Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33.067
Filtrar
1.
Nat Commun ; 12(1): 3543, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112803

RESUMO

Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings.


Assuntos
Neoplasias da Mama/sangue , Quimiocina CCL2/metabolismo , Exossomos/metabolismo , Receptores CCR2/metabolismo , Microambiente Tumoral , Animais , Neoplasias da Mama/patologia , Citocinas/metabolismo , Exossomos/imunologia , Exossomos/patologia , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Proteoglicanas/metabolismo , Receptores de Citocinas/metabolismo , Baço/imunologia , Baço/metabolismo , Baço/patologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
2.
Front Immunol ; 12: 661052, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995382

RESUMO

While lymphocytopenia is a common characteristic of coronavirus disease 2019 (COVID-19), the mechanisms responsible for this lymphocyte depletion are unclear. Here, we retrospectively reviewed the clinical and immunological data from 18 fatal COVID-19 cases, results showed that these patients had severe lymphocytopenia, together with high serum levels of inflammatory cytokines (IL-6, IL-8 and IL-10), and elevation of many other mediators in routine laboratory tests, including C-reactive protein, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase and natriuretic peptide type B. The spleens and hilar lymph nodes (LNs) from six additional COVID-19 patients with post-mortem examinations were also collected, histopathologic detection showed that both organs manifested severe tissue damage and lymphocyte apoptosis in these six cases. In situ hybridization assays illustrated that SARS-CoV-2 viral RNA accumulates in these tissues, and transmission electronic microscopy confirmed that coronavirus-like particles were visible in the LNs. SARS-CoV-2 Spike and Nucleocapsid protein (NP) accumulated in the spleens and LNs, and the NP antigen restricted in angiotensin-converting enzyme 2 (ACE2) positive macrophages and dendritic cells (DCs). Furthermore, SARS-CoV-2 triggered the transcription of Il6, Il8 and Il1b genes in infected primary macrophages and DCs in vitro, and SARS-CoV-2-NP+ macrophages and DCs also manifested high levels of IL-6 and IL-1ß, which might directly decimate human spleens and LNs and subsequently lead to lymphocytopenia in vivo. Collectively, these results demonstrated that SARS-CoV-2 induced lymphocytopenia by promoting systemic inflammation and direct neutralization in human spleen and LNs.


Assuntos
COVID-19/imunologia , Linfonodos/imunologia , Linfopenia/imunologia , SARS-CoV-2/imunologia , Baço/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , COVID-19/complicações , COVID-19/patologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Linfonodos/ultraestrutura , Linfopenia/etiologia , Linfopenia/patologia , Pessoa de Meia-Idade , Fosfoproteínas/imunologia , RNA Mensageiro/imunologia , Estudos Retrospectivos , SARS-CoV-2/patogenicidade , SARS-CoV-2/ultraestrutura , Baço/ultraestrutura
3.
Front Immunol ; 12: 597595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953706

RESUMO

The rapid response of neutrophils throughout the body to a systemic challenge is a critical first step in resolution of bacterial infection such as Escherichia coli (E. coli). Here we delineated the dynamics of this response, revealing novel insights into the molecular mechanisms using lung and spleen intravital microscopy and 3D ex vivo culture of living precision cut splenic slices in combination with fluorescent labelling of endogenous leukocytes. Within seconds after challenge, intravascular marginated neutrophils and lung endothelial cells (ECs) work cooperatively to capture pathogens. Neutrophils retained on lung ECs slow their velocity and aggregate in clusters that enlarge as circulating neutrophils carrying E. coli stop within the microvasculature. The absolute number of splenic neutrophils does not change following challenge; however, neutrophils increase their velocity, migrate to the marginal zone (MZ) and form clusters. Irrespective of their location all neutrophils capturing heat-inactivated E. coli take on an activated phenotype showing increasing surface CD11b. At a molecular level we show that neutralization of ICAM-1 results in splenic neutrophil redistribution to the MZ under homeostasis. Following challenge, splenic levels of CXCL12 and ICAM-1 are reduced allowing neutrophils to migrate to the MZ in a CD29-integrin dependent manner, where the enlargement of splenic neutrophil clusters is CXCR2-CXCL2 dependent. We show directly molecular mechanisms that allow tissue resident neutrophils to provide the first lines of antimicrobial defense by capturing circulating E. coli and forming clusters both in the microvessels of the lung and in the parenchyma of the spleen.


