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BACKGROUND: The Wnt signaling pathway has been implicated in the pathogenesis of fibrotic disorders and malignancies. Hence, we aimed to assess the potential of the induced pluripotent stem cells (IPS) in modulating the expression of the cardinal genes of the Wnt pathway in a mouse model of idiopathic pulmonary fibrosis (IPF). METHODS: C57Bl/6 mice were randomly divided into three groups of Control, Bleomycin (BLM), and BLM + IPS; the BLM mice received intratracheal instillation of bleomycin, BLM + IPS mice received tail vein injection of IPS cells 48 h post instillation of the BLM; The Control group received Phosphate-buffered saline instead. After 3 weeks, the mice were sacrificed and Histologic assessments including hydroxy proline assay, Hematoxylin and Eosin, and Masson-trichrome staining were performed. The expression of the genes for Wnt, ß-Catenin, Lef, Dkk1, and Bmp4 was assessed utilizing specific primers and SYBR green master mix. RESULTS: Histologic assessments revealed that the fibrotic lesions and inflammation were significantly alleviated in the BLM + IPS group. Besides, the gene expression analyses demonstrated the upregulation of Wnt, ß-Catenin, and LEF along with the significant downregulation of the Bmp4 and DKK1 in response to bleomycin treatment; subsequently, it was found that the treatment of the IPF mice with IPS cells results in the downregulation of the Wnt, ß-Catenin, and Lef, as well as upregulation of the Dkk1, but not the Bmp4 gene (P values < 0.05). CONCLUSION: The current study highlights the therapeutic potential of the IPS cells on the IPF mouse model in terms of regulating the aberrant expression of the factors contributing to the Wnt signaling pathway.
Assuntos
Fibrose Pulmonar Idiopática , Células-Tronco Pluripotentes Induzidas , Camundongos , Animais , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Bleomicina/toxicidade , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Camundongos Endogâmicos C57BL , Pulmão/patologiaRESUMO
Autoimmune diseases develop due to self-tolerance failure in recognizing self and non-self-antigens. Several factors play a role in inducing autoimmunity, including genetic and environmental elements. Several studies demonstrated the causative role of viruses; however, some studies showed the preventive effect of viruses in the development of autoimmunity. Neurological autoimmune diseases are classified based on the targets of autoantibodies, which target intracellular or extracellular antigens rather than neurons. Several theories have been hypothesized to explain the role of viruses in the pathogenesis of neuroinflammation and autoimmune diseases. This study reviewed the current data on the immunopathogenesis of viruses in autoimmunity of the nervous system.
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Doenças Autoimunes , Doenças do Sistema Nervoso , Viroses , Humanos , Autoimunidade , AutoanticorposRESUMO
INTRODUCTION: Severe congenital neutropenia (SCN) is one of the primary immunodeficiency diseases developed by genetic alterations. Mutations in several genes including HAX-1 , G6PC3 , jagunal , and VPS45 account for autosomal recessive SCN. PATIENTS AND METHODS: Patients with SCN registered in the Iranian Primary Immunodeficiency Registry and referred to our clinic at the Children's Medical Center were reviewed. RESULTS: Thirty-seven eligible patients with a mean age of 28.51 ± 24.38 months at the time of diagnosis were included. Nineteen cases had consanguineous parents and 10 cases had confirmed or unconfirmed positive family history. The most prevalent infectious symptoms were oral infections followed by respiratory infections. We identified HAX-1 mutation in 4, ELANE mutation in 4 cases, G6PC3 mutation in 1, and WHIM syndrome in 1 case. Other patients remained genetically unclassified. After the median follow-up of 36 months from the time of diagnosis, the overall survival was 88.88%. The mean event-free survival was 185.84 months (95% CI: 161.02, 210.66). DISCUSSION: Autosomal recessive SCN is more common in countries with high rates of consanguinity like Iran. The genetic classification was possible only for a few patients in our study. This might suggest that there are other autosomal recessive genes causative of neutropenia that have yet to be described.
