RESUMO
Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (family Flaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia. Patients experienced fever, skin rash, arthralgia and conjunctivitis. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain-Barré syndrome. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKV(BR)) strain causes birth defects remains absent. Here we demonstrate that ZIKV(BR) infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKV(BR) crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKV(BR) outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKV(BR) in human neurodevelopment.
Assuntos
Modelos Animais de Doenças , Microcefalia/virologia , Zika virus/patogenicidade , Animais , Apoptose , Autofagia , Encéfalo/patologia , Encéfalo/virologia , Brasil/epidemiologia , Proliferação de Células , Feminino , Retardo do Crescimento Fetal/patologia , Retardo do Crescimento Fetal/virologia , Feto/virologia , Camundongos , Microcefalia/epidemiologia , Microcefalia/etiologia , Microcefalia/patologia , Células-Tronco Neurais/patologia , Células-Tronco Neurais/virologia , Organoides/patologia , Organoides/virologia , Placenta/virologia , Gravidez , Infecção por Zika virus/complicações , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologiaRESUMO
Zika virus (ZIKV) is a flavivirus that is responsible for the current epidemic in Brazil and the Americas. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans and mice. The rapid development of a safe and effective ZIKV vaccine is a global health priority, but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization with a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a strain of ZIKV involved in the outbreak in northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice. We produced DNA vaccines expressing ZIKV pre-membrane and envelope (prM-Env), as well as a series of deletion mutants. The prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV, as measured by absence of detectable viraemia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and depletion of CD4 and CD8 T lymphocytes in vaccinated mice did not abrogate this protection. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans is likely to be achievable.
Assuntos
Vacinas Virais/imunologia , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologia , Zika virus/imunologia , Transferência Adotiva , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Brasil , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Deleção de Genes , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/isolamento & purificação , Camundongos , Microcefalia/complicações , Microcefalia/virologia , Vacinas de DNA/química , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de Produtos Inativados/química , Vacinas de Produtos Inativados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas de Subunidades Antigênicas/química , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Vacinas Virais/química , Vacinas Virais/genética , Zika virus/química , Zika virus/genética , Infecção por Zika virus/complicações , Infecção por Zika virus/imunologiaRESUMO
Viral infections have always been a serious burden to public health, increasing morbidity and mortality rates worldwide. Zika virus (ZIKV) is a flavivirus transmitted by the Aedes aegypti vector and the causative agent of severe fetal neuropathogenesis and microcephaly. The virus crosses the placenta and reaches the fetal brain, mainly causing the death of neuronal precursor cells (NPCs), glial inflammation, and subsequent tissue damage. Genetic differences, mainly related to the antiviral immune response and cell death pathways greatly influence the susceptibility to infection. These components are modulated by many factors, including microRNAs (miRNAs). MiRNAs are small noncoding RNAs that regulate post-transcriptionally the overall gene expression, including genes for the neurodevelopment and the formation of neural circuits. In this context, we investigated the pathways and target genes of miRNAs modulated in NPCs infected with ZIKV. We observed downregulation of miR-302b, miR-302c and miR-194, whereas miR-30c was upregulated in ZIKV infected human NPCs in vitro. The analysis of a public dataset of ZIKV-infected human NPCs evidenced 262 upregulated and 3 downregulated genes, of which 142 were the target of the aforementioned miRNAs. Further, we confirmed a correlation between miRNA and target genes affecting pathways related to antiviral immune response, cell death and immune cells chemotaxis, all of which could contribute to the establishment of microcephaly and brain lesions. Here, we suggest that miRNAs target gene expression in infected NPCs, directly contributing to the pathogenesis of fetal microcephaly.