Assuntos
Movimento Celular/imunologia , Infecções por Escherichia coli/imunologia , Escherichia coli/imunologia , Pulmão/imunologia , Neutrófilos/imunologia , Baço/imunologia , Animais , Quimiocina CXCL12/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Infecções por Escherichia coli/patologia , Feminino , Molécula 1 de Adesão Intercelular/imunologia , Pulmão/patologia , Camundongos , Neutrófilos/patologia , Baço/patologia
4.
Medicine (Baltimore) ; 100(21): e25966, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032708

RESUMO

BACKGROUND: Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder caused by dysfunction at the neuromuscular junction spreads. The main clinical features of this disease are fluctuating fatigue, and weakness of the skeletal muscles of the eyes and limbs. At present, the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine has been widely used for MG. The present study was conducted to evaluate the efficacy and safety of the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine for MG. METHODS: The following 10 databases were searched from inception to March 2021: PubMed, Cochrane Library, EMBASE, Web of Science, Springer, China National Knowledge Infrastructure (CNKI), Wan fang, VIP Chinese Science and Technique Journals Database, the Chinese Bio Medical Database (CBM), and Baidu Scholar. The language was limited to the Chinese and English language. Merely randomized controlled trials (RCTs) were included. The Cochrane Collaboration risk-of-bias tool was used for the methodological quality assessment and risk of bias. The meta-analysis was assessed using the Cochrane RevMan 5.3 software. RESULTS: In the present study, a meta-analysis was conducted, and RCTs that met the eligibility criteria were included. Furthermore, the different outcome indicators of different methods were objectively compared. The main outcome indicators included the effective rate, quantitative myasthenia gravis (QMG) scores, adverse events, and quality of life (QOL). The secondary outcome indicators included AchRAb, serum-related immune cells (such as CD3+CD4+cells and CD4+/CD8+cells), the traditional Chinese medicine syndrome score scale (TCMSSS), the serum interleukin-6 level, the level of IFN-γ and its mRNA, and the clinical score that contains the clinical absolute score (CAS) and clinical relative score (CRS). CONCLUSION: This study would provide credible evidence to determine whether the tonifying the spleen and replenishing the kidney method in traditional Chinese medicine is an effective treatment method for MG. TRIAL REGISTRATION NUMBER: INPLASY202110097.


Assuntos
Rim/fisiopatologia , Medicina Tradicional Chinesa/métodos , Miastenia Gravis/terapia , Qi , Baço/fisiopatologia , Humanos , Rim/imunologia , Medicina Tradicional Chinesa/efeitos adversos , Metanálise como Assunto , Miastenia Gravis/imunologia , Miastenia Gravis/fisiopatologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Baço/imunologia , Revisões Sistemáticas como Assunto , Resultado do Tratamento
5.
Science ; 372(6543): 738-741, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33846272

RESUMO

Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.


Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Coronavirus/imunologia , Memória Imunológica , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Pré-Escolar , Reações Cruzadas , Ebolavirus/imunologia , Feminino , Sangue Fetal/imunologia , Genes de Imunoglobulinas , Humanos , Switching de Imunoglobulina , Imunoglobulina D/genética , Imunoglobulina D/imunologia , Cadeias Pesadas de Imunoglobulinas/imunologia , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Lactente , Linfonodos/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos B/imunologia , Hipermutação Somática de Imunoglobulina , Baço/imunologia , Adulto Jovem
6.
Int J Mol Sci ; 22(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920631

RESUMO

BACKGROUND: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. METHODS: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. RESULTS: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4-CD8- T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. CONCLUSIONS: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Lúpus Eritematoso Sistêmico/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Diferenciação Celular , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/imunologia , Feminino , Rim/citologia , Rim/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Baço/citologia , Baço/imunologia , Linfócitos T/imunologia
7.
Front Immunol ; 12: 589200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841391

