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1.
Exp Parasitol ; 217: 107966, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32781094

RESUMO

Toxoplasma gondii has long been considered a ubiquitous parasite possessing the capacity of infecting virtually all warm-blooded animals globally. Occasionally, this parasite can also infect cold-blooded animals such as fish if their body temperature reaches 37 °C. However, we are currently lacking an understanding of key details such as the minimum temperature required for T. gondii invasion and proliferation in these cold-blooded animals and their cells. Here, we performed in vitro T. gondii infection experiments with rat embryo fibroblasts (REF cells), grouper (Epinephelus coioides) splenocytes (GS cells) and zebra fish (Danio rerio) hepatocytes (ZFL cells), at 27 °C, 30 °C, 32 °C, 35 °C and 37 °C, respectively. We found that T. gondii tachyzoites could penetrate REF, GS nd ZFL cells at 27 °C but clear inhibition of multiplication was observed. Intriguingly, the intracellular tachyzoites retained the ability to infect mice after 12 days of incubation in GS cells cultured at 27 °C as demonstrated by bioassay. At 30 °C, 32 °C and 35 °C, we observed that the mammalian cells (REF cells) and fish cells (GS and ZFL cells) could support T. gondii invasion and replication, which showed a temperature-dependent relationship in infection and proliferation rates. Our data demonstrated that the minimum temperature for T. gondii invasion and replication was 27 °C and 30 °C respectively, which indicated that temperature should be a key factor for T. gondii invasion and proliferation in host cells. This suggests that temperature-dependent infection determines the differences in the capability of T. gondii to infect cold- and warm-blooded vertebrates.


Assuntos
Bass/parasitologia , Fibroblastos/parasitologia , Hepatócitos/parasitologia , Temperatura , Toxoplasma/fisiologia , Peixe-Zebra/parasitologia , Animais , Bioensaio , Temperatura Corporal , Feminino , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Baço/citologia , Baço/parasitologia , Toxoplasma/crescimento & desenvolvimento
2.
Chemosphere ; 258: 127341, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32563067

RESUMO

Cadmium (Cd) is a primary environmental pollutant which causes the immune dysfunction of aquatic animals. MicroRNAs (miRNAs) play a key role in programmed necrosis and apoptosis of immune organs. Selenium (Se), known as an important element, can antagonize Cd toxicity in birds, but the impact of Se on common carps (Cyprinus carpio) has not been reported. To investigate the Cd-induced immunotoxicity mechanism mediated by miR-216a in splenic lymphocytes of common carp and antagonized by Se, we extracted lymphocytes from the spleen and divided them into control group, Se group (10-6 mol/L of Na2SeO3), Se + Cd group and Cd group (4 × 10-5 mol/L of CdCl2). After 6 h of incubation, AO/EB staining, Flow cytometry, qPCR and Western blot were performed. The results showed that Cd exposure caused the apoptosis (BAX, Bcl-2, Caspase 3, Caspase 9) and programmed necrosis (RIP, RIP3, MLKL) in lymphocytes, increased the expression of CYP enzymes, glycometabolism-related enzymes and production of ROS, while irritated the oxidative stress (MDA, SOD, CAT and GSH-PX), upregulated the expression of miR-216a which attenuated the levels of PI3K. However, those variations were apparently mitigated in the Se + Cd group. In short, we have proven that Cd activates oxidative stress and miR-216a-PI3K/AKT axis disorder, thus promoting apoptosis and necrosis in lymphocytes. Moreover, Se can antagonize Cd-triggered apoptosis and necrosis in lymphocytes.


Assuntos
Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Carpas/metabolismo , Linfócitos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Selênio/farmacologia , Animais , MicroRNAs/metabolismo , Necrose/induzido quimicamente , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Selênio/metabolismo , Baço/citologia
3.
Exp Parasitol ; 215: 107917, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32446699

RESUMO

Cystic echinococcosis (CE) is a worldwide hazardous zoonotic parasitosis caused by Echinococcus granulosus. CE development involves complex immunological mechanisms, including participation of multiple immune cells and effector molecules. Myeloid-derived suppressor cells (MDSCs) are known to be involved in chronic and acute inflammatory conditions. In this study, we aimed to characterize the immune function of MDSCs in CE to improve the understanding, prevention and treatment of CE. Our results indicated that MDSCs overexpressing Ly6C and Ly6G inhibit the formation and activity of T helper 2 cells in a NO-dependent manner during E. granulosus infection.


