RESUMO
Malaria remains a devastating global health problem, resulting in many annual deaths due to the complications of severe malaria. However, in endemic regions, individuals can acquire 'clinical immunity' to malaria, characterized by a decrease in severe malaria episodes and an increase of asymptomatic Plasmodium falciparum infections. Recently, it has been reported that tolerance to 'clinical malaria' and reduced disease severity correlates with a decrease in the numbers of circulating Vγ9Vδ2 T cells, the major subset of γδ T cells in the human peripheral blood. This is particularly interesting as this population typically undergoes dramatic expansions during acute Plasmodium infections and was previously shown to play antiparasitic functions. Thus, regulated γδ T-cell responses may be critical to balance immune protection with severe pathology, particularly as both seem to rely on the same pro-inflammatory cytokines, most notably TNF and IFN-γ. This has been clearly demonstrated in mouse models of experimental cerebral malaria (ECM) based on Plasmodium berghei ANKA infection. Furthermore, our recent studies suggest that the natural course of Plasmodium infection, mimicked in mice through mosquito bite or sporozoite inoculation, includes a major pathogenic component in ECM that depends on γδ T cells and IFN-γ production in the asymptomatic liver stage, where parasite virulence is seemingly set and determines pathology in the subsequent blood stage. Here, we discuss these and other recent advances in our understanding of the complex-protective versus pathogenic-functions of γδ T cells in malaria.
Assuntos
Malária/imunologia , Plasmodium/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Esporozoítos/imunologia , Linfócitos T/imunologia , Animais , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Hepatopatias Parasitárias/imunologia , Hepatopatias Parasitárias/parasitologia , Malária/metabolismo , Malária/parasitologia , Plasmodium/patogenicidade , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/metabolismo , Virulência/imunologiaRESUMO
The local immune mechanisms responsible for the establishment and development of Echinococcus granulosus sensu stricto infection in the liver, have been little explored. We developed a suitable experimental model that mimics naturally infected livers using portal injection of protoscoleces. Opposite to Echinococcus multilocularis infection which is dose-dependent, fully mature hydatid cysts can be established in the liver whatever the injection dose; although most of the infection sites were seen at the establishment phase as inflammatory granulomas associated with fibrosis, they never matured into cysts. At the establishment phase, a strong immune response was composed of T and B cells, with T1-type, T2-type cells and cytokines and IL-10-secreting CD8+ T cells in the liver. At the established phase, results suggested a local production of antibodies by B cells, and an involvement of NK and NKT cells. Infection outcome and local immune response in the liver, were different in the mouse models of Echinococcus granulosus sensu stricto and Echinococcus multilocularis respectively; however, only early specificities at the microenvironment level might explain the major differences found between the lesions induced by the two species. Our quantitative experimental model appears fully appropriate to further study this microenvironment and its relationship with each cestode species.
Assuntos
Equinococose , Echinococcus granulosus/imunologia , Hepatopatias Parasitárias , Fígado , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Equinococose/imunologia , Equinococose/patologia , Feminino , Interleucina-10/imunologia , Fígado/imunologia , Fígado/parasitologia , Fígado/patologia , Hepatopatias Parasitárias/imunologia , Hepatopatias Parasitárias/parasitologia , Hepatopatias Parasitárias/patologia , Camundongos , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologiaRESUMO
CD8+ T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around Plasmodium-infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8+ T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8+ T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8+ T cells specific for an unrelated antigen, respectively. While antigen-specific CD8+ T cells were essential for cluster formation, both antigen-specific and nonspecific CD8+ T cells joined the clusters. However, nonspecific CD8+ T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8+ T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8+ T cells interact with CD11c+ cells around infected hepatocytes. The depletion of CD11c+ cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c+ dendritic cells and presumably macrophages in the formation of CD8+ T cell clusters around Plasmodium-infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8+ T cells, specific and unrelated activated CD8+ T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8+ T cells seem to play a limited role in protective immunity against Plasmodium parasites.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Hepatopatias Parasitárias/imunologia , Macrófagos/imunologia , Malária/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Hepatócitos/imunologia , Hepatopatias Parasitárias/diagnóstico , Hepatopatias Parasitárias/parasitologia , Ativação Linfocitária/imunologia , Macrófagos/metabolismo , Malária/diagnóstico , Malária/parasitologia , Camundongos , Camundongos TransgênicosRESUMO
Type 2 immunity is characterized by the production of IL-4, IL-5, IL-9 and IL-13, and this immune response is commonly observed in tissues during allergic inflammation or infection with helminth parasites. However, many of the key cell types associated with type 2 immune responses - including T helper 2 cells, eosinophils, mast cells, basophils, type 2 innate lymphoid cells and IL-4- and IL-13-activated macrophages - also regulate tissue repair following injury. Indeed, these cell populations engage in crucial protective activity by reducing tissue inflammation and activating important tissue-regenerative mechanisms. Nevertheless, when type 2 cytokine-mediated repair processes become chronic, over-exuberant or dysregulated, they can also contribute to the development of pathological fibrosis in many different organ systems. In this Review, we discuss the mechanisms by which type 2 immunity contributes to tissue regeneration and fibrosis following injury.