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is a classical murine model for Multiple Sclerosis (MS), a human autoimmune disease characterized by Th1 and Th17 responses. Numerous studies have reported that C-reactive protein (CRP) mitigates EAE severity, but studies on the relevant pathologic mechanisms are insufficient. Our previous study found that CRP suppresses Th1 response directly by receptor binding on naïve T cells; however, we did not observe the effect on Th17 response at that time; thus it remains unclear whether CRP could regulate Th17 response. In this study, we verified the downregulation of Th17 response by a single-dose CRP injection in MOG-immunized EAE mice in vivo while the direct and indirect effects of CRP on Th17 response were differentiated by comparing its actions on isolated CD4+ T cells and splenocytes in vitro, respectively. Moreover, the immune cell composition was examined in the blood and CNS (Central Nervous System), and a blood (monocytes) to CNS (dendritic cells) infiltration pathway is established in the course of EAE development. The infiltrated monocyte derived DCs (moDCs) were proved to be the only candidate antigen presenting cells to execute CRP's function. Conversely, the decrease of Th17 responses caused by CRP disappeared in the above in vivo and in vitro studies with FcγR2B-/- mice, indicating that FcγR2B expressed on moDCs mediates CRP function. Furthermore, peripheral blood monocytes were isolated and induced to establish moDCs, which were used to demonstrate that the antigen presenting ability of moDCs was attenuated by CRP through FcγR2B, and then NF-κB and ERK signaling pathways were manifested to be involved in this regulation. Ultimately, we perfected and enriched the mechanism studies of CRP in EAE remission, so we are more convinced that CRP plays a key role in protecting against EAE development, which may be a potential therapeutic target for the treatment of MS in human.


Assuntos
Apresentação do Antígeno/imunologia , Proteína C-Reativa/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunomodulação , Células Th17/imunologia , Células Th17/metabolismo , Animais , Antígeno B7-2/metabolismo , Biomarcadores , Diferenciação Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Imunofenotipagem , Ativação Linfocitária/imunologia , Camundongos , Monócitos , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Receptores de IgG/metabolismo , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
8.
Toxins (Basel) ; 13(5)2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926136

RESUMO

The objective of this study was to determine the impact of Ageratina adenophora (A. adenophora) on splenic immune function in a rat model. Rats were fed with 10 g/100 g normal feed and an experimental feed, which was composed of 3:7 A. adenophora powder and normal feed for 60 days. On days 14, 28, and 60, subsets of rats (n = 8 rats/group/time point) were selected for blood and spleen tissue sample collection. The results showed that the proportion of CD3+ T cells in the spleen was decreased at day 60 (vs. control). Also, mRNA and protein expression of chemokines CCL21 and CCL19 and functional protein gp38 in spleen decreased significantly versus the control at day 60. In addition, ER-TR7 antigen protein expression was also decreased at day 60. Levels of T-helper (Th)1 cells significantly increased, whereas those of Th2 cells decreased significantly versus the control at day 60 in spleen. The finding revealed that A. adenophora could affect splenic immune function in rats by altering the fibroblast reticulocyte (FRC) network, as well as by causing an imbalance in Th1/Th2 cell ratios. This research provides new insights into potential mechanisms of spleen immunotoxicity due to exposures to A. Adenophora.


Assuntos
Ageratina/efeitos adversos , Reticulócitos/efeitos dos fármacos , Baço/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Fibroblastos/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Folhas de Planta , Ratos , Ratos Sprague-Dawley , Baço/citologia , Baço/imunologia
9.
J Virol ; 95(12)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33827944