Assuntos
MicroRNAs , Microcefalia , Malformações do Sistema Nervoso , Infecção por Zika virus , Zika virus , Animais , Antivirais , Morte Celular/genética , Quimiotaxia , Feminino , Humanos , Imunidade , MicroRNAs/genética , Microcefalia/genética , Mosquitos Vetores , Gravidez , Zika virus/fisiologiaRESUMO
Renal cell carcinoma (RCC) is a highly deadly urological tumor due to its high metastatic incidence and its notorious chemoresistance. The nuclear transcription factor kappa B (NF-κB) family has been associated with apoptosis resistance and cellular invasion in RCC. The purpose of this study was to evaluate the impact of NF-κB1 gene silencing on the colony formation, cell migration and invasion abilities of the RCC cell line. Renca-mock and Renca-shRNA-NF-κB1 cells were used in this work. NF-κB1 downregulation was assessed by western blotting. The mRNA expression levels of interleukin-1 beta (IL-1ß) and MMP-9 were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). The IL-1ß levels in the culture media were determined by a commercial ELISA kit. The MMP-9 protein expression and gelatinolytic activity were evaluated by western blotting and zymography, respectively, and the migration and invasion abilities were analysed. The expression levels of p105 and p50 in Renca-shRNA-NF-κBmoc1 cells were significantly reduced compared with those in the Renca-mock cells. The colony numbers of shRNA-NF-кB1 cells were lower than the colony numbers of the Renca-mock cells. NF-κB1 knockdown inhibited the cell migration and invasion of Renca-shRNA-NF-κB1 cells. These cells also exhibited reduced levels of IL-1ß. The MMP-9 expression and activity levels were significantly reduced in Renca-shRNA-NF-κB1 cells. Taken together, these results indicate that the downregulation of NF-κB1 suppresses the tumourigenicity of RCC by reducing MMP-9 expression and activity; thus, NF-κB1 could be a molecular target for RCC treatment.
Assuntos
Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Interleucina-1beta/genética , Neoplasias Renais/genética , Metaloproteinase 9 da Matriz/genética , NF-kappa B/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , RNA Interferente Pequeno/genéticaRESUMO
NLRP3 inflammasome [NLR (nucleotide-binding domain, leucine-rich repeat containing protein) Pyrin-domain-containing 3 ] functions as an innate sensor of several PAMPs and DAMPs (pathogen- and damage-associated molecular patterns). It has been also reported as a transcription factor related to Th2 pattern, although its role in the adaptive immunity has been controversial, mainly because the studies were performed using gene deletion approaches. In the present study, we have investigated the NLRP3 gain-of-function in the context of encephalomyelitis autoimmune disease (EAE), considered to be a Th1- and Th17-mediated disease. We took advantage of an animal model with NLRP3 gain-of-function exclusively to T CD4+ lymphocytes (CD4CreNLRP3fl/fl). These mice presented reduced clinical score, accompanied by less infiltrating T CD4+ cells expressing both IFN-γ and IL-17 at the central nervous system (CNS) during the peak of the disease. However, besides NLRP3 gain-of-function in lymphocytes, these mice lack NLRP3 expression in non-T CD4+ cells. Therefore, in order to circumvent this deficiency, we transferred naive CD4+ T cells from WT, NLRP3-/- or CD4CreNLRP3fl/fl into Rag-1-/- mice and immunized them with MOG35-55 Likewise, the animals repopulated with CD4CreNLRP3fl/fl T CD4+ cells presented reduced clinical score and decreased IFN-γ production at the peak of the disease. Additionally, primary effector CD4+ T cells derived from these mice presented reduced glycolytic profile, a metabolic profile compatible with Th2 cells. Finally, naive CD4+ T cells from CD4CreNLRP3fl/fl mice under a Th2-related cytokine milieu cocktail exhibited in vitro an increased IL-4 and IL-13 production. Conversely, naive CD4+ T cells from CD4CreNLRP3fl/fl mice under Th1 differentiation produced less IFN-γ and T-bet. Altogether, our data evidence that the NLRP3 gain-of-function promotes a Th2-related response, a pathway that could be better explored in the treatment of multiple sclerosis.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Leptin is an adipose-secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1-cell polarization and inhibit Th2-cell responses. Additionally, leptin induces Th17-cell responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg-cell immune responses in mice. We observed that leptin deficiency (i) reduced the expression of DC maturation markers, (ii) decreased DC production of IL-12, TNF-α, and IL-6, (iii) increased DC production of TGF-ß, and (iv) limited the capacity of DCs to induce syngeneic CD4(+) T-cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin-free conditions induced Treg or TH 17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs.