Assuntos
Citocinas/imunologia , Fibrose/imunologia , Regeneração/imunologia , Células Th2/imunologia , Alarminas/imunologia , Basófilos/imunologia , Eosinófilos/imunologia , Células Epiteliais , Humanos , Hipersensibilidade/imunologia , Imunidade Inata/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Interleucina-9/imunologia , Cirrose Hepática/imunologia , Hepatopatias Parasitárias/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Mastócitos/imunologia , Doenças Parasitárias/imunologia , Fibrose Pulmonar/imunologia , Esquistossomose/imunologiaRESUMO
BACKGROUND: Th1, Th2, Th17, Treg and Tfh cells play important roles in schistosomiasis. Th9 cells secrete IL-9 as a signature cytokine and contribute to several classes of inflammatory disease. However, the effects of Th9 cells in schistosomiasis are unknown. We aimed to explore the dynamic changes and potential roles of Th9 cells in the pathogenesis of hepatic egg granulomatous inflammation in mice infected with Schistosoma japonicum. METHODS: Twenty mice with S. japonicum infection and five normal controls (NC) were used as models. The average areas of egg granulomas were estimated by hematoxylin-eosin (H & E) staining. Hepatic IL-9 and transcription factor PU.1 levels were detected by immunohistochemistry. Flow cytometry techniques were used to analyze the proportions of Th9 cells. With the help of ELISA, serum levels of IL-9 were examined. RESULTS: The egg granulomas began to form from four weeks after infection and continued to develop. In parallel with the development of egg granulomas, the hepatic levels of IL-9 and PU.1 increased very slowly during the first four weeks post-infection and increased rapidly thereafter. Moreover, the proportions of splenic Th9 cells and levels of serum IL-9 had similar developmental trends with the egg granulomas. CONCLUSION: The proliferation of Th9 cells and levels of IL-9 were significantly higher in S. japonicum-infected mice compared to NC. In addition, dynamic changes of Th9 and IL-9 were synchronous with the developmental trend of hepatic egg granulomatous inflammation, suggesting that Th9 cells might be a new subset in the pathogenesis of schistosomiasis.
Assuntos
Granuloma/imunologia , Hepatopatias Parasitárias/imunologia , Esquistossomose Japônica/imunologia , Animais , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Granuloma/parasitologia , Granuloma/patologia , Imuno-Histoquímica , Interleucina-4/sangue , Interleucina-9/sangue , Fígado/metabolismo , Fígado/parasitologia , Fígado/patologia , Hepatopatias Parasitárias/parasitologia , Hepatopatias Parasitárias/patologia , Camundongos , Camundongos Endogâmicos ICR , Proteínas Proto-Oncogênicas/metabolismo , Distribuição Aleatória , Schistosoma japonicum/imunologia , Esquistossomose Japônica/etiologia , Esquistossomose Japônica/patologia , Caramujos/parasitologia , Organismos Livres de Patógenos Específicos , Baço/citologia , Baço/imunologia , Transativadores/metabolismo , Fator de Crescimento Transformador beta/sangueRESUMO
Entamoeba histolytica is the causative agent of amoebic liver abscess (ALA), which course with an uncontrolled inflammation and nitro-oxidative stresses, although it is well known that amoeba has an effective defence mechanisms against this toxic environment, the underlying molecular factors responsible for progression of tissue damage remain largely unknown. The purpose of the present study was to determine during the acute stage of ALA in hamsters, the involvement of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor-kappa B (NF-κB), which are activated in response to oxidative stress. From 12 h post-infection the ALA was visible, haematoxylin-eosin and Masson's trichrome stains were consistent with these observations, and alanine aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase serum activities were increased too. At 48 h after infection, liver glycogen content was significantly reduced. Western blot analyses showed that 4-Hydroxy-2-nonenal peaked at 12 h, while glycogen synthase kinase-3ß, cleaved caspase-3, pNF-κB, interleukin-1ß and tumour necrosis factor-α were overexpressed from 12 to 48 h post-infection. Otherwise, Nrf2 and superoxide dismutase-1, decreased at 48 h and catalase declined at 36 and 48 h. Furthermore, heme oxygenase-1 was increased at 12 and 24 h and decreased to normal levels at 36 and 48 h. These findings suggest for the first time that the host antioxidant system of Nrf2 is influenced during ALA.