Assuntos
Equinococose/imunologia , Echinococcus granulosus/imunologia , Células Supressoras Mieloides/imunologia , Células Th2/imunologia , Análise de Variância , Animais , Anticorpos Monoclonais , Arginase/análise , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Citocinas/análise , Feminino , Citometria de Fluxo , Humanos , Ceratolíticos/farmacologia , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/enzimologia , Óxido Nítrico/análise , Espécies Reativas de Oxigênio/análise , Organismos Livres de Patógenos Específicos , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Tretinoína/farmacologia
4.
Nat Commun ; 11(1): 2570, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444631

RESUMO

At present, it is not clear how memory B lymphocytes are maintained over time, and whether only as circulating cells or also residing in particular tissues. Here we describe distinct populations of isotype-switched memory B lymphocytes (Bsm) of murine spleen and bone marrow, identified according to individual transcriptional signature and B cell receptor repertoire. A population of marginal zone-like cells is located exclusively in the spleen, while a population of quiescent Bsm is found only in the bone marrow. Three further resident populations, present in spleen and bone marrow, represent transitional and follicular B cells and B1 cells, respectively. A population representing 10-20% of spleen and bone marrow memory B cells is the only one qualifying as circulating. In the bone marrow, all cells individually dock onto VCAM1+ stromal cells and, reminiscent of resident memory T and plasma cells, are void of activation, proliferation and mobility.


Assuntos
Linfócitos B/imunologia , Células da Medula Óssea/imunologia , Switching de Imunoglobulina , Memória Imunológica , Baço/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Animais Selvagens/imunologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Células da Medula Óssea/citologia , Ciclo Celular , Proliferação de Células/genética , Regulação da Expressão Gênica/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Baço/citologia , Células Estromais/citologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
Proc Natl Acad Sci U S A ; 117(23): 13056-13065, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32439708

RESUMO

Plasmodium vivax, the most widely distributed human malaria parasite, causes severe clinical syndromes despite low peripheral blood parasitemia. This conundrum is further complicated as cytoadherence in the microvasculature is still a matter of investigations. Previous reports in Plasmodium knowlesi, another parasite species shown to infect humans, demonstrated that variant genes involved in cytoadherence were dependent on the spleen for their expression. Hence, using a global transcriptional analysis of parasites obtained from spleen-intact and splenectomized monkeys, we identified 67 P. vivax genes whose expression was spleen dependent. To determine their role in cytoadherence, two Plasmodium falciparum transgenic lines expressing two variant proteins pertaining to VIR and Pv-FAM-D multigene families were used. Cytoadherence assays demonstrated specific binding to human spleen but not lung fibroblasts of the transgenic line expressing the VIR14 protein. To gain more insights, we expressed five P. vivax spleen-dependent genes as recombinant proteins, including members of three different multigene families (VIR, Pv-FAM-A, Pv-FAM-D), one membrane transporter (SECY), and one hypothetical protein (HYP1), and determined their immunogenicity and association with clinical protection in a prospective study of 383 children in Papua New Guinea. Results demonstrated that spleen-dependent antigens are immunogenic in natural infections and that antibodies to HYP1 are associated with clinical protection. These results suggest that the spleen plays a major role in expression of parasite proteins involved in cytoadherence and can reveal antigens associated with clinical protection, thus prompting a paradigm shift in P. vivax biology toward deeper studies of the spleen during infections.


Assuntos
Antígenos de Protozoários/imunologia , Genes de Protozoários , Malária Vivax/imunologia , Plasmodium vivax/imunologia , Baço/metabolismo , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Antígenos de Protozoários/genética , Aotidae , Células CHO , Adesão Celular/genética , Adesão Celular/imunologia , Criança , Cricetulus , Modelos Animais de Doenças , Fibroblastos , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Malária Vivax/sangue , Malária Vivax/parasitologia , Família Multigênica , Papua Nova Guiné , Plasmodium vivax/genética , Baço/citologia , Baço/parasitologia , Esplenectomia , Análise Serial de Tecidos
6.
Nature ; 581(7807): 204-208, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32405000