Assuntos
Diferenciação Celular/genética , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Leptina/deficiência , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Animais , Células Dendríticas/imunologia , Imunofenotipagem , Leptina/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th17/citologia , Células Th17/imunologiaRESUMO
HJURP is overexpressed in several cancer types and strongly correlates with patient survival. However, the mechanistic basis underlying the association of HJURP with cancer aggressiveness is not well understood. HJURP promotes the loading of the histone H3 variant, CENP-A, at the centromeric chromatin, epigenetically defining the centromeres and supporting proper chromosome segregation. In addition, HJURP is associated with DNA repair but its function in this process is still scarcely explored. Here, we demonstrate that HJURP is recruited to DSBs through a mechanism requiring chromatin PARylation and promotes epigenetic alterations that favor the execution of DNA repair. Incorporation of HJURP at DSBs promotes turnover of H3K9me3 and HP1, facilitating DNA damage signaling and DSB repair. Moreover, HJURP overexpression in glioma cell lines also affected global structure of heterochromatin independently of DNA damage induction, promoting genome-wide reorganization and assisting DNA damage response. HJURP overexpression therefore extensively alters DNA damage signaling and DSB repair, and also increases radioresistance of glioma cells. Importantly, HJURP expression levels in tumors are also associated with poor response of patients to radiation. Thus, our results enlarge the understanding of HJURP involvement in DNA repair and highlight it as a promising target for the development of adjuvant therapies that sensitize tumor cells to irradiation.
Assuntos
Cromatina , Glioma , Humanos , Centrômero/metabolismo , Proteína Centromérica A/genética , Proteína Centromérica A/metabolismo , Cromatina/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Glioma/genéticaRESUMO
We report on nine patients (eight cases of MS and one case of NMOSD) who presented a disease relapse in close temporal association with their first AZD1222 vaccination dose against COVID-19. These patients had been stable for a median period of six years, with no evidence of disease activity and no change in their medication. After a median of 13 days (7 to 25 days) from vaccination, they developed a new relapse with increased disability and new lesions on magnetic resonance imaging. Although this association may be rare, it might be an adverse event of AZD1222.
Assuntos
COVID-19 , Esclerose Múltipla , Neuromielite Óptica , ChAdOx1 nCoV-19 , Humanos , Recidiva , SARS-CoV-2 , VacinaçãoRESUMO
Hundreds of intracellular peptides that are neither antigens nor neuropeptides are present in mammalian cells and tissues. These peptides correspond to fragments of cytosolic, nuclear or mitochondrial proteins. Proteasome inhibition affects the levels of the intracellular peptides in human cell lines. Here, the effect of immuneproteasome expression on the intracellular peptide profile was evaluated, and its functional significance was investigated. The expression of the immuneproteasome in HeLa cells was induced by interferon gamma treatment, and the relative concentrations of the intracellular peptides were compared to those of the control cells using isotope labeling and electron spray mass spectrometry. One of the peptides identified, VGSELIQKY (EL28), corresponds to amino acids 251-259 of the human 19S ATPase regulatory subunit 4. This peptide was increased in the extracts of HeLa cells that had been treated with interferon gamma compared to those of control cells. In vitro, EL28 increased the chymotrypsin, trypsin and caspase-like proteasome activities. In vivo, when covalently linked to a cell-penetrating peptide, EL28 potentiated the ability of interferon gamma to stimulate the expression of the immuneproteasome ß5i subunit and to increase the proliferation of CD8+ T-cells. The EL28/cell-penetrating peptide construct also improved and positively modulated the secondary IgG anti-bovine serum albumin immune responsiveness elicited in high antibody-responder mice. Together, these results suggest that EL28 is a functional intracellular peptide that can potentiate interferon gamma activity. BIOLOGICAL SIGNIFICANCE: The functional identification of EL28 advances our understanding regarding the bioactive peptides generated by limited proteolysis within cells.