Assuntos
Antioxidantes/metabolismo , Entamebíase/parasitologia , Hepatopatias Parasitárias/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Animais , Cricetinae , Entamoeba histolytica , Entamebíase/imunologia , Entamebíase/metabolismo , Regulação da Expressão Gênica/fisiologia , Masculino , Mesocricetus , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genéticaRESUMO
Schistosoma mansoni antigens in the early life alter homologous and heterologous immunity during postnatal infections. We evaluate the immunity to parasite antigens and ovalbumin (OA) in adult mice born/suckled by schistosomotic mothers. Newborns were divided into: born (BIM), suckled (SIM) or born/suckled (BSIM) in schistosomotic mothers, and animals from noninfected mothers (control). When adults, the mice were infected and compared the hepatic granuloma size and cellularity. Some animals were OA + adjuvant immunised. We evaluated hypersensitivity reactions (HR), antibodies levels (IgG1/IgG2a) anti-soluble egg antigen and anti-soluble worm antigen preparation, and anti-OA, cytokine production, and CD4+FoxP3+T-cells by splenocytes. Compared to control group, BIM mice showed a greater quantity of granulomas and collagen deposition, whereas SIM and BSIM presented smaller granulomas. BSIM group exhibited the lowest levels of anti-parasite antibodies. For anti-OA immunity, immediate HR was suppressed in all groups, with greater intensity in SIM mice accompanied of the remarkable level of basal CD4+FoxP3+T-cells. BIM and SIM groups produced less interleukin (IL)-4 and interferon (IFN)-g. In BSIM, there was higher production of IL-10 and IFN-g, but lower levels of IL-4 and CD4+FoxP3+T-cells. Thus, pregnancy in schistosomotic mothers intensified hepatic fibrosis, whereas breastfeeding diminished granulomas in descendants. Separately, pregnancy and breastfeeding could suppress heterologous immunity; however, when combined, the responses could be partially restored in infected descendants.
Assuntos
Animais Lactentes/imunologia , Anticorpos Anti-Helmínticos/imunologia , Granuloma de Corpo Estranho/imunologia , Imunidade Humoral/fisiologia , Hepatopatias Parasitárias/imunologia , Esquistossomose mansoni/imunologia , Adjuvantes Imunológicos , Animais , Animais Recém-Nascidos , Animais Lactentes/parasitologia , Linfócitos T CD4-Positivos/parasitologia , Cercárias/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/sangue , Granuloma de Corpo Estranho/parasitologia , Granuloma de Corpo Estranho/patologia , Imunidade Heteróloga/fisiologia , Imunoglobulina G/sangue , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-4/sangue , Cirrose Hepática/imunologia , Cirrose Hepática/parasitologia , Hepatopatias Parasitárias/patologia , Masculino , Camundongos , Mães , Ovalbumina/imunologia , Gravidez , Schistosoma mansoni/imunologia , Baço/imunologia , Baço/patologiaRESUMO
Schistosoma mansoni antigens in the early life alter homologous and heterologous immunity during postnatal infections. We evaluate the immunity to parasite antigens and ovalbumin (OA) in adult mice born/suckled by schistosomotic mothers. Newborns were divided into: born (BIM), suckled (SIM) or born/suckled (BSIM) in schistosomotic mothers, and animals from noninfected mothers (control). When adults, the mice were infected and compared the hepatic granuloma size and cellularity. Some animals were OA + adjuvant immunised. We evaluated hypersensitivity reactions (HR), antibodies levels (IgG1/IgG2a) anti-soluble egg antigen and anti-soluble worm antigen preparation, and anti-OA, cytokine production, and CD4+FoxP3+T-cells by splenocytes. Compared to control group, BIM mice showed a greater quantity of granulomas and collagen deposition, whereas SIM and BSIM presented smaller granulomas. BSIM group exhibited the lowest levels of anti-parasite antibodies. For anti-OA immunity, immediate HR was suppressed in all groups, with greater intensity in SIM mice accompanied of the remarkable level of basal CD4+FoxP3+T-cells. BIM and SIM groups produced less interleukin (IL)-4 and interferon (IFN)-g. In BSIM, there was higher production of IL-10 and IFN-g, but lower levels of IL-4 and CD4+FoxP3+T-cells. Thus, pregnancy in schistosomotic mothers intensified hepatic fibrosis, whereas breastfeeding diminished granulomas in descendants. Separately, pregnancy and breastfeeding could suppress heterologous immunity; however, when combined, the responses could be partially restored in infected descendants.