Assuntos
Neutropenia , Criança , Humanos , Lactente , Pré-Escolar , Irã (Geográfico)/epidemiologia , Neutropenia/congênito , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Progressão da DoençaRESUMO
The eminence of Bacillus Calmette-Guerin (BCG) vaccine in newborn vaccination programs has been conspicuous throughout the years, especially in low-income developing countries where tuberculosis is prevalent; however, application of the BCG vaccine is not without constraints, especially in patients afflicted with immunodeficiency diseases, such as severe combined immunodeficiency (SCID). The present study aimed to evaluate whether the administration of BCG vaccine at birth could improve the outcomes of hematopoietic stem cell transplantation (HSCT) in pediatric patients with SCID. In this study, 30 SCID patients who underwent HSCT using a reduced-intensity conditioning regimen (RIC) were followed-up for 2 years post-HSCT. The outcomes of HSCT were evaluated in both non-BCG-vaccinated patients (n = 12) and BCG-vaccinated patients (n = 18). Our results show a higher incidence of acute graft-versus-host disease (aGVHD), but not of chronic GVHD, in the BCG-vaccinated patients, and a similar overall survival (OS) rate in the 2 groups. We speculate that the similar OS rate in the 2 groups, despite the risk of BGC vaccination, was because this group received an RIC conditioning regimen. There was no other difference between the 2 groups. Considering the effect of the BCG vaccine on HSCT outcome, we suggest that the administration of BCG vaccine be deferred until age 3 months so that APT testing without the interference of maternal antibodies can be performed. However, this study could benefit from a larger cohort to further validate our findings, as the possible reason for some factors not being statistically significant was our small sample size.
Assuntos
Vacina BCG , Transplante de Células-Tronco Hematopoéticas , Mycobacterium bovis , Imunodeficiência Combinada Severa , Tuberculose , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Vacina BCG/administração & dosagem , Vacina BCG/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/epidemiologia , Tuberculose/epidemiologia , Tuberculose/etiologia , Tuberculose/prevenção & controle , Vacinação/efeitos adversosRESUMO
Adult T-cell leukemia/lymphoma (ATLL) is a human T-cell leukemia virus (HTLV) type 1-associated disease of TCD4+ cell transformation. Despite extensive studies on ATLL development and progression, the fundamental processes of HTLV-1 oncogenicity are yet to be understood. This study aimed to integrate high-throughput microarray datasets to find novel genes involved in the mechanism of ATLL progression. For this purpose, five microarray datasets were downloaded from the Gene Expression Omnibus database and then profoundly analyzed. Differentially expressed genes and miRNAs were determined using the MetaDE package in the R software and the GEO2R web tool. The STRING database was utilized to construct the protein-protein interaction network and explore hub genes. Gene ontology and pathway enrichment analysis were carried out by employing the EnrichR web tool. Furthermore, flow cytometry was employed to assess the CD4/CD8 ratio, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to confirm the high-throughput data analysis results. Four miRNAs, including hsa-mir-146, hsa-mir-451, hsa-mir-31, and hsa-mir-125, were among the statistically significant differentially expressed miRNAs between healthy individuals and ATLL patients. Moreover, 924 differentially expressed genes were identified between normal and ATLL samples. Further network analysis highlighted 59 hub genes mainly regulating pathways implicated in viral interferences, immunological processes, cancer, and apoptosis pathways. Among the identified hub genes, RhoA and PRKACB were most considerable in the high-throughput analysis and were further validated by qRT-PCR. The RhoA and PRKACB expression were significantly down-regulated in ATLL patients compared to asymptomatic carriers (p<0.0001 and p=0.004) and healthy subjects (p=0.043 and p=0.002). Therefore, these corresponding miRNAs and proteins could be targeted for diagnosis purposes and designing effective treatments.
