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1.
Cell ; 183(1): 143-157.e13, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877699

RESUMO

Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.


Assuntos
Infecções por Coronavirus/imunologia , Centro Germinativo/imunologia , Pneumonia Viral/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Feminino , Centro Germinativo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Baço/imunologia , Baço/patologia , Fator de Necrose Tumoral alfa/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(30): 17727-17736, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32665441

RESUMO

Erythrocytes naturally capture certain bacterial pathogens in circulation, kill them through oxidative stress, and present them to the antigen-presenting cells (APCs) in the spleen. By leveraging this innate immune function of erythrocytes, we developed erythrocyte-driven immune targeting (EDIT), which presents nanoparticles from the surface of erythrocytes to the APCs in the spleen. Antigenic nanoparticles were adsorbed on the erythrocyte surface. By engineering the number density of adsorbed nanoparticles, (i.e., the number of nanoparticles loaded per erythrocyte), they were predominantly delivered to the spleen rather than lungs, which is conventionally the target of erythrocyte-mediated delivery systems. Presentation of erythrocyte-delivered nanoparticles to the spleen led to improved antibody response against the antigen, higher central memory T cell response, and lower regulatory T cell response, compared with controls. Enhanced immune response slowed down tumor progression in a prophylaxis model. These findings suggest that EDIT is an effective strategy to enhance systemic immunity.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos/imunologia , Eritrócitos/imunologia , Imunização , Animais , Formação de Anticorpos/imunologia , Antígenos/química , Biomimética , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Humanos , Camundongos , Nanopartículas , Baço/imunologia , Vacinação , Vacinas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Mol Immunol ; 125: 95-103, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659598

RESUMO

Myeloid-derived suppressor cells (MDSCs) are classified into polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. The predominant subtype of MDSCs in hepatocellular carcinoma (HCC) is still elusive. The spleen is the largest immune organ in the body and is the origin of many cells. It is still unknown whether the spleen is the origin of MDSCs. In this study, we investigated the expression, origin and mobilization of the predominant MDSC subtype in H22 orthotopic hepatoma mice. Compared with M-MDSCs, PMN-MDSCs were increased and dominant in the spleen, peripheral blood and tumor tissues. Splenectomy could decrease the percentages of PMN-MDSCs in the peripheral blood and tumor tissues, increase the frequencies of NK cells in the peripheral blood and CD3+CD4+T, CD3+CD8+T, NK and NKT cells in the tumor tissues, reduce the tumor weight and the amounts of ascites, and prolong survival time in hepatoma mice. The levels of chemokine (CC motif) ligand 9 (CCL9) and chemokine (CC motif) ligand 2 (CCL2) were elevated in the peripheral blood of tumor-bearing (TB) mice, and their receptors CCR1 and CCR2 were expressed on spleen PMN-MDSCs. Migration assay showed that CCL2 and CCL9 could attract spleen PMN-MDSCs in vitro. These results indicate that PMN-MDSCs were increased and dominant in orthotopic H22 hepatoma mice, the spleen contributed to the increase of PMN-MDSCs, and PMN-MDSCs could be mobilized from the spleen to the peripheral blood by CCL9 and CCL2, thus facilitated tumor growth.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Baço/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Camundongos , Evasão Tumoral/imunologia
4.
Nat Commun ; 11(1): 3187, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581235

RESUMO

The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNß infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNß. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.


Assuntos
Imunoterapia Adotiva , Interferon beta/metabolismo , Vírus Oncolíticos/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Terapia Combinada , Feminino , Interferon beta/genética , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Baço/imunologia
5.
PLoS Negl Trop Dis ; 14(6): e0008414, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574175