Assuntos
Animais , Feminino , Masculino , Camundongos , Gravidez , Animais Lactentes/imunologia , Anticorpos Anti-Helmínticos/imunologia , Granuloma de Corpo Estranho/imunologia , Imunidade Humoral/fisiologia , Hepatopatias Parasitárias/imunologia , Esquistossomose mansoni/imunologia , Adjuvantes Imunológicos , Animais Recém-Nascidos , Animais Lactentes/parasitologia , /parasitologia , Cercárias/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Fatores de Transcrição Forkhead/sangue , Granuloma de Corpo Estranho/parasitologia , Granuloma de Corpo Estranho/patologia , Imunidade Heteróloga/fisiologia , Imunoglobulina G/sangue , Interferon gama/sangue , /sangue , /sangue , Cirrose Hepática/imunologia , Cirrose Hepática/parasitologia , Hepatopatias Parasitárias/patologia , Mães , Ovalbumina/imunologia , Schistosoma mansoni/imunologia , Baço/imunologia , Baço/patologiaRESUMO
In C57BL/6 mice, Leishmania donovani infection in the liver provoked IFN-γ-induced expression of the immunity-related GTPases (IRG), Irgm1 and Irgm3. To gauge the antileishmanial effects of these macrophage factors in the liver, intracellular infection was analyzed in IRG-deficient mice. In early- (but not late-) stage infection, Irgm3(-/-) mice failed to properly control parasite replication, generated little tissue inflammation and were hyporesponsive to pentavalent antimony (Sb) chemotherapy. Observations limited to early-stage infection in Irgm1(-/-) mice demonstrated increased susceptibility and virtually no inflammatory cell recruitment to heavily-parasitized parenchymal foci but an intact response to chemotherapy. In L. donovani infection in the liver, the absence of either Irgm1 or Irgm3 impairs early inflammation and initial resistance; the absence of Irgm3, but not Irgm1, also appears to impair the intracellular efficacy of Sb chemotherapy.
Assuntos
GTP Fosfo-Hidrolases/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Interferon gama/imunologia , Leishmania donovani/imunologia , Leishmaniose Visceral/imunologia , Hepatopatias Parasitárias/imunologia , Animais , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/uso terapêutico , Feminino , GTP Fosfo-Hidrolases/imunologia , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/enzimologia , Fígado/enzimologia , Fígado/parasitologia , Fígado/patologia , Hepatopatias Parasitárias/tratamento farmacológico , Hepatopatias Parasitárias/enzimologia , Macrófagos/imunologia , Camundongos , Análise em MicrossériesRESUMO
Acute schistosomiasis is characterized by pro-inflammatory responses against tissue- or organ-trapped parasite eggs along with granuloma formation. Here, we describe studies in Cx3cr1(-/-) mice and demonstrate the role of Cx3cr1 in the pathoetiology of granuloma formation during acute schistosomiasis. Mice deficient in Cx3cr1 were protected from granuloma formation and hepatic injury induced by Schistosoma japonicum eggs, as manifested by reduced body weight loss and attenuated hepatomegaly along with preserved liver function. Notably, S. japonicum infection induced high levels of hepatic Cx3cr1 expression, which was predominantly expressed by infiltrating macrophages. Loss of Cx3cr1 rendered macrophages preferentially towards M2 polarization, which then led to a characteristic switch of the host immune defense from a conventional Th1 to a typical Th2 response during acute schistosomiasis. This immune switch caused by Cx3cr1 deficiency was probably associated with enhanced STAT6/PPAR-γ signaling and increased expression of indoleamine 2,3-dioxygenase (IDO), an enzyme that promotes M2 polarization of macrophages. Taken together, our data provide evidence suggesting that CX3CR1 could be a viable therapeutic target for treatment of acute schistosomiasis.