RESUMO

Koi herpesvirus (KHV) is highly contagious and lethal to cyprinid fish, causing significant economic losses to the carp aquaculture industry, particularly to koi carp breeders. Vaccines delivered through intramuscular needle injection or gene gun are not suitable for mass vaccination of carp. So, the development of cost-effective oral vaccines that are easily applicable at a farm level is highly desirable. In this study, we utilized chitosan-alginate capsules as an oral delivery system for a live probiotic (Lactobacillus rhamnosus) vaccine, pYG-KHV-ORF81/LR CIQ249, expressing KHV ORF81 protein. The tolerance of the encapsulated recombinant Lactobacillus to various digestive environments and the ability of the probiotic strain to colonize the intestine of carp was tested. The immunogenicity and the protective efficacy of the encapsulated probiotic vaccine was evaluated by determining IgM levels, lymphocyte proliferation, expression of immune-related genes, and viral challenge to vaccinated fish. It was clear that the chitosan-alginate capsules protected the probiotic vaccine effectively against extreme digestive environments, and a significant level (P < 0.01) of antigen-specific IgM with KHV-neutralizing activity was detected, which provided a protection rate of ca. 85% for koi carp against KHV challenge. The strategy of using chitosan-alginate capsules to deliver probiotic vaccines is easily applicable for mass oral vaccination of fish.IMPORTANCE An oral probiotic vaccine, pYG-KHV-ORF81/LR CIQ249, encapsulated by chitosan-alginate capsules as an oral delivery system was developed for koi carp against koi herpesvirus (KHV) infection. This encapsulated probiotic vaccine can be protected from various digestive environments and maintain effectively high viability, showing a good tolerance to digestive environments. This encapsulated probiotic vaccine has a good immunogenicity in koi carp via oral vaccination, and a significant level of antigen-specific IgM was effectively induced after oral vaccination, displaying effective KHV-neutralizing activity. This encapsulated probiotic vaccine can provide effective protection for koi carp against KHV challenge, which is handling-stress free for the fish, cost effective, and suitable for the mass oral vaccination of koi carp at a farm level, suggesting a promising vaccine strategy for fish.


Assuntos
Carpas , Doenças dos Peixes/prevenção & controle , Infecções por Herpesviridae/veterinária , Herpesviridae/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Probióticos , Proteínas Virais/imunologia , Administração Oral , Alginatos , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Cápsulas , Proliferação de Células , Quitosana , Infecções por Herpesviridae/prevenção & controle , Vacinas contra Herpesvirus/imunologia , Imunogenicidade da Vacina , Imunoglobulina M/sangue , Lactobacillus rhamnosus , Linfócitos/fisiologia , Vacinação em Massa/veterinária , Proteínas Recombinantes de Fusão , Baço/imunologia , Baço/metabolismo , Vacinas Sintéticas/administração & dosagem , Proteínas Virais/genética
10.
J Virol ; 95(12)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33827945

RESUMO

Immune memory represents the most efficient defense against invasion and transmission of infectious pathogens. In contrast to memory T and B cells, the roles of innate immunity in recall responses remain inconclusive. In this study, we identified a novel mouse spleen NK cell subset expressing NKp46 and NKG2A induced by intranasal influenza virus infection. These memory NK cells specifically recognize N-linked glycosylation sites on influenza hemagglutinin (HA) protein. Different from memory-like NK cells reported previously, these NKp46+ NKG2A+ memory NK cells exhibited HA-specific silence of cytotoxicity but increase of gamma interferon (IFN-γ) response against influenza virus-infected cells, which could be reversed by pifithrin-µ, a p53-heat shock protein 70 (HSP70) signaling inhibitor. During recall responses, splenic NKp46+ NKG2A+ NK cells were recruited to infected lung and modulated viral clearance of virus and CD8+ T cell distribution, resulting in improved clinical outcomes. This long-lived NK memory bridges innate and adaptive immune memory response and promotes the homeostasis of local environment during recall response.IMPORTANCE In this study, we demonstrate a novel hemagglutinin (HA)-specific NKp46+ NKG2A+ NK cell subset induced by influenza A virus infection. These memory NK cells show virus-specific decreased cytotoxicity and increased gamma interferon (IFN-γ) on reencountering the same influenza virus antigen. In addition, they modulate host recall responses and CD8 T cell distribution, thus bridging the innate immune and adaptive immune responses during influenza virus infection.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Memória Imunológica , Vírus da Influenza A Subtipo H1N1/imunologia , Células Matadoras Naturais/imunologia , Infecções por Orthomyxoviridae/imunologia , Transferência Adotiva , Animais , Antígenos Ly/análise , Antígenos Ly/metabolismo , Benzotiazóis/farmacologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cocultura , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Vírus da Influenza A Subtipo H9N2/imunologia , Interferon gama/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Subfamília C de Receptores Semelhantes a Lectina de Células NK/análise , Receptor 1 Desencadeador da Citotoxicidade Natural/análise , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Baço/citologia , Baço/imunologia , Tolueno/análogos & derivados , Tolueno/farmacologia
12.
Methods Mol Biol ; 2265: 111-118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33704709

