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 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 Chronic mild and acute severe glaucomatous neurodegeneration derived from silicone oil-induced ocular hypertension

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fang Fang ◽  
Jie Zhang ◽  
Pei Zhuang ◽  
Pingting Liu ◽  
Liang Li ◽  
...  
Keyword(s):  
Ocular Hypertension ◽  
High Frequency ◽  
Molecular Mechanisms ◽  
Silicone Oil ◽  
Early Time ◽  
Similar Degree ◽  
Pupillary Dilation ◽  
Early Time Point ◽  
Chronic Model ◽  
Iop Elevation

AbstractRecently, we established silicone oil-induced ocular hypertension (SOHU) mouse model with significant glaucomatous neurodegeneration. Here we characterize two additional variations of this model that simulate two distinct glaucoma types. The first is a chronic model produced by high frequency (HF) pupillary dilation after SO-induced pupillary block, which shows sustained moderate IOP elevation and corresponding slow, mild glaucomatous neurodegeneration. We also demonstrate that although SO removal quickly returns IOP to normal, the glaucomatous neurodegeneration continues to advance to a similar degree as in the HF group without SO removal. The second, an acute model created by no pupillary dilation (ND), shows a greatly elevated IOP and severe inner retina degeneration at an early time point. Therefore, by a straightforward dilation scheme, we extend our original SOHU model to recapitulate phenotypes of two major glaucoma forms, which will be invaluable for selecting neuroprotectants and elucidating their molecular mechanisms.

scholarly journals Gene Transcription as a Therapeutic Target in Leukemia

2021 ◽  
Vol 22 (14) ◽  
pp. 7340
Author(s):  
Alvina I. Khamidullina ◽  
Ekaterina A. Varlamova ◽  
Nour Alhuda Hammoud ◽  
Margarita A. Yastrebova ◽  
Alexandra V. Bruter
Keyword(s):  
Gene Transcription ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Mechanisms Of Action ◽  
Special Program ◽  
Cell Plasticity ◽  
Hematopoietic Stem ◽  
Promising Strategy ◽  
Tumor Cell Plasticity ◽  
Transcriptional Landscape

Blood malignancies often arise from undifferentiated hematopoietic stem cells or partially differentiated stem-like cells. A tight balance of multipotency and differentiation, cell division, and quiescence underlying normal hematopoiesis requires a special program governed by the transcriptional machinery. Acquisition of drug resistance by tumor cells also involves reprogramming of their transcriptional landscape. Limiting tumor cell plasticity by disabling reprogramming of the gene transcription is a promising strategy for improvement of treatment outcomes. Herein, we review the molecular mechanisms of action of transcription-targeted drugs in hematological malignancies (largely in leukemia) with particular respect to the results of clinical trials.

scholarly journals MECHANISMS OF NEPHROSCLEROSIS DEVELOPMENT IN CHILDREN WITH VESICOURETERAL REFLUX

2018 ◽  
Vol 17 (3) ◽  
pp. 186-193
Author(s):  
Olga L. Morozova ◽  
Peter F. Litvitskiy ◽  
Dmitri A. Morozov ◽  
Larisa D. Maltseva
Keyword(s):  
Vesicoureteral Reflux ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Reflux Nephropathy ◽  
Disease Development ◽  
Disease Course ◽  
Multiple Choice Tests ◽  
Lecture Material ◽  
Choice Tests ◽  
Higher Medical Education

The lecture discusses the issue of reflux nephropathy for specialists of the system of higher medical education: the article provides the definition, characterizes the epidemiology, risk factors for disease development in children with vesicoureteral reflux, causes and molecular mechanisms of renal fibrosis formation and progression in reflux nephropathy, and markers for diagnosing and predicting the disease course. In order to control the retention of the lecture material, the text includes case problems and multiple-choice tests.

scholarly journals Mapping Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells

2021 ◽  
Author(s):  
Ankitha Shetty ◽  
Santosh D. Bhosale ◽  
Subhash Kumar Tripathi ◽  
Tanja Buchacher ◽  
Rahul Biradar ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Affinity Purification ◽  
Mass Spectrometry Analysis ◽  
Binding Partners ◽  
Th17 Cell Differentiation

Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell-differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among these, FOSL1 and FOSL2 influence the effector responses of Th17 cells. However, the molecular mechanisms underlying their functions are unclear, owing to the poorly characterized protein interaction networks of these factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification–mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a major fraction of these interactors to be associated with RNA binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17-fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL1 and FOSL2 that potentially govern Th17 cell-differentiation and associated pathologies.

