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1.
Clin Transl Immunology ; 12(5): e1450, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37223338

RESUMO

Objectives: Myasthenia gravis (MG) is a classic autoantibody-mediated disease in which pathogenic antibodies target postsynaptic membrane components, causing fluctuating skeletal muscle weakness and fatigue. Natural killer (NK) cells are heterogeneous lymphocytes that have gained increasing attention owing to their potential roles in autoimmune disorders. This study will investigate the relationship between the distinct NK cell subsets and MG pathogenesis. Methods: A total of 33 MG patients and 19 healthy controls were enrolled in the present study. Circulating NK cells, their subtypes and follicular helper T cells were analysed by flow cytometry. Serum acetylcholine receptor (AChR) antibody levels were determined by ELISA. The role of NK cells in the regulation of B cells was verified using a co-culture assay. Results: Myasthenia gravis patients with acute exacerbations had a reduced number of total NK cells, CD56dim NK cells and IFN-γ-secreting NK cells in the peripheral blood, while CXCR5+ NK cells were significantly elevated. CXCR5+ NK cells expressed a higher level of ICOS and PD-1 and a lower level of IFN-γ than those in CXCR5- NK cells and were positively correlated with Tfh cell and AChR antibody levels. In vitro experiments demonstrated that NK cells suppressed plasmablast differentiation while promoting CD80 and PD-L1 expression on B cells in an IFN-γ-dependent manner. Furthermore, CXCR5- NK cells inhibited plasmablast differentiation, while CXCR5+ NK cells could more efficiently promote B cell proliferation. Conclusion: These results reveal that CXCR5+ NK cells exhibit distinct phenotypes and functions compared with CXCR5- NK cells and might participate in the pathogenesis of MG.

2.
Front Genet ; 13: 1022640, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36338967

RESUMO

Myotonic dystrophy type I (DM1), a CTG repeat expansion hereditary disorder, is primarily characterized by myotonia. Several studies have reported that abnormal autophagy pathway has a close relationship with DM1. However, the underlying key regulatory molecules dictating autophagy disturbance still remains elusive. Previous studies mainly focused on finding targeted therapies for DM1, but the clinical heterogeneity of the DM1 is rarely addressed. Herein, to identify potential regulator genes related to autophagy and cross-correlation among clinical symptoms, we performed weighted gene co-expression network analysis (WGCNA) to construct the co-expression network and screened out 7 core autophagy-related genes (DAPK1, KLHL4, ERBB3, SESN3, ATF4, MEG3, and COL1A1) by overlapping within differentially expressed genes (DEG), cytoHubba, gene significance (GS) and module membership (MM) score. Meanwhile, we here analyzed autophagy-related molecular subtypes of DM1 in relation to the clinical phenotype. Our results show that three genes (DAPK1, SESN3, and MEG3) contribute to distinguish these two molecular subtypes of DM1. We then develop an analysis of RNA-seq data from six human skin fibroblasts (3 DM1, 3 healthy donors). Intriguingly, of the 7 hallmark genes obtained, DAPK1 is the only confirmed gene, and finally identified in vitro by RT-PCR. Furthermore, we assessed the DAPK1 accuracy diagnosis of DM1 by plotting a receiver operating characteristic curve (ROC) (AUC = 0.965). In this study, we first validated autophagy status of DM1 individuals exhibits a clearly heterogeneity. Our study identified and validated DAPK1 serve as a novel autophagy-related biomarker that correlate with the progression of DM1.

3.
J Neuroinflammation ; 18(1): 244, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702288

RESUMO

BACKGROUND: Diabetes mellitus (DM) is a common concomitant disease of late-onset myasthenia gravis (MG). However, the impacts of DM on the progression of late-onset MG were unclear. METHODS: In this study, we examined the immune response in experimental autoimmune myasthenia gravis (EAMG) rats with DM or not. The phenotype and function of the spleen and lymph nodes were determined by flow cytometry. The serum antibodies, Tfh cells, and germinal center B cells were determined by ELISA and flow cytometry. The roles of advanced glycation end products (AGEs) in regulating Tfh cells were further explored in vitro by co-culture assays. RESULTS: Our results indicated clinical scores of EAMG rats were worse in diabetes rats compared to control, which was due to the increased production of anti-R97-116 antibody and antibody-secreting cells. Furthermore, diabetes induced a significant upregulation of Tfh cells and the subtypes of Tfh1 and Tfh17 cells to provide assistance for antibody production. The total percentages of B cells were increased with an activated statue of improved expression of costimulatory molecules CD80 and CD86. We found CD4+ T-cell differentiation was shifted from Treg cells towards Th1/Th17 in the DM+EAMG group compared to the EAMG group. In addition, in innate immunity, diabetic EAMG rats displayed more CXCR5 expression on NK cells. However, the expression of CXCR5 on NKT cells was down-regulated with the increased percentages of NKT cells in the DM+EAMG group. Ex vivo studies further indicated that Tfh cells were upregulated by AGEs instead of hyperglycemia. The upregulation was mediated by the existence of B cells, the mechanism of which might be attributed the elevated molecule CD40 on B cells. CONCLUSIONS: Diabetes promoted both adaptive and innate immunity and exacerbated clinical symptoms in EAMG rats. Considering the effect of diabetes, therapy in reducing blood glucose levels in MG patients might improve clinical efficacy through suppressing the both innate and adaptive immune responses. Additional studies are needed to confirm the effect of glucose or AGEs reduction to seek treatment for MG.