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Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Linfoma , MicroRNAs , Adulto , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Human cytomegalovirus (HCMV) is ubiquitously prevalent. Immune system in healthy individuals is capable of controlling HCMV infection; however, HCMV can be life-threatening for immunocompromised individuals, such as transplant recipients. Both innate and adaptive immune systems are critically involved in the HCMV infection. Recent studies have indicated that regulatory immune cells which play essential roles in maintaining a healthy immune environment are closely related to immune response in HCMV infection. However, the exact role of regulatory immune cells in immune regulation and homoeostasis during the battle between HCMV and host still requires further research. In this review, we highlight the protective and pathological roles of regulatory immune cells in HCMV infection following hematopoietic stem cell transplantation (HSCT).
Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Infecções por Herpesviridae , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Hospedeiro ImunocomprometidoRESUMO
IL-10R deficiency results in severe immune dysregulation. Herein, we describe the successful treatment of a girl aged 6.8 years with IL10R deficiency by using RIC prior to HSCT from a matched unrelated donor. The regimen was well tolerated, the engraftment was completely attained. On a follow-up of 7 months, the patient remained in good medical conditions with full donor chimerism. All complications before HSCT were completely resolved and her growth was accelerated. RIC regimen might be adequate to induce permanent engraftment and avoid severe organ toxicity in IL-10R deficiency patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/uso terapêutico , Doenças da Imunodeficiência Primária/terapia , Receptores de Interleucina-10/deficiência , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Criança , Esquema de Medicação , Quimioterapia Combinada , Feminino , Marcadores Genéticos , Humanos , Injeções Intravenosas , Doenças da Imunodeficiência Primária/genética , Receptores de Interleucina-10/genética , Vidarabina/uso terapêuticoRESUMO
Posterior reversible encephalopathy syndrome (PRES) is one of the most common neurologic complications following hematopoietic stem cell transplantation (HSCT). We aimed to evaluate the incidence, clinical, and imaging features of PRES in pediatric patients with Fanconi anemia (FA) following HSCT. This prospective study included all post-HSCT patients with underlying FA disease between 2014 and 2017. Brain computed tomography scan and magnetic resonance imaging (MRI) were performed in all individuals who developed neurologic symptoms. PRES was diagnosed based on clinic-radiological evidence. Follow-up MRI was performed in all patients with PRES within two months. Forty-one patients with FA (28 males; mean age, 8.19 ± 3.25 years) were enrolled. Out of 15 patients with acute neurologic symptoms, PRES was diagnosed in 9 individuals (21.95% of the total cohort). The occurrence of PRES was significantly higher in patients who had a donor with a 1-locus mismatch (P= .02). Donor relation, stem cell source, and graft-versus-host disease grade did not have any significant association with the development of PRES. MRI showed asymmetric vasogenic edema in 5 patients, an overt infarct in 1 patient, and foci of microhemorrhages in 3 patients, 1 of whom developed a hemorrhagic infarct. This patient died shortly, and persistent microhemorrhages were noted in the other 2 patients. Our findings demonstrate a greater risk of developing PRES after HSCT in patients with FA compared with those with other diseases (21.95% versus 1% to 10%), and in contrast to its term, it might be irreversible and has adverse effects on HSCT outcomes. The increased vascular and endothelial fragility in FA may contribute to the higher frequency of PRES in these individuals.
Assuntos
Anemia de Fanconi , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Síndrome da Leucoencefalopatia Posterior , Criança , Pré-Escolar , Anemia de Fanconi/terapia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/etiologia , Estudos ProspectivosRESUMO
Neutropenia is a dangerous and potentially fatal condition that renders patients vulnerable to recurrent infections. Its severity is commensurate with the absolute count of neutrophil granulocytes in the circulation. In paediatric patients, neutropenia can have many different aetiologies. Primary causes make up but a small portion of the whole and are relatively unknown. In the past decades, a number of genes has been discovered that are responsible for congenital neutropenia. By perturbation of mitochondrial energy metabolism, vesicle trafficking or synthesis of functional proteins, these mutations cause a maturation arrest in myeloid precursor cells in the bone marrow. Apart from these isolated forms, congenital neutropenia is associated with a multiplicity of syndromic diseases that includes among others: oculocutaneous albinism, metabolic diseases and bone marrow failure syndromes. Congenital neutropenia is a primary immunodeficiency disease that is associated with recurrent bacterial infections, auto-inflammatory and auto-immune phenomena, haematological malignancy and neuro-psychiatric manifestations. The aim of this review is to give a comprehensive overview of the most recent literature concerning the clinical, aetiological and genetic features of congenital neutropenia and the syndromes in which it might be encountered.