RESUMO

Chemokine receptor type 3 (CXCR3) plays an important role in CD8+ T cells migration during intracellular infections, such as Trypanosoma cruzi. In addition to chemotaxis, CXCR3 receptor has been described as important to the interaction between antigen-presenting cells and effector cells. We hypothesized that CXCR3 is fundamental to T. cruzi-specific CD8+ T cell activation, migration and effector function. Anti-CXCR3 neutralizing antibody administration to acutely T. cruzi-infected mice decreased the number of specific CD8+ T cells in the spleen, and those cells had impaired in activation and cytokine production but unaltered proliferative response. In addition, anti-CXCR3-treated mice showed decreased frequency of CD8+ T cells in the heart and numbers of plasmacytoid dendritic cells in spleen and lymph node. As CD8+ T cells interacted with plasmacytoid dendritic cells during infection by T. cruzi, we suggest that anti-CXCR3 treatment lowers the quantity of plasmacytoid dendritic cells, which may contribute to impair the prime of CD8+ T cells. Understanding which molecules and mechanisms guide CD8+ T cell activation and migration might be a key to vaccine development against Chagas disease as those cells play an important role in T. cruzi infection control.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Quimiocinas/metabolismo , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Receptores CXCR3/metabolismo , Trypanosoma cruzi/imunologia , Animais , Movimento Celular , Doença de Chagas/parasitologia , Citoplasma/metabolismo , Citoplasma/parasitologia , Modelos Animais de Doenças , Feminino , Coração , Controle de Infecções , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia
6.
PLoS One ; 15(6): e0234867, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569300

RESUMO

Different modes of exogenous electrical stimulation at physiological strength has been applied to various diseases. Previously, we extensively demonstrated the usability of mild electrical stimulation (MES) with low frequency pulse current at 55 pulses per second (MES55) for several disease conditions. Here we found that MES with high frequency pulse-current (5500 pulse per second; MES5500) suppressed the overproduction of pro-inflammatory cytokines induced by phorbol myristate acetate/ionomycin in Jurkat T cells and primary splenocytes. MES5500 also suppressed the overproduction of inflammatory cytokines, improved liver damage and reduced mouse spleen enlargement in concanavalin-A-treated BALB/c mice. The molecular mechanism underlying these effects included the ability of MES5500 to induce modest amount of hydrogen peroxide and control multiple signaling pathways important for immune regulation, such as NF-κB, NFAT and NRF2. In the treatment of various inflammatory and immune-related diseases, suppression of excessive inflammatory cytokines is key, but because immunosuppressive drugs used in the clinical setting have serious side effects, development of safer methods of inhibiting cytokines is required. Our finding provides evidence that physical medicine in the form of MES5500 may be considered as a novel therapeutic tool or as adjunctive therapy for inflammatory and immune-related diseases.


Assuntos
Citocinas/imunologia , Terapia por Estimulação Elétrica/métodos , Peróxido de Hidrogênio/imunologia , Imunossupressão/métodos , Inflamação/imunologia , Inflamação/terapia , Animais , Concanavalina A , Feminino , Humanos , Inflamação/induzido quimicamente , Células Jurkat , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/imunologia , Baço/patologia
7.
Mol Immunol ; 124: 180-189, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32592984

RESUMO

Stress is a physiological manifestation of the body's defense against adverse effects of external environment, but the molecular regulatory mechanism of stress effects on immune function of poultry has not been fully clarified. In this study, 7-day-old Chinese local breed Gushi cocks were used as model animal, and the stress model was successfully constructed by adding corticosterone (CORT) 30 mg/kg basic diet for 7 days. The spleen transcriptomes of the control group (B_S group) and the stress model group (C_S group) was determined by high-throughput mRNA sequencing (RNA-Seq) technology, and a total of 269 significantly differentially expressed genes (SDEGs) were obtained (Padj < 0.05, |FC| ≥ 2 and FPKM > 1). Compared with B_S group, there were 140 significantly up-regulated genes and 129 significantly down-regulated genes in C_S group. The immune/stress-related Gene Ontology (GO) terms included positive regulation of T cell mediated immunity, chemokine-mediated signaling pathway, T cell mediated immunity and so on. The SDEGs such as IL8L1, HSPA8, HSPA2, RSAD2, CCR8L and DMB1 were involved in these GO terms. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that the SDEGs participated in many immune-related signaling pathways. The immune-related genes HSPA2, HSPA8, HSP90AA1, HSPH1 and HERPUD1 were enriched in Protein processing in endoplasmic reticulum pathway, IL8L1, CXCL13L2, CCR6, LEPR, CCR9 and CCR8L were enriched in Cytokine-cytokine receptor interaction pathway. The protein-protein interactions (PPI) analysis showed HSPA8, HSPA2 and IL8L1 as key core nodes had 7 interactions and may play important roles in the regulation of CORT-induced stress effects on immune function. The data onto this study enriched the genomic study of stress effects on immune function, and provided unique insights into the molecular mechanism of stress effects on immune function, and the genes identified in this study can be candidates for future research on stress response.