Assuntos
Hepatopatias Parasitárias/etiologia , Macrófagos/imunologia , Receptores de Interleucina-8A/deficiência , Esquistossomose Japônica/imunologia , Esquistossomose Japônica/patologia , Doença Aguda , Animais , Modelos Animais de Doenças , Feminino , Granuloma/etiologia , Granuloma/imunologia , Granuloma/patologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/patologia , Hepatopatias Parasitárias/imunologia , Hepatopatias Parasitárias/patologia , Macrófagos/classificação , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óvulo/imunologia , PPAR gama/metabolismo , Receptores de Interleucina-8A/genética , Fator de Transcrição STAT6/metabolismo , Schistosoma japonicum/imunologia , Esquistossomose Japônica/complicações , Transdução de Sinais , Células Th2/imunologia , Células Th2/patologiaRESUMO
BACKGROUND: We report the use of an ex vivo precision cut liver slice (PCLS) mouse model for studying hepatic schistosomiasis. In this system, liver tissue is unfixed, unfrozen, and alive for maintenance in culture and subsequent molecular analysis. METHODS AND FINDINGS: Using thick naive mouse liver tissue and sterile culture conditions, the addition of soluble egg antigen (SEA) derived from Schistosoma japonicum eggs, followed 4, 24 and 48 hrs time points. Tissue was collected for transcriptional analysis and supernatants collected to quantitate liver enzymes, cytokines and chemokines. No significant hepatotoxicity was demonstrated by supernatant liver enzymes due to the presence of SEA. A proinflammatory response was observed both at the transcriptional level and at the protein level by cytokine and chemokine bead assay. Key genes observed elevated transcription in response to the addition of SEA included: IL1-α and IL1-ß, IL6, all associated with inflammation. The recruitment of antigen presenting cells was reflected in increases in transcription of CD40, CCL4 and CSF1. Indications of tissue remodeling were seen in elevated gene expression of various Matrix MetalloProteinases (MMP3, 9, 10, 13) and delayed increases in TIMP1. Collagen deposition was significantly reduced in the presence of SEA as shown in COL1A1 expression by qPCR after 24 hrs culture. Cytokine and chemokine analysis of the culture supernatants confirmed the elevation of proteins including IL6, CCL3, CCL4 and CXCL5. CONCLUSIONS: This ex vivo model system for the synchronised delivery of parasite antigen to liver tissue provides an insight into the early phase of hepatic schistosomiasis, corresponding with the release of soluble proteins from dying schistosome eggs.
Assuntos
Antígenos de Protozoários/imunologia , Hepatopatias Parasitárias/imunologia , Fígado/parasitologia , Óvulo/imunologia , Esquistossomose/imunologia , Animais , Antígenos CD40/imunologia , Quimiocina CCL4/imunologia , Quimiocina CXCL5/imunologia , Modelos Animais de Doenças , Expressão Gênica , Inflamação/imunologia , Inflamação/parasitologia , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Hepatopatias Parasitárias/parasitologia , Fator Estimulador de Colônias de Macrófagos/imunologia , Camundongos , Esquistossomose/parasitologia , Esquistossomose/patologia , Inibidor Tecidual de Metaloproteinase-1/biossínteseRESUMO
The non-classical human leukocyte antigen-G (HLA-G), plays an important role in inducing tolerance, through its immunosuppressive effects on all types of immune cells. Immune tolerance is a key issue in the liver, both in liver homeostasis and in the response to liver injury or cancer. It would therefore appear likely that HLA-G plays an important role in liver diseases. Indeed, this molecule was recently shown to be produced by mast cells in the livers of patients infected with hepatitis C virus (HCV). Furthermore, the number of HLA-G-positive mast cells was significantly associated with fibrosis progression. The generation of immune tolerance is a role common to both HLA-G, as a molecule, and the liver, as an organ. This review provides a summary of the evidence implicating HLA-G in liver diseases. In the normal liver, HLA-G transcripts can be detected, but there is no HLA-G protein. However, HLA-G protein is detectable in the liver tissues and/or plasma of patients suffering from hepatocellular carcinoma, hepatitis B or C, or visceral leishmaniasis and in liver transplant recipients. The cells responsible for producing HLA-G differ between diseases. HLA-G expression is probably induced by microenvironmental factors, such as cytokines. The expression of HLA-G receptors, such as ILT2, ILT4, and KIRD2L4, on liver cells has yet to be investigated, but these receptors have been detected on all types of immune cells, and such cells are present in liver. The tolerogenic properties of HLA-G explain its deleterious effects in cancers and its beneficial effects in transplantation. Given the key role of HLA-G in immune tolerance, new therapeutic agents targeting HLA-G could be tested for the treatment of these diseases in the future.