Assuntos
Adenosina Trifosfatases/química , Interferon gama/farmacologia , Peptídeos/isolamento & purificação , Complexo de Endopeptidases do Proteassoma/química , Adenosina Trifosfatases/imunologia , Sequência de Aminoácidos , Células HeLa , Humanos , Espectrometria de Massas , Peptídeos/análise , Peptídeos/fisiologia , Complexo de Endopeptidases do Proteassoma/imunologia , ProteóliseRESUMO
Zika virus (ZIKV) is responsible for a major ongoing epidemic in the Americas and has been causally associated with fetal microcephaly. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Here we demonstrate that three different vaccine platforms protect against ZIKV challenge in rhesus monkeys. A purified inactivated virus vaccine induced ZIKV-specific neutralizing antibodies and completely protected monkeys against ZIKV strains from both Brazil and Puerto Rico. Purified immunoglobulin from vaccinated monkeys also conferred passive protection in adoptive transfer studies. A plasmid DNA vaccine and a single-shot recombinant rhesus adenovirus serotype 52 vector vaccine, both expressing ZIKV premembrane and envelope, also elicited neutralizing antibodies and completely protected monkeys against ZIKV challenge. These data support the rapid clinical development of ZIKV vaccines for humans.
Assuntos
Imunogenicidade da Vacina , Vacinas de DNA/imunologia , Vacinas Virais/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Adenoviridae , Transferência Adotiva , Animais , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Brasil , Feminino , Vetores Genéticos , Humanos , Imunoglobulinas/imunologia , Imunoglobulinas/isolamento & purificação , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Porto Rico , Vacinas de DNA/administração & dosagem , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagemRESUMO
Experimental autoimmune uveitis (EAU) is a well established model for immune-mediated organ-specific disease. Our group has recently shown that the M. leprae Hsp65 aggravated the uveitis in mice; in the present study, we evaluated the action of M. leprae K(409)A mutant protein and the synthetic peptides Leader pep and K(409)A pep (covering amino acids residues 352-371 of WT and K(409)A proteins of M. leprae Hsp65, resp.) on the pathogenesis of EAU. Mice received the 161-180 IRBP peptide and B. pertussis toxin followed by the intraperitoneal inoculation of K(409)A protein or the Leader pep or K(409)A pep. The Leader pep aggravated the disease, but mice receiving the K(409)A pep did not develop the disease and presented an increase in IL-10 levels by spleen cells and a decrease in the percentage of CD4+ IFN-γ+ T cells. Moreover, animals receiving the Leader pep presented the highest scores of the disease associated with increase percentage of CD4+ IFN-γ+ T cells. These results would contribute to understanding of the pathogenesis of EAU and support the concept that immune responses to Hsp are of potential importance in exacerbating, perpetuating, or even controlling organ-restricted autoimmune diseases, and it is discussed the irreversibility of autoimmune syndromes.