Assuntos
Baço/imunologia , Estresse Fisiológico/imunologia , Animais , Galinhas , Perfilação da Expressão Gênica
8.
Nature ; 585(7826): 591-596, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32526765

RESUMO

Recent clinical and experimental evidence has evoked the concept of the gut-brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders1-4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pTreg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver-brain-gut neural arc that ensures the proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pTreg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver-brain-gut reflex arc controls the number of pTreg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut.


Assuntos
Encéfalo/citologia , Intestinos/citologia , Intestinos/inervação , Fígado/citologia , Fígado/inervação , Neurônios/fisiologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Vias Aferentes , Animais , Células Apresentadoras de Antígenos/imunologia , Colite/imunologia , Colite/metabolismo , Colite/patologia , Homeostase , Humanos , Intestinos/imunologia , Masculino , Camundongos , Ratos , Receptores Muscarínicos/metabolismo , Baço/citologia , Baço/imunologia , Nervo Vago/fisiologia
9.
Proc Natl Acad Sci U S A ; 117(24): 13659-13669, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482872

RESUMO

T cell maturation and activation depend upon T cell receptor (TCR) interactions with a wide variety of antigenic peptides displayed in a given major histocompatibility complex (MHC) context. Complementarity-determining region 3 (CDR3) is the most variable part of the TCRα and -ß chains, which govern interactions with peptide-MHC complexes. However, it remains unclear how the CDR3 landscape is shaped by individual MHC context during thymic selection of naïve T cells. We established two mouse strains carrying distinct allelic variants of H2-A and analyzed thymic and peripheral production and TCR repertoires of naïve conventional CD4+ T (Tconv) and naïve regulatory CD4+ T (Treg) cells. Compared with tuberculosis-resistant C57BL/6 (H2-Ab) mice, the tuberculosis-susceptible H2-Aj mice had fewer CD4+ T cells of both subsets in the thymus. In the periphery, this deficiency was only apparent for Tconv and was compensated for by peripheral reconstitution for Treg We show that H2-Aj favors selection of a narrower and more convergent repertoire with more hydrophobic and strongly interacting amino acid residues in the middle of CDR3α and CDR3ß, suggesting more stringent selection against a narrower peptide-MHC-II context. H2-Aj and H2-Ab mice have prominent reciprocal differences in CDR3α and CDR3ß features, probably reflecting distinct modes of TCR fitting to MHC-II variants. These data reveal the mechanics and extent of how MHC-II shapes the naïve CD4+ T cell CDR3 landscape, which essentially defines adaptive response to infections and self-antigens.


Assuntos
Regiões Determinantes de Complementaridade/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Tuberculose/genética , Alelos , Animais , Linfócitos T CD4-Positivos/imunologia , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Baço/imunologia , Linfócitos T Reguladores/química , Tuberculose/imunologia
10.
Scand J Immunol ; 92(3): e12915, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32533866

RESUMO

Systemic lupus erythematosus is an autoimmune syndrome characterized by the development of autoantibodies to a wide range of antigens. Together with B cells, respective self-reactive T cells have an important contribution in disease progression as being responsible for inflammatory cytokines secretion, B cell activation and promoting amplification of the autoimmune response. Annexin A1 is expressed by many cell types and binds to phospholipids in a Ca2+ -dependent manner. Abnormal expression of annexin A1 was found on activated B and T cells in both murine and human autoimmunity suggesting its potential role as a therapeutic target. In the present study, we have investigated the possibility to suppress autoimmune manifestation in spontaneous mouse model of lupus using anti-annexin A1 antibody. Groups of lupus-prone MRL/lpr mice were treated with the anti-annexin A1 monoclonal antibody, and the disease activity and survival of the animals were following up. Flow cytometry, ELISA assays, and histological and immunofluorescence kidney analyses were used to determine the levels of Annexin A1 expression, cytokines, anti-dsDNA antibodies and kidney injuries. The administration of this monoclonal antibody to MRL/lpr mice resulted in suppression of IgG anti-dsDNA antibody production, modulated IL-10 secretion, decreased disease activity and prolonged survival compared with the control group.