Assuntos
Síndromes de Imunodeficiência , Neutropenia/congênito , Criança , Síndrome Congênita de Insuficiência da Medula Óssea , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/genética , Neutropenia/complicações , Neutropenia/diagnóstico , Neutropenia/epidemiologia , Neutropenia/genética , FenótipoRESUMO
One of the prominent features of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is the excessive recruitment of leukocytes to the central nervous system (CNS), which leads to an inflammatory response-with chemokines and their receptors playing the main role in this recruitment. The aim of the study was to examine the relation of CXCR1 and CXCR2, both of which are involved in the trafficking of lymphocytes into the CNS, with the outcome of HTLV-1 infection. The mRNA levels of CXCR1 and CXCR2 were examined in peripheral blood mononuclear cells (PBMCs) of HAM/TSP patients, HTLV-1 asymptomatic carriers (ACs), and healthy controls (HCs). Furthermore, the frequency of CD4+ and CD8+ T cells expressing CXCR1 and CXCR2 was evaluated in the studied groups. The results of the present study showed a substantial increase in the mean mRNA expression of CXCR2 in the HAM/TSP patients compared to the HCs and ACs (p < 0.001). A positive correlation was also found between PVL and CXCR2 mRNA expression in the total population of HTLV-1-infected subjects (R = 0.526, p < 0.001). Moreover, the percentage of CD8+ CXCR2-expressing cells was higher in HAM/TSP patients compared to ACs and HCs (p < 0.05, p < 0.01, respectively). Although the percentage of CD4+ CXCR2-expressing cells was higher in HAM/TSP patients than in ACs and HCs, a significant difference was only found between HAM/TSP patients and HCs (p < 0.05). No significant difference in the CXCR1 mRNA expression was observed in the studied groups. The frequency of the CD8+ CXCR1- and CD4+ CXCR1-expressing cells was significantly lower in HAM/TSP patients than in ACs and HCs (p < 0.001 and p < 0.01, respectively). In conclusion, the high frequency of CXCR2 CD8+ T cells and the high levels of CXCR2 mRNA expression in HAM/TSP patients are associated with disease pathogenesis, while the high frequencies of CXCR1 T cells in ACs might suggest that these cells act as effector CD8 T cells and are involved in controlling the viral spread and modulation of the immune response.
Assuntos
Portador Sadio/fisiopatologia , Infecções por HTLV-I/fisiopatologia , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Perfilação da Expressão Gênica , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Humanos , Leucócitos Mononucleares/imunologiaRESUMO
BACKGROUND: Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that significantly affected spinal cord, nevertheless, the pathogenesis pathway and reliable biomarkers have not been well determined. This study aimed to employ high throughput meta-analysis to find major genes that are possibly involved in the pathogenesis of HAM/TSP. RESULTS: High-throughput statistical analyses identified 832, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. The protein-protein interactions between DEGs were identified in STRING and further network analyses highlighted 24 and 6 hub genes for normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. Moreover, four biologically meaningful modules including 251 genes were identified for normal vs. ACs. Biological network analyses indicated the involvement of hub genes in many vital pathways like JAK-STAT signaling pathway, interferon, Interleukins, and immune pathways in the normal vs. HAM/TSP group and Metabolism of RNA, Viral mRNA Translation, Human T cell leukemia virus 1 infection, and Cell cycle in the normal vs. ACs group. Moreover, three major genes including STAT1, TAP1, and PSMB8 were identified by network analysis. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P = 0.01 and P = 0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P = 0.04 and P = 0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P = 0.008 and P = 0.02, respectively). No significant difference was found among three groups in terms of the percentage of T helper and cytotoxic T lymphocytes (P = 0.55 and P = 0.12). CONCLUSIONS: High-throughput data integration disclosed novel hub genes involved in important pathways in virus infection and immune systems. The comprehensive studies are needed to improve our knowledge about the pathogenesis pathways and also biomarkers of complex diseases.