Assuntos
Antígenos HLA-G/metabolismo , Hepatopatias/imunologia , Doenças Autoimunes/imunologia , Expressão Gênica , Reação Enxerto-Hospedeiro/imunologia , Antígenos HLA-G/genética , Hepatite Viral Humana/imunologia , Humanos , Tolerância Imunológica , Fígado/imunologia , Hepatopatias Parasitárias/imunologia , Neoplasias Hepáticas/imunologia , Transplante de FígadoRESUMO
Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease. While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host. However, the exact mechanism of hepatic granuloma formation has remained obscure. In this study, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation and liver injury in S. japonicum-infected mice, and identified a novel function of macrophages in Tfh cell induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell-cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40-CD40L signaling. Our findings uncovered a previously unappreciated role for Tfh cells in liver pathology caused by S. japonicum infection in mice.
Assuntos
Granuloma/imunologia , Hepatopatias Parasitárias/imunologia , Schistosoma japonicum/patogenicidade , Esquistossomose Japônica/imunologia , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Células Cultivadas , Granuloma/parasitologia , Ligante Coestimulador de Linfócitos T Induzíveis/genética , Fígado/imunologia , Fígado/parasitologia , Fígado/patologia , Hepatopatias Parasitárias/parasitologia , Macrófagos/imunologia , Macrófagos/parasitologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Schistosoma japonicum/imunologia , Esquistossomose Japônica/patologia , Caramujos/parasitologiaRESUMO
It is well established that immunization with attenuated malaria sporozoites induces CD8(+) T cells that eliminate parasite-infected hepatocytes. Liver memory CD8(+) T cells induced by immunization with parasites undergo a unique differentiation program and have enhanced expression of CXCR6. Following immunization with malaria parasites, CXCR6-deficient memory CD8(+) T cells recovered from the liver display altered cell-surface expression markers as compared to their wild-type counterparts, but they exhibit normal cytokine secretion and expression of cytotoxic mediators on a per-cell basis. Most importantly, CXCR6-deficient CD8(+) T cells migrate to the liver normally after immunization with Plasmodium sporozoites or vaccinia virus, but a few weeks later their numbers severely decrease in this organ, losing their capacity to inhibit malaria parasite development in the liver. These studies are the first to show that CXCR6 is critical for the development and maintenance of protective memory CD8(+) T cells in the liver.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/fisiologia , Hepatopatias Parasitárias/imunologia , Receptores CXCR/fisiologia , Transferência Adotiva , Animais , Feminino , Citometria de Fluxo , Malária/imunologia , Malária/parasitologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasmodium berghei/imunologia , Receptores CXCR6RESUMO
Toxocariasis is a soil-transmitted helminthic disease due to infection of humans by larvae of Toxocara canis (T. canis). It is one of the most commonly reported zoonotic infections in the world. The aim of this study was to characterize the key immune cells and activity of Bcl-2 in hepatic inflammation during the course of experimental infection by T. canis. Mice experimentally infected with T. canis were divided into two groups: mice with primary infection by Toxocara, and those infected after sensitization by Toxocara excretory-secretory antigen. CD4+, CD8+, and Bcl-2-expressing T lymphocytes were identified in the liver by immunohistochemistry at different durations post-infection. Recruitment of both CD4+ and CD8+ T lymphocytes within the inflammatory reaction in the liver was observed, with difference in count and localization. These cells were detected within and around Toxocara-induced granulomas as well as in isolated inflammatory foci in the portal tracts or within the hepatic parenchyma. The antiapoptotic protein Bcl-2 showed no significant change at different periods post-infection. On the other hand, immunization of mice with Toxocara excretory-secretory antigen prior to experimental infection caused earlier and more pronounced recruitment of CD4+ and CD8+ T cells to the liver and enhanced expression of Bcl-2. Moreover, CD8+ cells became more diffuse within the inflammatory infiltrate. These results suggest a dynamic change in key immune cells according to the duration of infection as well as the immune status of the host.