RESUMO

Within the adaptive and innate immune system, effector lymphocytes known as cytotoxic T cells (CTLs) or natural killer (NK) cells play an essential role in host defense against tumor cells and virally infected cells. Here we describe a flow cytometry-based method to quantify CTLs or NK cell cytotoxic activity against melanoma cells. In this assay, spleen cells, peripheral blood mononuclear cells (PBMCs), or purified NK cell preparations are co-incubated at different ratios with a target tumor cell line. The target cells are pre-labeled with a fluorescent dye to allow their discrimination from the effector cells. After the incubation period, killed target cells are identified by a nucleic acid stain, which specifically permeates dead cells. This method is amenable to both diagnostic and research applications.


Assuntos
Testes Imunológicos de Citotoxicidade/métodos , Citometria de Fluxo/métodos , Células Matadoras Naturais/imunologia , Melanoma Experimental/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Técnicas de Cultura de Células/métodos , Morte Celular/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Feminino , Corantes Fluorescentes , Humanos , Leucócitos Mononucleares/imunologia , Camundongos , Baço/citologia , Baço/imunologia
13.
J Cell Mol Med ; 25(10): 4870-4876, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33733611

RESUMO

Under steady-state conditions, the pool size of peripheral CD8+ T cells is maintained through turnover and survival. Beyond TCR and IL-7R signals, the underlying mechanisms are less well understood. In the present study, we found a significant reduction of CD8+ T cell proportion in spleens but not in thymi of mice with T cell-specific deletion of Mediator Subunit 1 (Med1). A competitive transfer of wild-type (WT) and Med1-deficient CD8+ T cells reproduced the phenotype in the same recipients and confirmed intrinsic role of Med1. Furthermore, we observed a comparable degree of migration and proliferation but a significant increase of cell death in Med1-deficient CD8+ T cells compared with WT counterparts. Finally, Med1-deficient CD8+ T cells exhibited a decreased expression of interleukin-7 receptor α (IL-7Rα), down-regulation of phosphorylated-STAT5 (pSTAT5) and Bim up-regulation. Collectively, our study reveals a novel role of Med1 in the maintenance of CD8+ T cells through IL-7Rα/STAT5 pathway-mediated cell survival.


Assuntos
Linfócitos T CD8-Positivos , Subunidade 1 do Complexo Mediador/imunologia , Receptores de Interleucina-7/imunologia , Baço/imunologia , Animais , Apoptose , Células da Medula Óssea , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Subunidade 1 do Complexo Mediador/genética , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Transdução de Sinais , Baço/citologia
14.
Fish Shellfish Immunol ; 112: 143-150, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33741521

RESUMO

The melatonin hormone, which is a multifunctional molecule in vertebrates, has been shown to exert complex actions on the immune system of mammals. In teleosts, the immunomodulatory capacity of this hormone has seldom been investigated. In the present experiment, we exposed ex vivo spleen and head kidney tissues of pike-perch to melatonin (Mel) and cortisol (Cort). We applied three concentrations of both hormones, alone and in combination, namely (1) Mel (10, 100 or 1000 pg mL-1) (2) Cort (50, 500 or 5000 ng mL-1) (3) Mel + Cort (10 + 50, 100 + 500 or 1000 pg mL-1+5000 ng mL-1). Pure medium without Mel or Cort served as control. After 15 h of incubation, we assessed the expression of a set of immunity-related genes, including genes encoding for pro-inflammatory proteins (il-1ß, cxcl8 and tnf-α), acute-phase proteins (fgl2, fth1, hepc, hp and saa1) and key factors of the adaptive immune system (fκbp4 and tcrg). Both Mel and Cort, when used alone or combined at physiological concentrations, significantly influenced immune gene expressions that may lead to a global immune stimulation. Our results support both, an indirect action of the Mel hormone on the immune system through the regulation of intermediates such as Cort, as well as a direct action on immune targets through specific receptors.