Assuntos
Imunidade Adaptativa/fisiologia , Diabetes Mellitus Experimental/imunologia , Imunidade Inata/fisiologia , Mediadores da Inflamação/imunologia , Miastenia Gravis Autoimune Experimental/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Técnicas de Cocultura , Diabetes Mellitus Experimental/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Miastenia Gravis Autoimune Experimental/metabolismo , Ratos , Ratos Endogâmicos Lew , Células Th17/imunologia , Células Th17/metabolismo
4.
Int Immunopharmacol ; 96: 107511, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33915521

RESUMO

Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor antagonist, possesses potent immunomodulatory activity via lymphocyte homing. The effects of FTY720 have been widely studied in various T-cell-mediated autoimmune diseases, while the immunomodulatory effects on experimental autoimmune myasthenia gravis (EAMG), a typical disease model for antibody-mediated autoimmunity, remain elusive. In the present study, FTY720 was administered to EAMG rats as prophylaxis. The clinical scores were recorded every other day, and serum antibodies at different time points were measured by enzyme-linked immunosorbent assay (ELISA). The immune cell subsets in the spleen, bone marrow, circulation, and thymus were determined by flow cytometry. The prophylactic administration alleviated EAMG symptoms by reducing the level of serum antibodies IgG and its isotype IgG2b on days 30 and 46 post immunization, as well as IgG and Ig kappa antibody-secreting cells in the spleen and bone marrow. The mitigated humoral immune response can be attributed to the decreased dendritic cells, follicular T help cells (Tfh) and Tfh subsets (Tfh1, Tfh2, and Tfh17), and T helper cell subsets (Th1, Th2, and Th17) in the spleen. The promotion of lymphocyte homing and inhibition of thymocyte egress contribute to the effects of FTY720 on these effector T cell subsets. Overall, the prophylactic administration of FTY720 ameliorated EAMG partially by regulating humoral immune response,suggesting that FTY720 could be part of a pharmacological strategy for managing myasthenia gravis.


Assuntos
Células Produtoras de Anticorpos/imunologia , Células Dendríticas/imunologia , Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Miastenia Gravis/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoantígenos/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Humoral , Peptídeos/imunologia , Ratos , Ratos Endogâmicos Lew , Receptores Colinérgicos/imunologia
6.
Front Immunol ; 11: 1603, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793234

RESUMO

Guillain-Barré syndrome (GBS), an immune-mediated disorder affecting the peripheral nervous system, is the most common and severe acute paralytic neuropathy. GBS remains to be potentially life-threatening and disabling despite the increasing availability of current standard therapeutic regimens. Therefore, more targeted therapeutics are in urgent need. Macrophages have been implicated in both initiation and resolution of experimental autoimmune neuritis (EAN), the animal model of GBS, but the exact mechanisms remain to be elucidated. It has been increasingly appreciated that exosomes, a type of extracellular vesicles (EVs), are of importance for functions of macrophages. Nevertheless, the roles of macrophage derived exosomes in EAN/GBS remain unclear. Here we determined the effects of macrophage derived exosomes on the development of EAN in Lewis rats. M1 macrophage derived exosomes (M1 exosomes) were found to aggravate EAN via boosting Th1 and Th17 response, while M2 macrophage derived exosomes (M2 exosomes) showed potentials to mitigate disease severity via a mechanism bypassing Th1 and Th17 response. Besides, both M1 and M2 exosomes increased germinal center reactions in EAN. Further in vitro studies confirmed that M1 exosomes could directly promote IFN-γ production in T cells and M2 exosomes were not capable of inhibiting IFN-γ expression. Thus, our data identify a previously undescribed means that M1 macrophages amplify Th1 response via exosomes and provide novel insights into the crosstalk between macrophages and T cells as well.