Assuntos
Genes bcl-2/fisiologia , Hepatopatias Parasitárias/imunologia , Fígado/parasitologia , Subpopulações de Linfócitos/imunologia , Toxocara/imunologia , Toxocaríase/imunologia , Animais , Relação CD4-CD8 , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Cães , Expressão Gênica , Imuno-Histoquímica , Inflamação , Fígado/patologia , Masculino , CamundongosRESUMO
Accumulation of extracellular matrix components secreted by fibroblasts is a normal feature of wound healing during acute inflammation. However, during most chronic/persistent inflammatory diseases, this tissue repair mechanism is incorrectly regulated and results in irreversible fibrosis in various organs. Fibrosis that severely affects tissue architecture and can cause organ failure is a major cause of death in developed countries. Organ-recruited lymphoid (mainly T cells) and myeloid cells (eosinophils, basophils, macrophages and DCs) have long been recognized in their participation to the development of fibrosis. In particular, a central role for recruited monocyte-derived macrophages in this excessive connective tissue deposit is more and more appreciated. Moreover, the polarization of monocyte-derived macrophages in classically activated (IFNγ-dependent) M1 cells or alternatively activated (IL-4/IL-13) M2 cells, that mirrors the Th1/Th2 polarization of T cells, is also documented to contribute differentially to the fibrotic process. Here, we review the current understanding of how myeloid cell subpopulations affect the development of fibrosis in parasite infections.
Assuntos
Cirrose Hepática/parasitologia , Hepatopatias Parasitárias/parasitologia , Fígado/parasitologia , Células Mieloides/parasitologia , Animais , Equinococose Hepática/imunologia , Equinococose Hepática/parasitologia , Equinococose Hepática/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/parasitologia , Matriz Extracelular/patologia , Humanos , Mediadores da Inflamação/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Hepatopatias Parasitárias/imunologia , Hepatopatias Parasitárias/metabolismo , Hepatopatias Parasitárias/patologia , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Esquistossomose/imunologia , Esquistossomose/parasitologia , Esquistossomose/patologiaRESUMO
Wild ruminants sharing pastures with domestic livestock are at risk of infection by liver trematodes. Detection of antibodies provides a very useful tool to gain more knowledge about the distribution of these parasites. Non-lethal methods are strongly encouraged for the analysis of the risk of infection among wild ruminants. A seroepidemiological survey was conducted to analyze exposure to hepatic trematodes ( Fasciola hepatica and Dicrocoelium dendriticum ) in wild ruminants from southern Spain. Blood samples were collected from 69 bovids (Mouflon + Spanish ibex) and 143 cervids (red deer + fallow deer) from Sierra de Cazorla, Segura and Las Villas Natural Park. The samples were analyzed using the excretory/secretory antigens of each trematode to determine the IgG response. All the animals were examined at necropsy for the presence of flukes, and the species, age, and gender of the animals were recorded. Fasciola hepatica were only observed in cervids (3%; 95% confidence interval [CI] â=â 2-8), while D. dendriticum specimens were recorded in 1% (0-8) of bovids and 4% (CI â=â 2-9) of the cervids. The IgG-seroprevalence against F. hepatica was significantly higher in the cervids. Statistical differences according to gender were observed. The bovids exhibited the greatest percentages of positive cases to D. dendriticum antigens, and the DdES-seroprevalence was related to age of the animals. When considering all the factors, the FhES-seroprevalence was initially distributed according to the type of ruminant (cervids), gender (male), and age (>2 yr).
Assuntos
Animais Selvagens/parasitologia , Anticorpos Anti-Helmínticos/sangue , Hepatopatias Parasitárias/veterinária , Ruminantes/parasitologia , Trematódeos/imunologia , Infecções por Trematódeos/veterinária , Determinação da Idade pelos Dentes/veterinária , Animais , Cervos/parasitologia , Dicrocoelium/imunologia , Dicrocoelium/isolamento & purificação , Ensaio de Imunoadsorção Enzimática/veterinária , Fasciola hepatica/imunologia , Fasciola hepatica/isolamento & purificação , Feminino , Cabras , Fígado/parasitologia , Hepatopatias Parasitárias/epidemiologia , Hepatopatias Parasitárias/imunologia , Masculino , Estudos Soroepidemiológicos , Carneiro Doméstico , Espanha/epidemiologia , Infecções por Trematódeos/epidemiologia , Infecções por Trematódeos/imunologiaRESUMO
Hepcidin is one of the regulators of iron metabolism. The expression of hepcidin is induced in spleens and livers of mice infected with pathogenic bacteria. Recent studies have indicated that serum hepcidin level is also increased in human subjects infected with Plasmodium falciparum. The mechanism of the regulation of hepcidin expression and its role in the infection of malaria remains unknown. In this study, we determined the expression of hepcidin in livers of mice infected with Plasmodium berghei. The expression of hepcidin in the liver was upregulated and downregulated during the early and late stages of malaria infection, respectively. Inflammation and erythropoietin, rather than the iron-sensing pathway, are involved in the regulation of hepcidin expression in livers of infected mice. Meanwhile, we investigated the effect of hepcidin on the survival of mice infected with P. berghei. Treatment of malaria-infected mice with anti-hepcidin neutralizing Abs promoted the rates of parasitemia and mortality. In contrast, lentiviral vector-mediated overexpression of hepcidin improved the outcome of P. berghei infection in mice. Our data demonstrate an important role of hepcidin in modulating the course and outcome of blood-stage malaria.