RESUMO

It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain-spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/fisiologia , Imunidade Humoral/imunologia , Baço/imunologia , Baço/inervação , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Neurônios Adrenérgicos/metabolismo , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hemocianinas/imunologia , Imunoglobulina G/imunologia , Ativação Linfocitária , Masculino , Camundongos , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Plasmócitos/citologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Receptores Nicotínicos/deficiência , Receptores Nicotínicos/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Linfócitos T/imunologia
7.
Nat Commun ; 11(1): 1794, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286285

RESUMO

Although group 3 innate lymphoid cells (ILC3s) are efficient inducers of T cell responses in the spleen, they fail to induce CD4+ T cell proliferation in the gut. The signals regulating ILC3-T cell responses remain unknown. Here, we show that transcripts associated with MHC II antigen presentation are down-modulated in intestinal natural cytotoxicity receptor (NCR)- ILC3s. Further data implicate microbiota-induced IL-23 as a crucial signal for reversible silencing of MHC II in ILC3s, thereby reducing the capacity of ILC3s to present antigen to T cells in the intestinal mucosa. Moreover, IL-23-mediated MHC II suppression is dependent on mTORC1 and STAT3 phosphorylation in NCR- ILC3s. By contrast, splenic interferon-γ induces MHC II expression and CD4+ T cell stimulation by NCR- ILC3s. Our results thus identify biological circuits for tissue-specific regulation of ILC3-dependent T cell responses. These pathways may have implications for inducing or silencing T cell responses in human diseases.


Assuntos
Apresentação do Antígeno/imunologia , Imunidade Inata , Linfócitos/imunologia , Microbiota , Baço/citologia , Animais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD/metabolismo , Polaridade Celular , Regulação para Baixo , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon gama/metabolismo , Interleucina-23/metabolismo , Ativação Linfocitária/imunologia , Linfócitos/citologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Microbiota/genética , Microbiota/imunologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fenótipo , Fosforilação , Análise de Componente Principal , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/imunologia , Transativadores/genética , Transativadores/metabolismo , Transcrição Genética
8.
J Parasitol ; 106(2): 283-290, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32296849

RESUMO

The erythrocytic-stage surface protein equi merozoite antigen 1 (EMA-1) of Theileria equi is a major candidate for the development of a diagnostic antigen for equine piroplasmosis. In this study, BALB/c mice were immunized with purified recombinant EMA-1 to prepare monoclonal antibody (mAb) against T. equi EMA-1, and 1 mAb 5H2 was obtained that showed good reaction with infected red blood cells (RBC) in the indirect immunofluorescence assay (IFA). To develop a rapid serological detection method for T. equi infection in Xinjiang Uygur Autonomous Region, China, recombinant EMA-1 originating from the local T. equi strain and the mAb to EMA-1 were employed to develop an immunochromatographic test (ICT) to detect antibodies to T. equi in horse sera. The ICT showed high sensitivity and specificity and no cross-reaction with Babesia caballi. Ninety-two horse serum samples collected from Ili, Xinjiang, were tested by ICT and compared with the detection results of a commercial ELISA kit. The results showed that 56 of 92 (61%) serum samples were seropositive according to the ICT assay, and 50 (54%) samples were seropositive according to the ELISA kit. The ICT had a high coincidence (91.3%) but was more sensitive than the reference ELISA kit. To confirm whether the horses were infected by T. equi, 30 blood DNA samples from 92 horses were examined by PCR. The results showed that 14 of 30 (47%) horses were confirmed to be infected with T. equi by PCR, while 16 of 30 (53%) horses were seropositive by ICT. All PCR-positive horses were ICT-positive. The findings indicate that T. equi is endemic in Ili, Xinjiang, and that the ICT is reliable as a serological diagnosis method. The ICT developed in this study could be an efficient diagnostic tool to detect T. equi infection in horses in the Xinjiang area.


Assuntos
Antígenos de Protozoários/imunologia , Doenças dos Cavalos/parasitologia , Proteínas de Protozoários/imunologia , Theileria/isolamento & purificação , Theileriose/parasitologia , Animais , Anticorpos Monoclonais/imunologia , Antígenos de Protozoários/genética , Antígenos de Protozoários/isolamento & purificação , Western Blotting , China , Cromatografia de Afinidade , Eletroforese em Gel de Poliacrilamida , Ensaio de Imunoadsorção Enzimática , Eritrócitos/parasitologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Doenças dos Cavalos/sangue , Doenças dos Cavalos/diagnóstico , Cavalos , Hibridomas/citologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase , Proteínas de Protozoários/genética , Proteínas de Protozoários/isolamento & purificação , Sensibilidade e Especificidade , Baço/citologia , Baço/imunologia , Theileria/imunologia , Theileriose/sangue , Theileriose/diagnóstico , Células Tumorais Cultivadas
9.
J Neuroimmunol ; 341: 577191, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32113006