RESUMO
PURPOSE: FTY720 (fingolimod) is an immunomodulatory drug capable of preventing T-cell migration to inflammatory sites by binding to and subsequently downregulating the expression of sphingosine-1 phosphate receptor 1 (S1P(1)) leading in turn to T-cell retention in lymphoid organs. Additional effects of FTY720 by increasing functional activity of regulatory T cells have recently been demonstrated, raising the conversion of conventional T cells into regulatory T cells and affecting the sequestration of regulatory T cells in normal mice. In this study, the action of FTY720 in the ocular autoimmune model in mice was investigated. METHODS: Mice were immunized with 161-180 peptide and pertussis toxin and were treated with 1 mg/kg/d FTY720 by gavage (7-21 days postimmunization [dpi]) or left untreated. Spleen cells, harvested 21 dpi, were cultured and assayed for cytokine production. Draining lymph node, spleen, and eye cells 21 dpi were assayed for quantification of T-cell populations. Disease severity was evaluated by histologic examination of the enucleated eyes at 21 and 49 dpi. In addition, anti-IRBP antibodies were analyzed by ELISA. RESULTS: FTY720 was effective in suppressing the experimental autoimmune uveitis score. Although there was a reduction in the number of eye-infiltrating cells, FTY did not prevent Treg accumulation at this site. FTY720 leads to a significant increase of CD4(+)IFN-gamma(+) and CD4(+)Foxp3(+) cell percentages in lymph nodes, suggesting that this site could be the source of Treg cells found in the eye. CONCLUSIONS: The data showed that treatment in vivo with FTY720 was able to suppress EAU in mice. These results are indicative of the possible therapeutic use of FTY720 in ocular autoimmune processes.
Assuntos
Doenças Autoimunes/prevenção & controle , Modelos Animais de Doenças , Imunossupressores/administração & dosagem , Propilenoglicóis/administração & dosagem , Esfingosina/análogos & derivados , Uveíte Posterior/prevenção & controle , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Movimento Celular/imunologia , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Proteínas do Olho/imunologia , Cloridrato de Fingolimode , Citometria de Fluxo , Imunoglobulina G/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Intubação Gastrointestinal , Linfonodos/imunologia , Camundongos , Fragmentos de Peptídeos/imunologia , Proteínas de Ligação ao Retinol/imunologia , Esfingosina/administração & dosagem , Linfócitos T Reguladores/imunologia , Uveíte Posterior/imunologia , Uveíte Posterior/patologiaRESUMO
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory immune response directed against myelin antigens of the central nervous system. In its murine model, EAE, Th17 cells play an important role in disease pathogenesis. These cells can induce blood-brain barrier disruption and CNS immune cells activation, due to the capacity to secrete high levels of IL-17 and IL-22 in an IL-6+TGF-ß dependent manner. Thus, using the oral tolerance model, by which 200 µg of MOG 35-55 is given orally to C57BL/6 mice prior to immunization, we showed that the percentage of Th17 cells as well as IL-17 secretion is reduced both in the periphery and also in the CNS of orally tolerated animals. Altogether, our data corroborates with the pathogenic role of IL-17 and IFN-γ in EAE, as its reduction after oral tolerance, leads to an overall reduction of pro-inflammatory cytokines, such as IL-1α, IL-6, IL-9, IL-12p70 and the chemokines MIP-1ß, RANTES, Eotaxin and KC in the CNS. It is noteworthy that this was associated to an increase in IL-10 levels. Thus, our data clearly show that disease suppression after oral tolerance induction, correlates with reduction in target organ inflammation, that may be caused by a reduced Th1/Th17 response.
Assuntos
Alérgenos/administração & dosagem , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Tolerância Imunológica , Interleucina-17/antagonistas & inibidores , Depleção Linfocítica , Proteínas do Tecido Nervoso/administração & dosagem , Linfócitos T Auxiliares-Indutores/imunologia , Administração Oral , Alérgenos/imunologia , Sequência de Aminoácidos , Animais , Encefalomielite Autoimune Experimental/terapia , Glicoproteínas/administração & dosagem , Glicoproteínas/imunologia , Glicoproteínas/uso terapêutico , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Interleucina-17/metabolismo , Depleção Linfocítica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Glicoproteína Mielina-Oligodendrócito , Proteínas do Tecido Nervoso/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Linfócitos T Auxiliares-Indutores/patologiaRESUMO
Studies evaluating immune function in obese humans and experimental animals indicate that the excess adiposity is associated with impaired in immune responses. Obesity is related to a higher rate of infections and to some types of cancer. Nutritional, metabolic and endocrine factors are implicated in the immunological changes. The adipose tissue directly produces substances with various functions related to immune system. Furthermore, some investigations suggest that certain types of weight reduction strategies can alter the immune function. Nevertheless, long-term studies should be carried out to address whether these changes positively affects the ability of these obese individuals to control infections and tumor development.