Assuntos
Imunidade Adaptativa , Rim Cefálico/imunologia , Imunidade Inata , Melatonina/administração & dosagem , Percas/imunologia , Baço/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Rim Cefálico/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Baço/efeitos dos fármacos
15.
Poult Sci ; 100(4): 100990, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33647718

RESUMO

Goose nephritic astrovirus (GNAstV) was first isolated in 2018, causing great economic losses to the goose industry. However, little is known about host immune response to GNAstV infection. In this study, forty 2-day-old goslings were randomly divided into 2 groups: infection and negative control groups. Each gosling in the infection group was challenged with 0.5 mL GNAstV-JSHA intramuscularly, whereas the gosling in the negative control group was inoculated with the same amount of PBS. Histopathological changes and virus location in the spleen and kidney were examined, and the expression of immune-related genes was determined by qPCR at 7 and 14 d after infection. Our results showed that GNAstV infection induced degeneration and necrosis of splenic lymphocytes and renal epithelial cells, and these cells were positive for the virus. In addition, GNAstV infection induced the activation of pattern recognition receptors (RIG-I, MDA-5, and TLR3) and key adaptor molecules (MyD88, MAVS, and IRF7) in the spleen and kidney, and upregulated the gene expression of interferon-α in the spleen and antiviral proteins (MX1, OASL, and IFITM3) in the spleen and kidney. Moreover, high expression levels of interleukin (IL)-1ß and IL-8 in the spleen and iNOS in the spleen and kidney were found. These results indicated that GNAstV infection activated host innate immune response. Furthermore, GNAstV infection increased the expression levels of CD8+, MHCI, and MHCII, indicating that adaptive immune response was activated. Besides, TGF-ß was highly expressed in the spleen and kidney, which may be an immune evasion strategy of GNAstV to cause infection. Interestingly, both IL-1ß and IL-6 mRNA levels were decreased in the kidney, which may help reduce kidney lesions. This is the first study to report changes in immune-related gene expression in response to GNAstV infection, and our results provide insights into viral pathogenesis.


Assuntos
Infecções por Astroviridae , Gansos , Regulação da Expressão Gênica , Baço , Animais , Infecções por Astroviridae/imunologia , Infecções por Astroviridae/veterinária , Avastrovirus/imunologia , Galinhas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Imunidade Inata/imunologia , Rim/virologia , Baço/imunologia , Baço/virologia
16.
Aging (Albany NY) ; 13(6): 8895-8915, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33714945

RESUMO

Licochalcone A (LA), a flavonoid found in licorice, has anticancer, antioxidant, anti-inflammatory, and neuroprotective properties. Here, we explored the effect of injecting LA into the tail vein of middle-aged C57BL/6 mice on their cognitive ability as measured by the Morris water maze (MWM) test and cerebral blood flow (CBF). The related mechanisms were assessed via RNA-seq, and T (CD3e+) and B (CD45R/B220+) cells in the spleen and whole blood were quantified via flow cytometry. LA improved the cognitive ability, according to the MWM test results, and upregulated the CBF level of treated mice. The RNA-seq results indicate that LA affected the interleukin (IL)-17 signaling pathway, which is related to T- and B-cell proliferation, and the flow cytometry data suggest that LA promoted T- and B-cell proliferation in the spleen and whole blood. We also performed immune reconstruction via a tail vein injection of lymphocytes into B-NDG (NOD-PrkdcscidIl2rgtm1/Bcge) mice before treating them with LA. We tested cognitive ability by subjecting these animals to new object recognition tests and quantified the splenic and whole blood T and B cells. Cognitive ability improved after immune reconstruction and LA treatment, and LA promoted T- and B-cell proliferation in the spleen and whole blood. This study demonstrates that LA, by activating the IL-17 signaling pathway, promotes T- and B-cell proliferation in the spleen and whole blood of mice and improves cognitive ability. Thus, LA may have immune-modulating therapeutic potential for improving cognition.