RESUMO

Morphine- and Concanavalin A-induced changes of protein composition of rat spleen lymphocytes were determined by high-resolution proteomic analysis, gel-free, label-free quantification, MaxLFQ. Stimulation by Con A resulted in a major reorganization of spleen cell protein composition evidenced by increased expression level of 94 proteins; 101 proteins were down-regulated (>2-fold). Interestingly, among proteins that were up-regulated to the largest extent were the prototypical brain proteins as a neuron specific enolase, synapsin-1, brain acid-soluble protein-1 and myelin basic protein. Morphine-induced change was limited to no more than 5 up-regulated and 18 down-regulated proteins (>2-fold).


Assuntos
Concanavalina A/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Morfina/farmacologia , Proteoma/efeitos dos fármacos , Proteômica/métodos , Baço/citologia , Animais , Perfilação da Expressão Gênica , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Linfócitos/metabolismo , Masculino , Ratos , Ratos Wistar
10.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 32(1): 33-38, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32148228

RESUMO

OBJECTIVE: To investigate the role and mechanism of splenic myeloid-derived suppressor cells (MDSCs) in sepsis-induced adrenal injury (SAI). METHODS: Thirty male C57 mice aged 6-8 weeks were randomly divided into normal control group (n = 5), sham operation group (Sham group, n = 5), sepsis model group [cecal ligation and perforation (CLP) group, n = 10] and sepsis+splenectomy group (CLPS group, n = 10). The sepsis model of mice was reproduced by CLP method. In Sham group, only the cecum was opened and separated, then closed, without CLP. In CLPS group, the spleen was removed before CLP. In normal control group, no challenge was given. After 24 hours, the rats were sacrificed by anesthesia, and peripheral blood, spleen, bone marrow, and bilateral adrenal glands were harvested. The pathological of adrenal gland was assessed by hematoxylin-eosin (HE) staining under optical microscope. The ratio of MDSCs in peripheral blood, spleen and bone marrow was determined by flow cytometry. The expressions of MDSCs surface antigen CD11b, Gr-1 and interleukins (IL-6, IL-1ß) mRNA in adrenal tissue were measured by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Western Blot was used to detect the expressions of mammalian rapamycin target protein (mTOR) pathway related proteins including total mTOR (T-mTOR), phosphorylation of mTOR (p-mTOR) and caspase-3. RESULTS: The adrenal cortex and medulla of the normal control group and Sham group were intact and the structure was clear under optical microscope, while in the CLP group, the adrenal gland showed edema, cortical hemorrhage and cell edema. Compared with the CLP group, the adrenal tissue injury was significantly reduced in the CLPS group. Compared with the normal control group and Sham group, MDSCs ratio in the peripheral blood was significantly increased and significantly reduced in the spleen in the CLP group, but there was no significant difference in bone marrow, the expression levels of CD11b, Gr-1, IL-6, IL-1ß mRNA and caspase-3 protein were increased significantly and p-mTOR protein expression was significantly decreased in adrenal tissue, there was no significant difference in the expression of T-mTOR protein. Compared with the CLP group, in the CLPS group, the MDSCs ratio in the peripheral blood was significantly decreased (0.143±0.011 vs. 0.324±0.023, P < 0.01), the expression levels of CD11b, Gr-1, IL-6 , IL-1ß mRNA and caspase-3 protein in adrenal gland were significantly decreased [CD11b mRNA (2-ΔΔCt): 2.90±0.56 vs. 5.74±0.13, Gr-1 mRNA (2-ΔΔCt): 2.71±0.14 vs. 4.59±0.46, IL-6 mRNA (2-ΔΔCt): 2.44±0.64 vs. 5.17±1.04, IL-1ß mRNA (2-ΔΔCt): 3.58±0.52 vs. 4.44±0.26, caspase-3 protein (caspase-3/GAPDH): 0.05±0.01 vs. 0.13±0.02, all P < 0.01], the p-mTOR protein expression was significantly increased (p-mTOR/GAPDH: 0.61±0.11 vs. 0.27±0.04, P < 0.01). CONCLUSIONS: The spleen is the major source of MDSCs in SAI. Splenectomy can attenuate SAI by reducing mobilization of MDSCs and activating the mTOR signaling pathway.


