scholarly journals Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of central nervous system autoimmunity

Cell Reports ◽  
2021 ◽  
Vol 34 (10) ◽  
pp. 108833
Author(s):  
Prenitha Mercy Ignatius Arokia Doss ◽  
Muhammad Umair ◽  
Joanie Baillargeon ◽  
Reda Fazazi ◽  
Neva Fudge ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Th17 Cells ◽  
Chromosomal Complement ◽  
Chronic Model ◽  
Male Sex

scholarly journals Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of CNS autoimmunity

2019 ◽  
Author(s):  
Prenitha Mercy Ignatius Arokia Doss ◽  
Joanie Baillargeon ◽  
Asmita Pradeep Yeola ◽  
John B. Williams ◽  
Mickael Leclercq ◽  
...  
Keyword(s):  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Transfer Model ◽  
Disease Course ◽  
Cell Plasticity ◽  
Chromosomal Complement ◽  
Chronic Model ◽  
Cns Autoimmunity ◽  
Male Sex ◽  
Cell Adoptive Transfer

SummarySex differences in the incidence and severity of multiple sclerosis (MS) have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive and debilitating disease remain poorly defined. Using an T cell adoptive transfer model of chronic EAE, we find that male Th17 cells induced disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produced the heterodox cytokine IFNγ, a hallmark of pathogenic Th17 responses. Intriguingly, sex chromosomal complement, and not hormones, were responsible for the increased pathogenicity of male Th17 cells and an X-linked immune regulator, Jarid1c, was downregulated in both pathogenic male Th17 and CD4+ T cells from men with MS. Together, our data indicate that male sex critical regulates Th17 cell plasticity and pathogenicity via sex chromosomal complement.

scholarly journals ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid

2016 ◽  
Vol 197 (7) ◽  
pp. 2598-2609 ◽  
Author(s):  
Maria Aggelakopoulou ◽  
Evangelia Kourepini ◽  
Nikolaos Paschalidis ◽  
Davina C. M. Simoes ◽  
Dimitra Kalavrizioti ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Th17 Cells ◽  
Direct Suppression

scholarly journals The Th17–ELR+ CXC chemokine pathway is essential for the development of central nervous system autoimmune disease

2008 ◽  
Vol 205 (4) ◽  
pp. 811-823 ◽  
Author(s):  
Thaddeus Carlson ◽  
Mark Kroenke ◽  
Praveen Rao ◽  
Thomas E. Lane ◽  
Benjamin Segal
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Th17 Cells ◽  
Polymorphonuclear Leukocytes ◽  
Autoimmune Encephalomyelitis ◽  
Cxc Chemokine ◽  
The Central Nervous System ◽  
Autoimmune Demyelination ◽  
Clinical Deficits ◽  
Experimental Autoimmune

The ELR+ CXC chemokines CXCL1 and CXCL2 are up-regulated in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, their functional significance and the pathways regulating their expression are largely unknown. We show that transfer of encephalitogenic CD4+ Th17 cells is sufficient to induce CXCL1 and CXCL2 transcription in the spinal cords of naive, syngeneic recipients. Blockade or genetic silencing of CXCR2, a major receptor for these chemokines in mice, abrogates blood–brain barrier (BBB) breakdown, CNS infiltration by leukocytes, and the development of clinical deficits during the presentation as well as relapses of EAE. Depletion of circulating polymorphonuclear leukocytes (PMN) had a similar therapeutic effect. Furthermore, injection of CXCR2+ PMN into CXCR2−/− mice was sufficient to restore susceptibility to EAE. Our findings reveal that a Th17–ELR+ CXC chemokine pathway is critical for granulocyte mobilization, BBB compromise, and the clinical manifestation of autoimmune demyelination in myelin peptide–sensitized mice, and suggest new therapeutic targets for diseases such as MS.

scholarly journals Study of the switch-over from the profile Th17 lymphocytes to Th1-like during the evolution of experimental autoimmune encephalomyelitis

2018 ◽  
Author(s):  
Bruna Bueno de Campos ◽  
Alessandro dos Santos Farias ◽  
Rani Cocenza ◽  
Fernando Pradella
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Cytotoxic Activity ◽  
Crucial Role ◽  
Th17 Cells ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Lymphocytes ◽  
The Central Nervous System ◽  
Experimental Autoimmune

It has been demonstrated the cytotoxic activity of TCD4+ encaphalitogenic lymphocytes and it's crucial role in the development of Experimental Autoimmune Encephalomyelitis (EAE). Furthermore, our laboratory has seen a switch from Th17 profile to Th1-like during the evolution of EAE. Thus, these lymphocytes decreased IL-17A production while begin to produce IFNγ when infiltrate the central nervous system. Therefore, our goal was to verify the mechanisms that governs the convertion of Th17 cells into IFNγ-producing cells.