scholarly journals Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity

2019 ◽  
Vol 20 (1) ◽  
pp. 190 ◽  
Author(s):  
Stefanie Scheu ◽  
Shafaqat Ali ◽  
Ritu Mann-Nüttel ◽  
Lisa Richter ◽  
Volker Arolt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Molecular Mechanisms ◽  
Chronic Inflammatory Disease ◽  
Clinical Severity ◽  
Interferon Β ◽  
Treatment Regimens ◽  
Cns Autoimmunity ◽  
And Function ◽  
The Impact

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE.

scholarly journals Indigo Naturalis Suppresses Colonic Oxidative Stress and Th1/Th17 Responses of DSS-Induced Colitis in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Hai-tao Xiao ◽  
Jiao Peng ◽  
Bo Wen ◽  
Dong-dong Hu ◽  
Xiao-peng Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chinese Medicine ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Activity Index ◽  
Disease Activity Index ◽  
Protective Effects ◽  
Mesenteric Lymph Nodes ◽  
Indigo Naturalis

Indigo naturalis (also known as Qing-dai, or QD), a traditional Chinese medicine, has been widely used as an anticolitis regimen in the clinical practice of Chinese medicine. However, the precise mechanisms behind its efficacy remain unknown. We investigated the protective effects and associated molecular mechanisms of QD in DSS-induced colitis in mice. We found that QD administration attenuated DSS-induced colon shortening, tissue damage, and the disease activity index during the onset of colitis. Moreover, QD administration significantly suppressed colonic MPO activity and increased the activities of colonic T-SOD, CAT, and GSH-Px, as well the expression of p-AMPK and Nrf-2 in colon tissues of colitic mice. In addition, QD was capable of reducing the colonic Th1 and Th17 cell cytokines, the frequencies of Th1 and Th17 cells, and the phosphorylation of p-STAT1 and p-STAT3 in the mesenteric lymph nodes of colitic mice. An in vitro assay showed that QD significantly suppressed the differentiation of Th1 and Th17 cells. These findings suggest that QD has the potential to alleviate experimental colitis by suppressing colonic oxidative stress and restraining colonic Th1/Th17 responses, which are associated with activating AMPK/Nrf-2 signals and inhibiting STAT1/STAT3 signals, respectively. These findings also support QD as an effective regimen in the treatment of IBD.

scholarly journals Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

2009 ◽  
Vol 206 (11) ◽  
pp. 2407-2416 ◽  
Author(s):  
Jyoti Das ◽  
Guangwen Ren ◽  
Liying Zhang ◽  
Arthur I. Roberts ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Th2 Cells ◽  
Th17 Cell Differentiation ◽  
Th1 And Th2

Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor γt, a Th17-specific transcription factor. Interestingly, in Stat-6−/−T-bet−/− mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6−/−T-bet−/− mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.

scholarly journals Abundant c-Fas–associated death domain–like interleukin-1–converting enzyme inhibitory protein expression determines resistance of T helper 17 cells to activation-induced cell death

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1026-1028 ◽  
Author(s):  
Yu Yu ◽  
Cristina Iclozan ◽  
Tomohide Yamazaki ◽  
Xuexian Yang ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
Cell Death ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Interleukin 17 ◽  
Death Domain ◽  
Converting Enzyme ◽  
T Helper ◽  
Inhibitory Protein ◽  
Activation Induced Cell Death

Activation-induced cell death (AICD) plays an important role in peripheral T-cell tolerance. AICD in CD4 T helper (Th) cells, including Th1 and Th2 effectors, has been extensively studied. Recently, interleukin-17–producing CD4+ T cells (Th17 cells) have been identified as a unique Th subset, but their susceptibility to AICD and the underlying molecular mechanisms have not been defined. In this study, we found that Th17 cells were significantly less susceptible to AICD than Th1 cells, and Th17 cell resistance to AICD is due to the high levels of c-Fas–associated death domain–like interleukin-1–converting enzyme inhibitory protein preventing Fas-mediated apoptosis. The resistance of Th17 cells to AICD reveals a novel mechanism to explain the high pathogenicity of Th17 cells in autoimmune diseases, and may also provide a rationale to generate tumor-specific Th17 cells for adoptive immunotherapy.

scholarly journals Molecular Mechanisms Involved in Schwann Cell Plasticity

2017 ◽  
Vol 10 ◽  
Author(s):  
Angélique Boerboom ◽  
Valérie Dion ◽  
Alain Chariot ◽  
Rachelle Franzen
Keyword(s):  
Schwann Cell ◽  
Molecular Mechanisms ◽  
Cell Plasticity
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