Assuntos
Lesão Renal Aguda/imunologia , Células Supressoras Mieloides/imunologia , Sepse/complicações , Baço/citologia , Lesão Renal Aguda/etiologia , Animais , Caspase 3/metabolismo , Citocinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro , Distribuição Aleatória , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
11.
PLoS One ; 15(3): e0229778, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187186

RESUMO

BACKGROUND: Memory B cell (mBC) induction and maintenance is one of the keys to long-term protective humoral immunity. MBCs are fundamental to successful medical interventions such as vaccinations and therapy in autoimmunity. However, their lifestyle and anatomic residence remain enigmatic in humans. Extrapolation from animal studies serves as a conceptual basis but might be misleading due to major anatomical distinctions between species. METHODS AND FINDINGS: Multicolor immunofluorescence stainings on fixed and unfixed frozen tissue sections were established using primary antibodies coupled to haptens and secondary signal amplification. The simultaneous detection of five different fluorescence signals enabled the localization and characterization of human CD27+CD20+Ki67- mBCs for the first time within one section using laser scanning microscopy. As a result, human tonsillar mBCs were initially identified within their complex microenvironment and their relative location to naïve B cells, plasma cells and T cells could be directly studied and compared to the human splenic mBC niche. In all investigated tonsils (n = 15), mBCs appeared to be not only located in a so far subepithelial defined area but were also follicle associated with a previous undescribed gradual decline towards the follicular mantle comparable to human spleen. However, mBC areas around secondary follicles with large germinal centers (GCs) in tonsils showed interruptions and a general widening towards the epithelium while in spleen the mBC-containing marginal zones (MZ) around smaller GCs were relatively broad and symmetrical. Considerably fewer IgM+IgD+/- pre-switch compared to IgA+ or IgG+ post-switch mBCs were detected in tonsils in contrast to spleen. CONCLUSIONS: This study extends existing insights into the anatomic residence of human mBCs showing structural similarities of the superficial follicular area in human spleen and tonsil. Our data support the debate of renaming the human splenic MZ to 'superficial zone' in order to be aware of the differences in rodents and, moreover, to consider this term equally for the human palatine tonsil.


Assuntos
Linfócitos B/metabolismo , Centro Germinativo/citologia , Tonsila Palatina/citologia , Baço/citologia , Adolescente , Adulto , Idoso , Linfócitos B/citologia , Microambiente Celular , Criança , Humanos , Pessoa de Meia-Idade , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
12.
Mol Immunol ; 121: 81-91, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32172028

RESUMO

Traumatic injury to the peripheral nervous system (PNS) is the most common cause of acquired nerve damage and impairs the quality of life of patients. The success of nerve regeneration depends on distal stump degeneration, tissue clearance and remodeling, processes in which the immune system participates. We previously reported improved motor recovery in sciatic nerve crush mice following adoptive transfer of lymphocytes, which migrated to the lesion site. However, lymphocyte activity and the nerve tissue response remain unexplored. Thus, in the present study, we evaluated sciatic nerve regeneration and T cell polarization in lymphocyte recipient mice. Splenic lymphocytes were isolated from mice 14 days after sciatic nerve crush and transferred to axotomized animals three days postinjury. Immediate lymphocyte migration to the crushed nerve was confirmed by in vivo imaging. Phenotyping of T helper (Th) cells by flow cytometry revealed an increased frequency of the proinflammatory Th1 and Th17 cell subsets in recipient mice at 7 days and showed that the frequency of these cells remained unchanged for up to 21 days. Moreover, nerve regeneration was improved upon cell therapy, as shown by sustained immunolabeling of axons, Schwann cells, growth-associated protein 43 and BDNF from 14 to 28 days after lesion. Macrophage and IgG immunolabeling were also higher in cell-transferred mice at 14 and 21 days following nerve crush. Functionally, we observed better sensory recovery in the lymphocyte-treated group. Overall, our data demonstrate that enhanced inflammation early after nerve injury has beneficial effects for the regenerative process, improving tissue clearance and axonal regrowth towards the target organs.