Assuntos
Anexina A1/antagonistas & inibidores , Anexina A1/imunologia , Anticorpos Monoclonais/farmacologia , Fatores Imunológicos/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Animais , Autoanticorpos/imunologia , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Imunoglobulina G/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Proteinúria/etiologia , Proteinúria/urina , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
11.
Scand J Immunol ; 92(3): e12920, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32594535

RESUMO

The maintenance of inner integrity of an organism is founded on the proper performance of two immunity branches, innate and adaptive immune responses. Recently, it became apparent that subset of splenic B cells named marginal zone B cells (MZB cells) exhibits unique developmental and functional features that bridge these two immunity branches. Strategically positioned at the site where blood and lymph are filtered, MZB cells represent a population of sentinels that rapidly proliferate and differentiate into IgM plasmablast cells when encountered with blood-borne, thymus-independent (TI) Ags. Moreover, MZB cells have intrinsic capability to induce potent CD4+ helper T cell response and cytokine production upon stimulation with soluble antigens. Due to their ability to overcome a time gap prior the establishment of the full adaptive response towards pathogens, MZB cells connect and direct innate and adaptive immunity. An additional interesting characteristic of MZB cells is capacity to function as regulatory cells in autoimmune processes. MZB cells may also contribute to the control of autoimmunity via the induction of tolerance by apoptotic cells. Importantly, in the clear association with inflammation and autoimmunity, MZB cells may transform into MALT lymphoma, representing a concurrence point for the infection, immunity and malignancy. This paper presents an insight into the complex biology of marginal zone B cells and their role in intertwining and directing innate and adaptive immune processes at the physiological and pathological level.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Suscetibilidade a Doenças , Homeostase , Baço/imunologia , Baço/metabolismo , Imunidade Adaptativa , Animais , Microambiente Celular/imunologia , Humanos , Ativação Linfocitária/imunologia , Baço/patologia
12.
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
13.
Life Sci ; 253: 117747, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376270

RESUMO

AIMS: Multiple sclerosis (MS) whose pathogenesis is still unclear is a chronic progressive disease in the central nervous system. Gut microbiota can directly or indirectly affect the immune system through the brain gut axis to engage in the occurrence and development of the disease. MATERIALS AND METHODS: C57BL/6 mice which were immunized by MOG35-55 to prepare experimental autoimmune encephalomyelitis (EAE) animal models were treated with rapamycin and MCC950 (CP-456773) in combination or separately. After sequencing the 16S rRNA V4 region of gut microbiota, the species, abundance and composition of gut microbiota were analyzed by Alpha diversity, Bata diversity and LEfSe analysis. The pathological changes and the expression of CD4 and CD8 of brain, large intestine and spleen were detected. KEY FINDINGS: The results showed that rapamycin and MCC950 could alleviate the progression of the disease by inducing autophagy and inhibiting the immune response. The Alpha diversity of EAE model group was no significant difference compering to control group while the number of OTUs was decreased. After the treatment by rapamycin and MCC950, the abundance and composition of gut microbiota was relatively recovered, which was close to that of normal mice. SIGNIFICANCE: Inhibiting immune cell-mediated inflammation and restoring the composition of gut microbiota may help to alleviate the clinical symptoms of multiple sclerosis. Furthermore, to research the regulatory effect between immune response and gut microbiota may be a new strategy for the prevention and treatment of multiple sclerosis.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Furanos/farmacologia , Microbioma Gastrointestinal/imunologia , Esclerose Múltipla/tratamento farmacológico , Sirolimo/farmacologia , Sulfonamidas/farmacologia , Animais , Encéfalo/imunologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/microbiologia , Feminino , Furanos/administração & dosagem , Inflamação/imunologia , Inflamação/patologia , Intestino Grosso/imunologia , Intestino Grosso/patologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , RNA Ribossômico 16S , Sirolimo/administração & dosagem , Baço/imunologia , Baço/patologia , Sulfonamidas/administração & dosagem
14.
Mol Biol (Mosk) ; 54(2): 267-277, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392196