Assuntos
Expressão Gênica , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Paraparesia Espástica Tropical/genética , Paraparesia Espástica Tropical/virologia , Interpretação Estatística de Dados , Redes Reguladoras de Genes , Ensaios de Triagem em Larga Escala , Humanos , Análise em Microsséries , Provírus/genética , Linfócitos T Citotóxicos/virologia , Linfócitos T Auxiliares-Indutores/virologia , Carga ViralRESUMO
Regulatory T cells (Tregs) play a major role in the prevention of autoimmune diseases. Transfer of Foxp3 gene into conventional T cells converts their phenotype to regulatory T cells. Therefore, the question arises as to whether adoptively transferred in vitro differentiated Treg cells specific for a locally expressed antigen might have better inhibitory effects on the progression of the disease as compared with antigen-nonspecific T reg cells. Herein, we investigated the therapeutic potential of primed and unprimed retrovirus mediated Foxp3-overexpression T cells following intravenously injected of these cells into affected rats with collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. Our analyses demonstrate that systemic administration of collagen II primed Foxp3-transduced T cells could markedly ameliorate CIA inflammatory responses at clinical (p<0.0014) and pathological exchanges including cellular infiltration (p=0.002), bone erosion (p=0.0013) and synovial hyperplasia (p=0.002). In contrast, collagen II unprimed Foxp3-transduced T cells like as collagen II primed or unprimed GFP-transduced T cells did not reveal any beneficial effects on arthritis features as compared with untreated group (p>0.05). Therefore, we believe that collagen II primed Foxp3-transduced T cells are interacting locally and systemically with immune cells which reveled with decreasing of T cells infiltration into joints along with specific CII IgG production. Considering the results described here, it appears that the using patients' T cells which previously exposed to specific antigens may have more effective therapeutic advantage in the production of induced regulatory T cells in the treatment of arthritis.
Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Imunoterapia Adotiva/métodos , Membrana Sinovial/imunologia , Linfócitos T Reguladores/imunologia , Animais , Artrite Experimental/terapia , Artrite Reumatoide/terapia , Reabsorção Óssea , Células Cultivadas , Colágeno Tipo II/imunologia , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Vetores Genéticos/genética , Ativação Linfocitária , Ratos , Ratos Wistar , Retroviridae/genética , Linfócitos T Reguladores/transplanteRESUMO
Regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) are the two important and interactive immunosuppressive components of the tumor microenvironment that hamper anti-tumor immune responses. Therefore, targeting these two populations together might be beneficial for overcoming immune suppression in the tumor microenvironment. We have recently shown that prophylactic Foxp3 DNA/recombinant protein vaccine (Foxp3 vaccine) promotes immunity against Treg in tumor-free conditions. In the present study, we investigated the immune modulatory effects of a prophylactic regimen of the redesigned Foxp3 vaccine in the B16F10 melanoma model. Our results indicate that Foxp3 vaccination continuously reduces Treg population in both the tumor site and the spleen. Surprisingly, Treg reduction was associated with a significant decrease in the frequency of MDSC, both in the spleen and in the tumor environment. Furthermore, Foxp3 vaccination resulted in a significant reduction of arginase-1(Arg-1)-induced nitric oxide synthase (iNOS), reactive oxygen species (ROS) and suppressed MDSC activity. Moreover, this concurrent depletion restored production of inflammatory cytokine IFN-γ and enhanced tumor-specific CTL response, which subsequently resulted in the reduction of tumor growth and the improved survival rate of vaccinated mice. In conclusion, our results revealed that Foxp3 vaccine promotes an immune response against tumor by targeting both Treg and MDSC, which could be exploited as a potential immunotherapy approach.