Assuntos
Antimaláricos/sangue , Peptídeos Catiônicos Antimicrobianos/biossíntese , Malária Cerebral/imunologia , Malária Cerebral/prevenção & controle , Plasmodium berghei/imunologia , Animais , Antimaláricos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/fisiologia , Citocinas/sangue , Citocinas/fisiologia , Hemeproteínas/administração & dosagem , Hepcidinas , Mediadores da Inflamação/sangue , Mediadores da Inflamação/fisiologia , Interleucina-6/biossíntese , Interleucina-6/sangue , Hepatopatias Parasitárias/sangue , Hepatopatias Parasitárias/imunologia , Hepatopatias Parasitárias/prevenção & controle , Malária Cerebral/patologia , Camundongos , Camundongos Endogâmicos ICR , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
Identification of correlates of protection for infectious diseases including malaria is a major challenge and has become one of the main obstacles in developing effective vaccines. We investigated protection against liver-stage malaria conferred by vaccination with adenoviral (Ad) and modified vaccinia Ankara (MVA) vectors expressing pre-erythrocytic malaria Ags. By classifying CD8(+) T cells into effector, effector memory (T(EM)), and central memory subsets using CD62L and CD127 markers, we found striking differences in T cell memory generation. Although MVA induced accelerated central memory T cell generation, which could be efficiently boosted by subsequent Ad administration, it failed to protect against malaria. In contrast, Ad vectors, which permit persistent Ag delivery, elicit a prolonged effector T cell and T(EM) response that requires long intervals for an efficient boost. A preferential T(EM) phenotype was maintained in liver, blood, and spleen after Ad/MVA prime-boost regimens, and animals were protected against malaria sporozoite challenge. Blood CD8(+) T(EM) cells correlated with protection against malaria liver-stage infection, assessed by estimation of number of parasites emerging from the liver into the blood. The protective ability of Ag-specific T(EM) cells was confirmed by transfer experiments into naive recipient mice. Thus, we identify persistent CD8 T(EM) populations as essential for vaccine-induced pre-erythrocytic protection against malaria, a finding that has important implications for vaccine design.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/parasitologia , Memória Imunológica , Hepatopatias Parasitárias/imunologia , Hepatopatias Parasitárias/prevenção & controle , Malária/imunologia , Malária/prevenção & controle , Adenoviridae/genética , Adenoviridae/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/imunologia , Vetores Genéticos/uso terapêutico , Antígenos H-2/administração & dosagem , Antígenos H-2/genética , Antígenos H-2/imunologia , Humanos , Memória Imunológica/genética , Hepatopatias Parasitárias/patologia , Malária/patologia , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/genética , Vacinas Antimaláricas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei/genética , Plasmodium berghei/imunologia , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Transgenes/imunologia , Vacínia/genética , Vacínia/imunologiaRESUMO
CONTEXT: Blood transfusion is one of the major risk factors for the transmission of the hepatitis B (HBV) and C (HCV) viruses. However, there are no reports describing the endoscopic transmission of these viruses in patients with the hepatosplenic form of schistosomiasis. OBJECTIVE: To estimate the prevalence of serological markers of HBV and HCV in patients with the hepatosplenic form of schistosomiasis and evaluate the possible risk factors associated with these infections. METHODS: A cross-sectional study was conducted on 230 patients with hepatosplenic form of schistosomiasis who attended a university hospital in Recife, Northeastern Brazil, from February to August 2008. The patients answered a standardized questionnaire about risk factors. Serum samples were analyzed for anti-HBc total, anti-HBs, HBsAg, and anti-HCV using enzyme-linked immunosorbent assays. Univariate analysis and multiple logistic regression were performed. RESULTS: The prevalence was 30% for anti-HBc total and/or HBsAg and 7.4% for anti-HCV. There was a higher frequency of the serological markers in females and in patients aged .50 years. A significant association was detected between the presence of anti-HCV and the receipt of six or more blood transfusions. There was no association of history and number of digestive endoscopies with the serological markers analyzed. CONCLUSIONS: We observed a higher prevalence of serological markers for HBV and a lower prevalence of anti-HCV. Our results indicate that females and patients of an advanced age are the most affected categories and that patients that received multiple transfusions are at a higher probability of HCV infection.