Assuntos
Transferência Adotiva/métodos , Transfusão de Linfócitos , Regeneração Nervosa/imunologia , Traumatismos dos Nervos Periféricos/terapia , Nervo Isquiático/lesões , Animais , Axônios/fisiologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Compressão Nervosa/efeitos adversos , Traumatismos dos Nervos Periféricos/imunologia , Traumatismos dos Nervos Periféricos/patologia , Qualidade de Vida , Nervo Isquiático/citologia , Nervo Isquiático/fisiologia , Baço/citologia
13.
Cell ; 180(4): 749-763.e13, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32059780

RESUMO

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT.


Assuntos
Envelhecimento/imunologia , Células Matadoras Naturais/citologia , Linfopoese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos CD/metabolismo , Células Cultivadas , Criança , Feminino , Humanos , Imunidade Inata , Mucosa Intestinal/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Pulmão/citologia , Linfonodos/citologia , Masculino , Pessoa de Meia-Idade , Baço/citologia
14.
Cell Immunol ; 349: 104043, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32044112

RESUMO

Type I Interferon (IFN) signaling plays a critical role in dendritic cell (DC) development and functions. Inhibition of hyper type I IFN signaling promotes cDC2 subtype development. Relb is essential to development of cDC2 subtype and here we analyzed its effect on type I IFN signaling in DCs. We show that Relb suppresses the homeostatic type I IFN signaling in cDC2 cultures. TLR stimulation of FL-DCs led to RelB induction coinciding with fall in IFN signatures; conforming with the observation Relb expression reduced TLR stimulated IFN induction along with decrease in ISGs. Towards understanding mechanism, we show that effects of RelB are mediated by increased levels of IκBα. We demonstrate that RelB dampened antiviral responses by lowering ISG levels and the defect in cDC2 development in RelB null mice can be rescued in Ifnar1-/- background. Overall, we propose a novel role of RelB as a negative regulator of the type I IFN signaling pathway; fine tuning development of cDC2 subtype.


Assuntos
Células Dendríticas/imunologia , Interferon Tipo I/imunologia , Inibidor de NF-kappaB alfa/fisiologia , Fator de Transcrição RelB/fisiologia , Sequência de Aminoácidos , Animais , Diferenciação Celular , Células Cultivadas , Cruzamentos Genéticos , Células Dendríticas/classificação , Células Dendríticas/citologia , Regulação da Expressão Gênica/imunologia , Camundongos , Células NIH 3T3 , Vírus da Doença de Newcastle/imunologia , Peptídeos/farmacologia , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/fisiologia , Transdução de Sinais/imunologia , Baço/citologia , Fator de Transcrição RelB/deficiência , Fator de Transcrição RelB/genética , Carga Viral
15.
Nat Commun ; 11(1): 723, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024827

RESUMO

How activated B cells build biosynthetic pathways and organelle structures necessary for subsequent robust antibody secretion is still unclear. The dominant model holds that nascent plasma cells adapt to increased antibody synthesis by activating the unfolded protein response (UPR) under the control of the transcription factor Xbp1. Here, by analyzing gene expression in activated B cells with or without plasma cell-inductive signals, we find that follicular B cells up-regulate a wide array of UPR-affiliated genes before initiating antibody secretion; furthermore, initial transcription of these loci requires the mTORC1 kinase adaptor, Raptor, but not Xbp1. Transcriptomic analyses of resting marginal zone B cells, which generate plasma cells with exceptionally rapid kinetics, reinforce these results by revealing the basal expression of UPR-affiliated mRNA networks without detectable Xbp1 activity. We thus conclude that B cells utilize mTORC1 to prepare for subsequent plasma cell function, before the onset of antibody synthesis.


Assuntos
Anticorpos/metabolismo , Linfócitos B/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Diferenciação Celular , Regulação da Expressão Gênica , Lipopolissacarídeos/farmacologia , Ativação Linfocitária , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteína Regulatória Associada a mTOR/genética , Proteína Regulatória Associada a mTOR/metabolismo , Baço/citologia , Resposta a Proteínas não Dobradas/genética , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismo
16.
Life Sci ; 240: 117078, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759041