Assuntos
Vacinas Anticâncer/imunologia , Fatores de Transcrição Forkhead/metabolismo , Melanoma Experimental/imunologia , Células Supressoras Mieloides/imunologia , Linfócitos T Reguladores/imunologia , Vacinas de DNA/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Ativação Linfocitária/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Linfócitos T Reguladores/metabolismo , Microambiente Tumoral/imunologiaRESUMO
Severe congenital neutropenia (SCN) is a primary immunodeficiency disease in which a number of underlying gene defects are responsible for abnormalities in neutrophil development. The HCLS1-associated protein X1 (HAX1) mutation is associated with an autosomal-recessive form of SCN. Considering the potential of gene therapy approaches for the treatment of monogenic disorders, in this study we aimed to develop retroviral vectors expressing coding sequences (CDS) to be used for the removal of the genetic blockade in deficient hematopoietic cells. Following amplification of CDS with primers containing appropriate restriction sites, HAX1 CDS was cloned into an intermediate vector using TA-cloning. The sequence was transferred into a retroviral vector, followed by retroviral packaging in Plat-A cells. To show HAX1 protein expression, HEK293T cells were exposed to 10 multiplicity of infection (MOI) of retroviral particles and HAX1 expression was confirmed in these cells, using indirect intracellular flow cytometry. This vector was applied for in vitro transduction of hematopoietic stem cell with HAX1 mutation; after 11 days, cultured cells were analyzed for CD66acde and CD177 (neutrophil surface markers) expression. Increased neutrophil production in HAX1 viral vector-expressing hematopoietic cells was observed as compared to control vector transduced cells. Hence, according to the results, this type of therapy could be considered a potential treatment protocol for the disease.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neutropenia/congênito , Retroviridae/genética , Antígenos CD/genética , Moléculas de Adesão Celular/genética , Linhagem Celular , Síndrome Congênita de Insuficiência da Medula Óssea , Terapia Genética/métodos , Células HEK293 , Células-Tronco Hematopoéticas/metabolismo , Humanos , Isoantígenos/genética , Mutação/genética , Neutropenia/genética , Neutrófilos/metabolismo , Transdução Genética/métodosRESUMO
Interleukin-21 (IL-21) enhances the survival and cytotoxic properties of cytotoxic T cells (CTLs) and exhibits essential roles in controlling chronic viral infections. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive inflammatory disease of the nervous system. The main determinant of disease progression is efficiency of the CTL response to Human T lymphotropic virus types I (HTLV-1). In this study, the expression of host IL-21 and HTLV-I Tax and proviral load (PVL) was evaluated to understand the role and mechanism of IL-21 in HTLV-1 infections and the subsequent development of HAM/TSP. A cross-sectional study was carried out on 20 HAM/TSP patients, 20 asymptomatic HTLV-1 carriers (ACs) and 20 healthy controls (HCs) to evaluate the expression of IL-21 and Tax and PVL in non-activated and phorbol myristate acetate (PMA)-ionomycin-activated peripheral blood mononuclear cells (PBMCs). The mean mRNA expression of IL-21 in the non-activated and activated PBMCs was higher (by 5-13 times) in the HAM/TSP patients than in ACs and HCs (p < 0.05); however, there was no significant difference between ACs and HCs. In contrast to the IL-21 mRNA expression, the serum level of the IL-21 protein was significantly lower in the HAM/TSP patients than in ACs and HCs (p < 0.05). Furthermore, higher expression of Tax and PVL was observed in the HAM/TSP subjects than ACs (p < 0.05). In addition, Tax gene expression was positively correlated with PVL (R = 0.595, p = 0.000) and IL-21 gene expression (R = 0.395, p = 0.021) in the HTLV-1-infected subjects. In conclusion, the increase in IL-21 mRNA expression may reflect the attempt of infected T cells to induce an appropriate antiviral response, and the decrease in IL-21 protein expression may reflect the inhibition of IL-21 mRNA translation by viral factors in favour of virus evasion and dissemination.