Assuntos
Linfócitos B/efeitos dos fármacos , Chalconas/farmacologia , Cognição/efeitos dos fármacos , Interleucina-17/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/imunologia
17.
Front Immunol ; 12: 584414, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717066

RESUMO

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE). Our previous studies demonstrated increased serum and renal Interleukin (IL)-22 in LN patients and MRL/lpr mice. This study investigated the role of IL-22 and its mechanism in LN. Here, we found that IL-22 was mainly produced by type 3 innate lymphoid cells (ILC3) in kidney of MRL/lpr mice. The systemic illness and local renal lesion were significantly alleviated in IL-22 or IL-22R gene knockout (KO) mice (IL-22 KO or IL-22R KO MRL/lpr mice) than control mice (MRL/lpr mice). IL-22 KO or IL-22R KO MRL/lpr mice had significantly slighter infiltration of macrophage in kidney than MRL/lpr mice. Consistently, by RNA-Seq, the expression of (CC motif) ligand 2 (CCL2) and (CXC motif) ligand 10 (CXCL10) was decreased in kidney of KO mice compared with control mice. By immunoblotting, significantly increased levels of STAT3 phosphorylation were found in the kidney of control mice compared to KO mice. In vitro, primary kidney epithelial cells from control mouse stimulated with recombinant IL-22 (rIL-22) expressed higher levels of CCL2, CXCL10, and phosphorylated STAT3. At the same time, when primary kidney epithelial cells were treated with rIL-22, transwell assay demonstrated their supernatant recruited more macrophages. In human kidney epithelial cell line (HK2) cells, when treated with rIL-22, we observed similar results with primary mouse kidney epithelial cells. Moreover, when cells were stimulated with rIL-22 following pre-treatment with STAT3 pathway inhibitor, the expression of CCL2 and CXCL10 were significantly reversed. Our findings demonstrate that IL-22 binding to IL-22R in kidney epithelial cells activated the STAT3 signaling pathway, enhanced the chemokine secretion and then promoted macrophage infiltration to the kidney of MRL/lpr mice, thus aggravated LN in lupus-prone mice. These findings indicate that IL-22 may play a pathogenic role in LN and may provide a promising novel therapeutic target for LN.


Assuntos
Imunidade Inata , Interleucinas/metabolismo , Nefrite Lúpica/etiologia , Nefrite Lúpica/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Autoanticorpos/imunologia , Biomarcadores , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Proteínas do Sistema Complemento/imunologia , Células Epiteliais/metabolismo , Feminino , Humanos , Imunofenotipagem , Interleucinas/genética , Rim/imunologia , Rim/metabolismo , Rim/patologia , Nefrite Lúpica/patologia , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Receptores de Interleucina/metabolismo , Fator de Transcrição STAT3 , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Baço/patologia
18.
Viruses ; 13(2)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572146

RESUMO

B-cell follicles constitute large reservoirs of infectious HIV/SIV associated to follicular dendritic cells and infecting follicular helper (TFH) and regulatory (TFR) T-cells in germinal centers (GCs). Thus, follicular and GC B-cells are persistently exposed to viral antigens. Despite recent development of potent HIV immunogens, numerous questions are still open regarding GC reaction during early HIV/SIV infection. Here, we dissect the dynamics of B- and T-cells in GCs of macaques acutely infected by SIV (Group SIV+) or vaccinated with Tetanus Toxoid (Group TT), a T-dependent model antigen. Systemic inflammation and mobilization of antigen-presenting cells in inguinal lymph nodes and spleen are lower in Group TT than in Group SIV+. Despite spleen GC reaction of higher magnitude in Group SIV+, the development of protective immunity could be limited by abnormal helper functions of TFH massively polarized into TFH1-like cells, by inflammation-induced recruitment of fCD8 (either regulatory or cytotoxic) and by low numbers of TFR limiting TFH/TFR competition for high affinity B-cells. Increased GC B-cells apoptosis and accumulation of CD21lo memory B-cells, unable to further participate to GC reaction, likely contribute to eliminate SIV-specific B-cells and decrease antibody affinity maturation. Surprisingly, functional GCs and potent TT-specific antibodies develop despite low levels of CXCL13.