RESUMO

AIM: The cross regulation between neuroendocrine system, particularly Hypothalamus-Pituitary-Thyroid (HPT) axis and immune system during embryonic/early neonatal developmental stages shapes the functional attribute of immune response throughout the life. Thus, disruption of immune system was anticipated on exposure to thyroid disrupting pesticides (TDPs) mancozeb (MCZ) and fipronil (FPN) during critical windows of early postnatal days (PND) development. MAIN METHODS: Mice were exposed to MCZ and FPN as individual (0.5% LD 50 each) and as mixtures (0.25% and 0.5% LD 50 each) from PND 31 (initiation phase of immune response) till PND 60 (Maturation phase). Thyroxine (T4) supplementation was given from PND 51 to PND 60. Assessment was done at PND 61 as well as at PND 91 (adults). KEY FINDINGS: Plasma level of thyroid hormones (T3 and T4) was reduced but pituitary hormone (TSH) increased till adulthood on exposure to mixture pesticides but not on individual exposure. Mixture pesticides also increased body weight gain and reduced survival rate in adults. Exposure of individual pesticides exert immunotoxicity but more pronounced immune suppression was observed in mixture pesticides exposed group as reflected in reduced relative weight and cellularity in spleen and thymus, reduced in vitro mitogenic (Con A/LPS) response of splenocytes and thymocytes (reduced proliferative index and increased apoptotic/necrotic death). T4 supplementation ameliorated thyroid disruptive and immunotoxic effect of pesticides. SIGNIFICANCE: The additive/synergistic toxicity as well as hypothyroidism induced by mixture pesticides has produced pronounced immune suppression that reflected till adulthood. Supplementation of T4 prevented thyroid axis disruption mediated immunosuppression.


Assuntos
Disruptores Endócrinos/toxicidade , Fungicidas Industriais/toxicidade , Sistema Imunitário/efeitos dos fármacos , Inseticidas/toxicidade , Maneb/toxicidade , Praguicidas/antagonistas & inibidores , Praguicidas/toxicidade , Pirazóis/toxicidade , Tiroxina/metabolismo , Tiroxina/uso terapêutico , Zineb/toxicidade , Animais , Peso Corporal , Feminino , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Análise de Sobrevida , Timo/citologia , Timo/efeitos dos fármacos , Timo/imunologia
17.
Fitoterapia ; 140: 104445, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790771

RESUMO

Thallactones A (1) and B (2), enantiomeric aporphine alkaloids with rare cleaved rings A and B, as well as thaliglucine N-oxide (3) and their biosynthetically related precursor, northalphenine (4), were isolated from the whole plant of Thalictrum wangii. Their structures with absolute configurations were elucidated by spectral techniques and electronic circular dichroism (ECD). Moreover, compounds 1, 3, and northalphenine inhibited concanavalin A (Con A)-stimulated proliferation of mice splenocyte significantly in a dose-dependent manner.


Assuntos
Aporfinas/farmacologia , Imunossupressores/farmacologia , Thalictrum/química , Animais , Aporfinas/isolamento & purificação , China , Relação Dose-Resposta a Droga , Imunossupressores/isolamento & purificação , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Baço/citologia , Baço/efeitos dos fármacos , Estereoisomerismo
18.
J Microbiol Biotechnol ; 30(3): 439-447, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-31838831

RESUMO

We investigated the immune restoration activity of Undaria pinnatifida fucoidan-rich extract in cyclophosphamide-induced immunosuppressed mice. C57BL/6 mice were intraperitoneally injected with 80 mg/kg of cyclophosphamide (CP) and orally administered with either drinking water (DW), red ginseng extract (RG), or one of three different doses of Undaria pinnatifida fucoidan-rich extract (DSU02 50, 100, and 150 mg/kg). After 14 days, liver, spleen, and whole blood were isolated from each animal. The frequencies of NK and CD3+, CD4+, and CD8+ T cells were significantly increased in splenocytes isolated from the DSU02 100 mg/kg and DSU02 150 mg/kg groups (NK1.1+, 5.4% or 4.9% vs 3.8%; CD3+, 39.3% or 37.9% vs 32.3%; CD4+, 22% or 20.2% vs 17.4%; CD8+, 12.7% or 11.6% vs 10.1%). NK cytotoxicity was enhanced in the DSU02-fed groups at all doses (CP-treated DW, 93.4%; RG, 107.2%; DSU02 50, 107.3%; DSU02 100, 107.3%; DSU02 150, 107.1%), and the proliferation of T cells (CD3+, CD4+, and CD8+) was also greater in the DSU02 100 mg/kg and DSU02 150 mg/kg administered groups compared with the unfed group. Plasma concentrations of TNF-α, IgM, and total IgG from the DSU02 150 mg/kg group were also significantly higher compared with the other groups (TNF- α: CP-treated DW - 21.5 pg/ml, DSU02 150 - 47.1 pg/ml; IgM: CP-treated DW - 82.9 ng/ml, DSU02 150 - 110.8 ng/ml; total IgG: CP-treated DW - 114.4 ng/ml, DSU02 150 - 162.7 ng/ml). We suggest that Undaria pinnatifida fucoidan-rich extract could be a promising candidate for a marine natural immune stimulator.