Assuntos
Tecido Adiposo/imunologia , Composição Corporal/imunologia , Obesidade/imunologia , Redução de Peso/fisiologia , Animais , Cirurgia Bariátrica , Humanos , Sistema Imunitário/fisiologia , Obesidade/cirurgiaRESUMO
The 60 kDa heat shock protein family, Hsp60, constitutes an abundant and highly conserved class of molecules that are highly expressed in chronic-inflammatory and autoimmune processes. Experimental autoimmune uveitis [EAU] is a T cell mediated intraocular inflammatory disease that resembles human uveitis. Mycobacterial and homologous Hsp60 peptides induces uveitis in rats, however their participation in aggravating the disease is poorly known. We here evaluate the effects of the Mycobacterium leprae Hsp65 in the development/progression of EAU and the autoimmune response against the eye through the induction of the endogenous disequilibrium by enhancing the entropy of the immunobiological system with the addition of homologous Hsp. B10.RIII mice were immunized subcutaneously with interphotoreceptor retinoid-binding protein [IRBP], followed by intraperitoneally inoculation of M. leprae recombinant Hsp65 [rHsp65]. We evaluated the proliferative response, cytokine production and the percentage of CD4(+)IL-17(+), CD4(+)IFN-gamma(+) and CD4(+)Foxp3(+) cells ex vivo, by flow cytometry. Disease severity was determined by eye histological examination and serum levels of anti-IRBP and anti-Hsp60/65 measured by ELISA. EAU scores increased in the Hsp65 group and were associated with an expansion of CD4(+)IFN-gamma(+) and CD4(+)IL-17(+) T cells, corroborating with higher levels of IFN-gamma. Our data indicate that rHsp65 is one of the managers with a significant impact over the immune response during autoimmunity, skewing it to a pathogenic state, promoting both Th1 and Th17 commitment. It seems comprehensible that the specificity and primary function of Hsp60 molecules can be considered as a potential pathogenic factor acting as a whistleblower announcing chronic-inflammatory diseases progression.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/fisiologia , Chaperonina 60/metabolismo , Chaperonina 60/fisiologia , Mycobacterium leprae/metabolismo , Uveíte/imunologia , Uveíte/fisiopatologia , Animais , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo/métodos , Fatores de Transcrição Forkhead/metabolismo , Interferon gama/metabolismo , Interleucina-17/biossíntese , Camundongos , Células Th1/metabolismoRESUMO
Studies evaluating immune function in obese humans and experimental animals indicate that the excess adiposity is associated with impaired in immune responses. Obesity is related to a higher rate of infections and to some types of cancer. Nutritional, metabolic and endocrine factors are implicated in the immunological changes. The adipose tissue directly produces substances with various functions related to immune system. Furthermore, some investigations suggest that certain types of weight reduction strategies can alter the immune function. Nevertheless, long-term studies should be carried out to address whether these changes positively affects the ability of these obese individuals to control infections and tumor development.
Estudos acerca da função imunológica em animais experimentais e humanos obesos indicam que o excesso de adiposidade associa-se ao prejuízo da resposta imune. A obesidade está relacionada a uma taxa maior de infecções e a alguns tipos de câncer. Fatores nutricionais, metabólicos e endócrinos estão implicados nessas alterações imunológicas. O próprio tecido adiposo produz diretamente substâncias com várias funções relacionadas ao sistema imune. Além disso, algumas investigações sugerem que certas estratégias para perda de peso podem alterar a função imune. Entretanto, estudos em longo prazo são necessários para avaliar se tais alterações afetam positivamente a capacidade desses pacientes obesos de controlar infecções e desenvolver tumores.