercise (RE). The purpose of this study was to examine the effects of acute CRE and acute RE on the T-cell response among a cohort of physically active older adults (PA) compared to a cohort of physically inactive older adults (PI).METHODSTwenty-four healthy older adults (PA n=12; PI n=12; mean ± SD; age (yrs) PA 62 ± 5, PI 64 ± 5; height (cm) PA 170.9 ± 6.9, PI 162.9 ± 8.0; weight (kg) PA 69.3 ± 10.2, PI 68.2 ± 12.8; BMI (kg/m2) PA 23.9 ± 3.0, PI 25.6 ± 3.5) completed one bout of CRE and one bout of RE in a randomized order, both at a moderate intensity, and separated by at least 7 days. Blood samples drawn pre-exercise, post-exercise, and 1h post-exercise (recovery) were analyzed for CD4+ and CD8+ T-cells and their differentiation status using surface markers CD45RA, CD62L, and CD57, as well as for Th17 cells (CD4+ CD161+ CD196+) using flow cytometry.RESULTSPI had higher numbers of circulating CD57+ EMRA CD4+ T-cells (PA, mean ± SE, 1 ± 2 cells/uL; PI, 6 ± 2 cells/uL; p=0.01; z=2.32) than PA at pre-exercise. Both CRE and RE elicited a significant mobilization of highly-differentiated (CD45RA+ CD62L-; CD57+ CD45RA+ CD62L-) CD8+ T-cells into the circulation post-exercise in both PA and PI groups. Furthermore, CRE resulted in a decrease in the number of circulating Th17 cells post-exercise, while RE increased Th17 cell mobilization compared to the CRE response.CONCLUSIONTaken together, T-cells in PA and PI respond similarly to acute CRE and support previously reported data showing a significant mobilization of highly differentiated T-cells. The present study confirms that moderate intensity RE also elicits this response, but highlights potential differences between CRE and RE on the immune responses of T-cells, particularly in PI individuals.Clinical trial registrationThis research study was registered at clinicaltrials.gov NCT03794050

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