RESUMO

Melanoma is one of the most aggressive tumors and is accompanied by the induction of local and systemic inflammatory responses. Combinations of chemotherapeutic agents with immunotherapy are therefore commonly used for melanoma treatment. A B16 melanoma model was used to study the tumor suppressive, immunostimulating, and hepatotoxic effects of a combination of a small double-stranded immunostimulatory RNA (isRNA) with 3'-trinucleotide overhangs and the cytotoxic drug dacarbazine compared with respective monotherapies. The drugs efficiently suppressed the tumor growth and acted synergistically. Histological and immunohistochemical examinations of tumor nodes showed that the combination of isRNA and dacarbazine significantly decreased mitotic activity and more efficiently increased apoptosis in tumor tissue as compared with either monotherapy. Regardless of the treatment regimen, signs of immune activation were observed in the spleen, including an increase in the number and diameter of lymphoid follicles and the volume density of the white pulp. Destructive changes were detected in the livers of nontreated animals with B16 melanoma. Administration of isRNA in combination with dacarbazine did not cause any additional damage to liver parenchyma, while stimulating regenerative processes in hepatic tissue of tumor-bearing animals.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Dacarbazina/farmacologia , Melanoma Experimental/tratamento farmacológico , RNA/farmacologia , Animais , Imunoterapia , Fígado/efeitos dos fármacos , Camundongos , Baço/imunologia
15.
Ecotoxicol Environ Saf ; 200: 110715, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32450432

RESUMO

Copper (Cu) is a necessary trace mineral due to its biological activity. Excessive Cu can induce inflammatory response in humans and animals, but the underlying mechanism is still unknown. Here, 240 broilers were used to study the effects of excessive Cu on oxidative stress and NF-κB-mediated inflammatory responses in immune organs. Chickens were fed with diet containing different concentrations of Cu (11, 110, 220, and 330 mg of Cu/kg dry matter). The experiment lasted for 49 days. Spleen, thymus, and bursa of Fabricius (BF) on day 49 were collected for histopathological observation and assessment of oxidative stress status. Additionally, the mRNA and protein levels of NF-κB and inflammatory cytokines were also analyzed. The results indicated that excess Cu could increase the number and area of splenic corpuscle as well as the ratio of cortex and medulla in thymus and BF. Furthermore, excessive Cu intake could decrease activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); but increase contents of malondialdehyde (MDA), TNF-α, IL-1, IL-1ß; up-regulate mRNA levels of TNF-α, IFN-γ, IL-1, IL-1ß, IL-2, iNOS, COX-2, NF-κB and protein levels of TNF-α, IFN-γ, NF-κB, p-NF-κB in immune organs. In conclusion, excessive Cu could cause pathologic changes and induce oxidative stress with triggered NF-κB pathway, and might further regulate the inflammatory response in immune organs of chicken.


Assuntos
Galinhas/imunologia , Cobre/toxicidade , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Bolsa de Fabricius/enzimologia , Bolsa de Fabricius/imunologia , Bolsa de Fabricius/metabolismo , Bolsa de Fabricius/patologia , Catalase/metabolismo , Galinhas/genética , Galinhas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Glutationa Peroxidase/metabolismo , Inflamação/genética , Inflamação/metabolismo , Malondialdeído/metabolismo , NF-kappa B/genética , Baço/enzimologia , Baço/imunologia , Baço/metabolismo , Baço/patologia , Superóxido Dismutase/metabolismo , Timo/enzimologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
16.
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
17.
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
18.
PLoS One ; 15(5): e0232884, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32384121

RESUMO

BACKGROUND: Obliterative bronchiolitis (OB) is a known issue during minor histocompatibility antigen (mHA) disparity during lung transplantation. This study evaluated gene expression in a murine orthotropic lung transplantation model using microarray analysis. METHODS: Left lungs from C57BL/10(H-2b) donor mice were transplanted into mHA-mismatched C57BL/6(H-2b) recipient mice. Three groups (OB, non-OB, and sham controls) were confirmed pathologically and analyzed. Gene expression changes in the lung grafts were determined by microarray and immunohistochemical staining, and genes were verified by quantitative PCR in the lungs and mediastinal lymph nodes (LNs). RESULTS: A total of 1343 genes were upregulated in the OB lungs compared to the sham group. Significant upregulation was observed for genes related to innate, e.g. Tlr2 and CCL3 and adaptive immunity, e.g. H2-ab1 and Il-21. Positive labeling for MHC class II antigen was observed in the bronchial epithelium of OB accompanied with B cells. We found increased Tlr2, Ccl3, H2-ab1, Il-21, Ighg3, Ifng, and Pdcd1 mRNA expression in the OB lung, and increased Il-21, Ighg3, and Pdcd1 expression in the OB LNs. CONCLUSIONS: Adaptive and innate immune reactions were involved in OB after lung transplantation, and genetic examination of related genes could be used for detection of OB.


