RESUMO
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.
Assuntos
Doenças Autoimunes , Doenças do Sistema Nervoso , Viroses , Humanos , Autoimunidade , AutoanticorposRESUMO
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
Recruitment of leukocytes by chemokines and chemokine receptors to CNS plays a crucial role in the induction of inflammatory response in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In the present study, chemokine and chemokine receptors involved in trafficking of lymphocytes to the CNS were measured in HAM/TSP patients, HTLV-1 asymptomatic carriers (ACs), and healthy controls. The PVL, CCR6, and CXCR3 mRNA expression, and CXCL9 and CXCL10 protein levels were measured in all subjects. The PVL of HAM/TSP patients was higher than that of ACs (P = 0.02). CCR6 expression was higher in HAM/TSP patients and in ACs compared to the healthy controls (P = 0.005 and P = 0.04, respectively). A significant difference was observed in CCR6 expression when a combination of HAM/TSP patients and ACs were compared to the healthy individuals (P = 0.005). Furthermore, there was a significantly lower CXCR3 expression between HAM/TSP and control groups (P = 0.001), and between the ACs and healthy controls (P = 0.001). However, the increased CXCR3 expression in ACs compared to HAM/TSP patients was not significant. Furthermore, the CXCL10 protein levels in HAM/TSP patients was higher than in controls (P = 0.012), and CXCL9 protein levels was also higher in the HAM/TSP and ACs groups than in the controls (P = 0.001 and P = 0.004, respectively). In conclusion, it seems that decreased expression of CXCR3 and higher expression of CCR6 were associated with HTLV-1 infection, what indicate that these alterations may favor virus dissemination but not disease manifestation.
Assuntos
Portador Sadio/patologia , Infecções por HTLV-I/patologia , Receptores CCR6/análise , Receptores CXCR3/análise , Adulto , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteoma/análise , RNA Mensageiro/análise , Adulto JovemRESUMO
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.
Assuntos
Produtos do Gene tax/análise , Infecções por HTLV-I/patologia , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Interleucinas/biossíntese , Interleucinas/sangue , Provírus/isolamento & purificação , Carga Viral , Adulto , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Provírus/genética , RNA Mensageiro/análise , Adulto JovemRESUMO
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
BACKGROUND: Previous studies have suggested debatable roles of Tax and HBZ gene expression in the pathogenesis of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In this study, HTLV-1 and host interactions in the manifestation of HAM/TSP were evaluated. METHODS: A cross-sectional study was conducted on 33 HAM/TSP patients and 38 HTLV-1 asymptomatic carriers (ACs). HTLV-1-Tax, HBZ gene expression, and proviral load (PVL) were assessed using the quantitative real-time PCR (TaqMan), host plasma neopterin level, and HLA-I, and the clinical manifestation were evaluated. RESULTS: The HTLV-1 PVLs in HAM/TSP and ACs were 306±360.741 copies/104 PBMCs and 250.98±629.94 copies/104 PBMCs, respectively; the PVL was higher in HAM/TSP than that in ACs (p=0.004). HTLV-1 Tax and HBZ expression in HAM/TSP was higher than that in ACs, wherein only the Tax expression was statistically significant (p=0.039). In contrast to Japanese HTLV-1-infected subjects, HLA-A*02, HLA-A*24, HLA-Cw*08, and HLA-B*5401 did not exhibit preventive effects for HAM/TSP manifestation. The plasma neopterin level was significantly higher in HAM/TSPs than that in ACs; furthermore, there was a strong significant correlation between plasma neopterin and PVL (R=0.76, p=0.001). Moreover, there were significant correlation between urinary disturbances and haematological indices, including the RBC count (R=-0.61, p=0.01) and Hematocrit (Ht) index (R=-0.75, p=0.002), and between mobility disturbances with Tax expression (R=-0.58, p=0.02) and WBC counts (R=-0.54, p=0.04), and finally, a significant association was found between the sensory disturbances and PVL (p=0.05). CONCLUSION: Overall, HTLV-1 PVL and Tax may be the valid predictors of disease development, and the neopterin level may be a valid predictor of disease progression. In addition, Tax and neopterin are more helpful than PVL for the monitoring of HTLV-1-infected patients.
Assuntos
Genes MHC Classe I , Infecções por HTLV-I/genética , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Neopterina/sangue , Paraparesia Espástica Tropical/diagnóstico , Paraparesia Espástica Tropical/etiologia , Adulto , Fatores de Transcrição de Zíper de Leucina Básica/genética , Contagem de Células Sanguíneas , Estudos Transversais , Índices de Eritrócitos , Feminino , Regulação Viral da Expressão Gênica , Genes pX , Infecções por HTLV-I/sangue , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Provírus/genética , Proteínas dos Retroviridae/genética , Avaliação de Sintomas , Carga Viral , Fatores de Virulência/genéticaRESUMO
OBJECTIVE(S): The aim of this study was to investigate the association between HLA class I alleles (HLA-A*02, HLA-A*24, HLA-Cw*08, HLA-B5401) and proviral load in HTLV-I associated myelopathy/tropical spastic paraperesis (HAM/TSP) patients in Iranian population. MATERIALS AND METHODS: 20 new cases of HAM/TSP patients and 30 HTLV-I infected healthy carriers were recruited. Peripheral blood samples were collected. Peripheral blood mononuclear cells (PBMCs) were isolated. DNA was extracted from PBMC.HTLV-I proviral load was calculated by Taqman quantitative real time polymerase chain reaction (qRT-PCR). PCR sequence-speciï¬c primer (PCR-SSP) reactions were performed to detect HLA-A, HLA-B and, HLA-Cw alleles. RESULTS: There was no signiï¬cant difference in sex and age between asymptomatic and HAM/TSP group. The Mann-Whitney U test was used to compare proviral load between HAM/TSP patients and healthy carrier. Provirus load of HAM/TSP patients was signiï¬cantly higher than that of HCs (P=0.003, Mann-Whitney U test).Odd ratio was calculated to determine association between class I alleles including (HLA-A*02, HLA-A*24, HLA-Cw*08) and risk of HAM/TSP development. We couldn't find any association between these class I alleles and risk of HAM/TSP development in our study. In our survey HLA-A*02, HLA-A24, HLA-Cw*08 didn't have protective effect on proviral load (P=0.075, P=0.060 and 0.650 Mann-Whitney U test respectively). CONCLUSION: In conclusion, certain HLA alleles with protective effect in one population may have not similar effect in other population. This may be because of pathogen polymorphism or host genetic heterogeneity and allele frequency in desired population.