scholarly journals Th17 Cells Induce Ectopic Lymphoid Follicles in Central Nervous System Tissue Inflammation

Immunity ◽  
2011 ◽  
Vol 35 (6) ◽  
pp. 986-996 ◽  
Author(s):  
Anneli Peters ◽  
Lisa A. Pitcher ◽  
Jenna M. Sullivan ◽  
Meike Mitsdoerffer ◽  
Sophie E. Acton ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Th17 Cells ◽  
Central Nervous System Tissue ◽  
Lymphoid Follicles ◽  
Tissue Inflammation

scholarly journals Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease

2014 ◽  
Vol 120 (5) ◽  
pp. 1055-1062 ◽  
Author(s):  
Russell R. Lonser ◽  
John A. Butman ◽  
Kristin Huntoon ◽  
Ashok R. Asthagiri ◽  
Tianxia Wu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Natural History ◽  
Cauda Equina ◽  
Area Under The Curve ◽  
Neurological Impairment ◽  
Clinical Trial Registration ◽  
Von Hippel Lindau ◽  
Male Sex

Object The tumors most frequently associated with von Hippel-Lindau (VHL) disease are hemangioblastomas. While they are associated with significant neurological impairment and mortality, their natural history and optimal management have not been fully defined. Methods Patients with VHL were enrolled in a prospective study designed to define the natural history of CNS hemangioblastomas. In the present analysis, serial imaging, laboratory, genetic, and clinical data were evaluated in those with at least 2 years of follow-up data. Results At study entrance 225 patients (111 males, 114 females) harbored 1921 CNS hemangioblastomas in the supratentorial compartment (21 tumors [1%]), cerebellum (865 [45%]), brainstem (129 [7%]), spinal cord (689 [36%]), cauda equina (212 [11%]), and nerve roots (5 [0.3%]; follow-up 15,819 hemangioblastoma-years). Increased tumor burden was associated with partial deletions in the VHL gene (p = 0.005) and male sex (p = 0.002). Hemangioblastoma development (median 0.3 new tumors/year) was associated with younger age (p < 0.0001) and more tumors at study entrance (p < 0.0001). While 1278 hemangioblastomas (51%) did not grow, 1227 hemangioblastomas (49%) grew in a saltatory (886 [72%]), linear (76 [6%]), or exponential (264 [22%]) pattern. Faster tumor growth was associated with male sex (p = 0.001), symptomatic tumors (p < 0.0001), and tumors associated with cysts (p < 0.0001). Location-dependent tumor size was the primary predictor of eventual symptom formation (159 symptomatic tumors [6.3%]; area under the curve > 0.9). Conclusions Central nervous system hemangioblastoma burden in VHL is associated with partial germline deletions and male sex. Unpredictable growth of hemangioblastomas compromises assessment of nonsurgical therapies. The judicious treatment of symptom-producing hemangioblastomas, while avoiding unnecessary treatment of asymptomatic tumors that may not progress, can provide clinical stability. Clinical trial registration no.: NCT00005902 (ClinicalTrials.gov).

scholarly journals Th17 lymphocytes traffic to the central nervous system independently of α4 integrin expression during EAE

2011 ◽  
Vol 208 (12) ◽  
pp. 2465-2476 ◽  
Author(s):  
Veit Rothhammer ◽  
Sylvia Heink ◽  
Franziska Petermann ◽  
Rajneesh Srivastava ◽  
Malte C. Claussen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Th17 Cells ◽  
Brain Parenchyma ◽  
Th1 Cells ◽  
Th17 Lymphocytes ◽  
The Central Nervous System ◽  
The Brain

The integrin α4β1 (VLA-4) is used by encephalitogenic T cells to enter the central nervous system (CNS). However, both Th1 and Th17 cells are capable of inducing experimental autoimmune encephalomyelitis (EAE), and the molecular cues mediating the infiltration of Th1 versus Th17 cells into the CNS have not yet been defined. We investigated how blocking of α4 integrins affected trafficking of Th1 and Th17 cells into the CNS during EAE. Although antibody-mediated inhibition of α4 integrins prevented EAE when MOG35-55-specific Th1 cells were adoptively transferred, Th17 cells entered the brain, but not the spinal cord parenchyma, irrespective of α4 blockade. Accordingly, T cell–conditional α4-deficient mice were not resistant to actively induced EAE but showed an ataxic syndrome with predominantly supraspinal infiltrates of IL-23R+CCR6+CD4+ T cells. The entry of α4-deficient Th17 cells into the CNS was abolished by blockade of LFA-1 (αLβ2 integrin). Thus, Th1 cells preferentially infiltrate the spinal cord via an α4 integrin–mediated mechanism, whereas the entry of Th17 cells into the brain parenchyma occurs in the absence of α4 integrins but is dependent on the expression of αLβ2. These observations have implications for the understanding of lesion localization, immunosurveillance, and drug design in multiple sclerosis.

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