Assuntos
Polissacarídeos/farmacologia , Undaria/química , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Imunossupressão , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/imunologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
19.
Carbohydr Polym ; 229: 115457, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826423

RESUMO

We previously demonstrated that porphyran, a sulfated polysaccharide extracted from Pyropia yezoensis, shows protective effects on LPS-induced septic shock in the mouse. However, the immune cell-mediated inhibitory effect of porphyran in LPS-induced activation of immune cells has not been well investigated. In this study, we found that treatment of porphyran suppressed LPS-induced upregulation of costimulatory molecule and C-C chemokine receptor type 7 (CCR7) expression in bone marrow-derived dendritic cells (BMDCs) in vitro and spleen DCs in vivo. Moreover, the LPS-induced expression of IL-6, IL-12, and TNF-α in the culture medium of BMDCs and serum dose-dependently decreased by porphyran treatment, which contributed to the inhibition of the intracellular cytokine production in spleen DCs. In addition, LPS-induced differentiation of helper T1 (Th1) and cytotoxic T1 (Tc1) cells was effectively suppressed by porphyran treatment in mice. The inhibitory effect of porphyran in LPS-induced immune activation was mediated by competitive binding of porphyran with LPS in spleen DCs. Thus, these results suggest that porphyran is a promising potential therapeutic agent in endotoxin-mediated inflammatory disease and septic shock.


Assuntos
Anti-Inflamatórios/farmacologia , Células Dendríticas/efeitos dos fármacos , Polissacarídeos Bacterianos/farmacologia , Sefarose/análogos & derivados , Animais , Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Imunidade Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Rodófitas/química , Sefarose/farmacologia , Baço/citologia , Linfócitos T Citotóxicos/metabolismo , Células Th1/metabolismo
20.
J Ethnopharmacol ; 246: 112209, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31479708

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Scrophulariae (RS), is a renowned traditional Chinese medicine used as nourishing 'Yin'. The iridoid glycosides (IG) and phenylpropanoid glycosides (PG) are main chemical constituents in RS. However, there had been no pharmacological experiment studies of synergy between IG and PG. Due to the constituents interactions, exploring their synergy profile is of great important for explaining the essence of nourishing 'Yin' efficacy of RS. AIM OF STUDY: The present study was undertaken to evaluate synergistic nourishing 'Yin' effect of IG and PG from RS in vivo and in vitro through their immunoregulation and antioxidant activities. MATERIALS AND METHODS: In this study, IG and PG fractions in RS were isolated and identified by High Performance Liquid Chromatography coupled with tandem quadrupole time-of-flight Mass Spectrometry (HPLC-Q-TOF-MS). The synergistic nourishing 'Yin' effect of two fractions were investigated in vivo and in vitro with thyroxine-induced 'Yin' deficiency (YD) mice model and primary splenic lymphocyte, respectively. The exterior syndrome signs and serologic and cellular biomarkers changes were detected. Then, the synergistic coefficient (SC) of IG and PG on every pharmacodynamics index were calculated by Webb method. RESULTS: Compared with model and mono-therapy group (IG or PG group), IG combined with PG group significantly ameliorated YD by exerting immunoregulation and antioxidant effects. Based on the SC, IG and PG possessed a synergistic effect on heart rate, average speed, upright times, spleen index, LPO, SOD, IL-6, Na+-K+-ATP enzyme in vivo, and cAMP/cGMP, IFN-γ/IL-10, and MDA in vitro with SC > 1. CONCLUSIONS: The nourishing 'Yin' benefits were clearly produced when IG and PG were used in combination, which provided the scientific evidence of multiple-components and multiple-approach synergistic effect of Chinese traditional herbal medicine to control and management of diseases.


Assuntos
Glicosídeos/uso terapêutico , Scrophularia , Deficiência da Energia Yin/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Metabolismo Energético/efeitos dos fármacos , Feminino , Glicosídeos/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas , Baço/citologia , Tiroxina , Deficiência da Energia Yin/induzido quimicamente
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