Assuntos
Bronquiolite/etiologia , Bronquiolite/imunologia , Transplante de Pulmão , Imunidade Adaptativa , Animais , Bronquiolite/genética , Bronquiolite/patologia , Modelos Animais de Doenças , Expressão Gênica/imunologia , Perfilação da Expressão Gênica , Imunidade Inata , Pulmão/imunologia , Pulmão/patologia , Pulmão/cirurgia , Linfonodos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Antígenos de Histocompatibilidade Menor , RNA Mensageiro/metabolismo , Organismos Livres de Patógenos Específicos , Baço/imunologia , Transcriptoma , Imunologia de Transplantes
19.
J Vis Exp ; (158)2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32420987

RESUMO

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases, affecting patients suffering from pain and physical limitations. Recent evidence indicates a potential inflammatory component of the disease, with both T-cells and monocytes/macrophages potentially associated with the pathogenesis of OA. Further studies postulated an important role for subsets of both inflammatory cell lineages, such as Th1, Th2, Th17, and T-regulatory lymphocytes, and M1, M2, and synovium-tissue-resident macrophages. However, the interaction between the local synovial and systemic inflammatory cellular response and the structural changes in the joint is unknown. To fully understand how T-cells and monocytes/macrophages contribute towards OA, it is important to be able to quantitively identify these cells and their subsets simultaneously in synovial tissue, secondary lymphatic organs and systemically (the spleen and bone marrow). Nowadays, the different inflammatory cell subsets can be identified by a combination of cell-surface markers making multi-color flow cytometry a powerful technique in investigating these cellular processes. In this protocol, we describe detailed steps regarding the harvest of synovial tissue and secondary lymphatic organs as well as generation of single cell suspensions. Furthermore, we present both an extracellular staining assay to identify monocytes/macrophages and their subsets as well as an extra- and intra-cellular staining assay to identify T-cells and their subsets within the murine spleen, bone marrow, lymph nodes and synovial tissue. Each step of this protocol was optimized and tested, resulting in a highly reproducible assay that can be utilized for other surgical and non-surgical OA mouse models.


Assuntos
Medula Óssea/imunologia , Citometria de Fluxo/métodos , Linfonodos/imunologia , Osteoartrite/imunologia , Osteoartrite/patologia , Baço/imunologia , Membrana Sinovial/imunologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos
20.
Proc Natl Acad Sci U S A ; 117(22): 12295-12305, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424104

RESUMO

The mechanisms that regulate germinal center (GC) B cell responses in the spleen are not fully understood. Here we use a combination of pharmacologic and genetic approaches to delete SIGN-R1+ marginal zone (MZ) macrophages and reveal their specific contribution to the regulation of humoral immunity in the spleen. We find that while SIGN-R1+ macrophages were not essential for initial activation of B cells, they were required for maturation of the response and development of GC B cells. These defects could be corrected when follicular helper T (Tfh) cells were induced before macrophage ablation or when Tfh responses were enhanced. Moreover, we show that in the absence of SIGN-R1+ macrophages, DCIR2+ dendritic cells (DCs), which play a key role in priming Tfh responses, were unable to cluster to the interfollicular regions of the spleen and were instead displaced to the MZ. Restoring SIGN-R1+ macrophages to the spleen corrected positioning of DCIR2+ DCs and rescued the GC B cell response. Our study reveals a previously unappreciated role for SIGN-R1+ macrophages in regulation of the GC reaction and highlights the functional specification of macrophage subsets in the MZ compartment.


Assuntos
Linfócitos B/imunologia , Moléculas de Adesão Celular/imunologia , Centro Germinativo/imunologia , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Receptores de Superfície Celular/imunologia , Baço/imunologia , Animais , Moléculas de Adesão Celular/genética , Lectinas Tipo C/genética , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Superfície Celular/genética , Linfócitos T Auxiliares-Indutores
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