Assuntos
Centro Germinativo/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Imunidade Humoral , Memória Imunológica , Inflamação , Macaca mulatta , Masculino , Baço/imunologia , Células T Auxiliares Foliculares/imunologia , Células T Auxiliares Foliculares/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Toxoide Tetânico/administração & dosagem , Toxoide Tetânico/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo
19.
Mol Biol Rep ; 48(2): 1055-1068, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33595783

RESUMO

Exact mechanisms of autoimmune disease development are still yet unknown. However, it is known that the development of autoimmune diseases is associated with defects in the immune system, namely, the violation of the bone marrow hematopoietic stem cells (HSCs) differentiation profiles. Different characteristics of autoimmune reaction development in experimental autoimmune encephalomyelitis (EAE) prone Th mice characterizing T-lymphocytes response were analyzed using standard approaches. Profiles of several HSCs differentiation of bone marrow (BFU-E, CFU-E, CFU-GM, CFU-GEMM, T- and B-lymphocytes) of Th male and female mice during spontaneous development of EAE were noticeably different. Patterns of total lymphocytes, B- and T-cells proliferation in several different organs (bone marrow, blood, spleen, thymus, and lymph nodes) were also remarkably different. In addition, there were in time noticeable differences in their changes for some organs of male and female mice. Characters of changes in the profiles of CD4 and CD8 cells proliferation in some organs not always coincide with those for total T lymphocytes. The changes in the differentiation profiles of HSCs and the level of lymphocytes proliferation in the bone marrow and other organs were associated with the increase in the concentration of antibodies against DNA, myelin basic protein, and myelin oligodendrocyte glycoprotein, and catalytic antibodies hydrolyzing these substrates. Despite some differences in changes in the analyzed parameters, in general, the spontaneous development of EAE in male and female mice occurs to some extent in a comparable way.


Assuntos
Anticorpos Catalíticos/imunologia , Diferenciação Celular/genética , Encefalomielite Autoimune Experimental/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Animais , Anticorpos Catalíticos/genética , Células da Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Ativação Linfocitária/genética , Contagem de Linfócitos , Camundongos , Glicoproteína Mielina-Oligodendrócito/genética , Glicoproteína Mielina-Oligodendrócito/imunologia , Baço/imunologia
20.
Int Immunopharmacol ; 94: 107482, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33639567

RESUMO

Heme is an important iron-containing porphyrin molecule expressed ubiquitously in organisms. Recently, this endogenous molecule has been widely reported to be involved in the pathogenesis of numerous diseases such as sepsis, atherosclerosis and inflammatory bowel disease. However, the role of heme during systemic lupus erythematosus (SLE) pathogenesis has not been previously evaluated. Herein, we have measured the levels of heme in lupus-prone mice and explored the influence of heme on the pathogenesis of lupus. We revealed that heme levels in serum, kidney and spleen lymphocytes are all negatively associated with the levels of proteinuria in lupus-prone mice. Heme supplementation at 15 mg/kg could significantly ameliorate the syndromes of lupus in MRL/lpr mice, extending lifespan, reducing the level of proteinuria and alleviating splenomegaly and lymphadenopathy. Further study demonstrated that heme replenishment corrected the abnormal compartment of T cell subsets, plasma cells and macrophages in the spleen and alleviates inflammation and oxidative damage in kidney of MRL/lpr mice. Our study well defined heme as a relevant endogenous molecule in the etiology of SLE, as well as a potential therapeutic target for treating this autoimmune disease. Meanwhile, heme replenishment might be a new choice to therapeutically modulate immune homeostasis and prevent SLE.


Assuntos
Heme/imunologia , Nefrite Lúpica/imunologia , Baço/imunologia , Animais , Linhagem Celular , Citocinas/imunologia , Feminino , Heme/uso terapêutico , Humanos , Rim/efeitos dos fármacos , Rim/imunologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Camundongos Endogâmicos MRL lpr , Estresse Oxidativo/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...