Assuntos
Exossomos/imunologia , Síndrome de Guillain-Barré/imunologia , Macrófagos/imunologia , Neurite Autoimune Experimental/imunologia , Células Th1/imunologia , Animais , Progressão da Doença , Feminino , Centro Germinativo/imunologia , Síndrome de Guillain-Barré/patologia , Imunidade Celular , Imunidade Inata , Interferon gama/imunologia , Ativação de Macrófagos , Neurite Autoimune Experimental/patologia , Ratos Endogâmicos Lew , Linfócitos T/imunologia , Células Th17/imunologia
7.
J Neuroinflammation ; 16(1): 202, 2019 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-31679515

RESUMO

BACKGROUND: The thymus plays an essential role in the pathogenesis of myasthenia gravis (MG). In patients with MG, natural regulatory T cells (nTreg), a subpopulation of T cells that maintain tolerance to self-antigens, are severely impaired in the thymuses. In our previous study, upregulated nTreg cells were observed in the thymuses of rats in experimental autoimmune myasthenia gravis after treatment with exosomes derived from statin-modified dendritic cells (statin-Dex). METHODS: We evaluated the effects of exosomes on surface co-stimulation markers and Aire expression of different kinds of thymic stromal cells, including cTEC, mTEC, and tDCs, in EAMG rats. The isolated exosomes were examined by western blot and DLS. Immunofluorescence was used to track the exosomes in the thymus. Flow cytometry and western blot were used to analyze the expression of co-stimulatory molecules and Aire in vivo and in vitro. RESULTS: We confirmed the effects of statin-Dex in inducing Foxp3+ nTreg cells and found that both statin-Dex and DMSO-Dex could upregulate CD40 but only statin-Dex increased Aire expression in thymic stromal cells in vivo. Furthermore, we found that the role of statin-Dex and DMSO-Dex in the induction of Foxp3+ nTreg cells was dependent on epithelial cells in vitro. CONCLUSIONS: We demonstrated that statin-Dex increased expression of Aire in the thymus, which may further promote the Foxp3 expression in the thymus. These findings may provide a new strategy for the treatment of myasthenia gravis.


Assuntos
Exossomos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Miastenia Gravis Autoimune Experimental/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Animais , Atorvastatina/farmacologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Dendríticas/metabolismo , Feminino , Ratos , Ratos Endogâmicos Lew , Linfócitos T Reguladores/citologia , Timo , Fatores de Transcrição/metabolismo , Proteína AIRE
8.
J Neuroinflammation ; 15(1): 51, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29467007

RESUMO

BACKGROUND: With the recognition of the key roles of cellular metabolism in immunity, targeting metabolic pathway becomes a new strategy for autoimmune disease treatment. Guillain-Barré syndrome (GBS) is an acute immune-mediated inflammatory demyelinating disease of the peripheral nervous system, characterized by inflammatory cell infiltration. These inflammatory cells, including activated macrophages, Th1 cells, and Th17 cells, generally undergo metabolic reprogramming and rely mainly on glycolysis to exert functions. This study aimed to explore whether enhanced glycolysis contributed to the pathogenesis of experimental autoimmune neuritis (EAN), a classic model of GBS. METHODS: Preventive and therapeutic treatments with glycolysis inhibitor, 2-deoxy-D-glucose (2-DG), were applied to EAN rats. The effects of treatments were determined by clinical scoring, weighting, and tissue examination. Flow cytometry and ELISA were used to evaluate T cell differentiation, autoantibody level, and macrophage functions in vivo and in vitro. RESULTS: Glycolysis inhibition with 2-DG not only inhibited the initiation, but also prevented the progression of EAN, evidenced by the improved clinical scores, weight loss, inflammatory cell infiltration, and demyelination of sciatic nerves. 2-DG inhibited the differentiation of Th1, Th17, and Tfh cells but enhanced Treg cell development, accompanied with reduced autoantibody secretion. Further experiments in vitro proved glycolysis inhibition decreased the nitric oxide production and phagocytosis of macrophages and suppressed the maturation of dendritic cells (DC). CONCLUSION: The effects of glycolysis inhibition on both innate and adaptive immune responses and the alleviation of animal clinical symptoms indicated that enhanced glycolysis contributed to the pathogenesis of EAN. Glycolysis inhibition may be a new therapy for GBS.


Assuntos
Glicólise/fisiologia , Neurite Autoimune Experimental/induzido quimicamente , Neurite Autoimune Experimental/metabolismo , Animais , Desoxiglucose/farmacologia , Desoxiglucose/uso terapêutico , Glicólise/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/fisiologia , Lipopolissacarídeos/toxicidade , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Neurite Autoimune Experimental/tratamento farmacológico , Células RAW 264.7 , Ratos , Ratos Endogâmicos Lew
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