Low frequency of regulatory B-cells and increased CD4+ and CD8+ interferon-γ-producing cells in patients with tropical spastic paraparesis associated with human T-cell lymphotropic virus type

Abstract INTRODUCTION: Tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) is a disease caused by human T-cell lymphotropic virus type 1 (HTLV-I) that mainly infects CD4 T cells-for example, those of the CD4+CD25hiFOXP3+ [Treg] phenotype-where it inhibits forkhead box protein P3 (FOXP3) expression and promotes interferon-γ (IFN-γ) expression. However, the role it exerts on regulatory B cells (CD19+CD24hiCD38hi; Breg) is unknown. METHODS: The frequencies of Treg and Breg cells was evaluated and the Th1 profiles were assessed in TSP/HAM patients and healthy control subjects. RESULTS: Low percentages of Breg cells and high production of IFN-γ were observed in patients compared to those in healthy control subjects. CONCLUSIONS: The low percentage of Breg cells in patients and the increase in the frequency of Th1 cells suggest an imbalance in the control of the inflammatory response that contributes to the immunopathogenesis of TSP/HAM.

The relationship between atopy and neurological manifestations in HTLV-1 infection

Abstract INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1)induces exaggerated Th1 responses, whereas atopy is associated with exacerbated Th2 responses. METHODS: Here, a cross-sectional study compared the prevalence of atopy in HTLV-1 carriers and HAM/TSP patients. It also compared the spontaneous cytokine production in HTLV-1-infected individuals. A retrospective cohort study evaluated the development of neurological manifestations in atopic and non-atopic carriers. RESULTS: Atopic HAM/TSP patients with high IFN-γ production exhibited higher IL-5 levels than non-atopic patients. Allergic rhinitis accelerated the development of Babinski signals and overactive bladders. CONCLUSIONS: Abnormal Th1 and Th2 responses coexist in HTLV-1-infected individuals and allergic diseases may worsen the clinical course of HTLV-1 infections.

T cell receptor signaling pathway is overexpressed in CD4 + T cells from HAM/TSP individuals

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus related to the chronic neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4+ T cells activation appears to play a key role on HTLV-1 infection. Here we investigated the expression of genes associated to T cell activation CD3e molecule, epsilon (CD3?), lymphocyte-specific protein tyrosine kinase (LCK), vav 1 guanine nucleotide exchange factor (VAV1), and zeta-chain (TCR) associated protein kinase 70 kDa (ZAP70) on T lymphocytes of HTLV-1-infected individuals and compared to healthy uninfected individuals (CT). We observed that CD3?, LCK, ZAP70, and VAV1 gene expression were increased in CD4+ T cells from HAM/TSP group compared to HTLV-1 asymptomatic patients (HAC). Moreover, ZAP70 and VAV1 were also upregulated in HAM/TSP compared to CT group. We detected a positive correlation among all these genes. We also observed that CD3?, LCK, and VAV1 genes had a positive correlation with the proviral load (PVL) and Tax expression. These results suggest that PVL and Tax protein could drive CD3?, LCK, and VAV1 gene expression in CD4+ T cells, and these genes function on a synchronized way on the CD4+ T cell activation. The elucidation of the mechanisms underlying T cell receptor signaling pathway is of considerable interest and might lead to new insights into the mechanism of HAM/TSP.

Standardisation of Western blotting to detect HTLV-1 antibodies synthesised in the central nervous system of HAM/TSP patients

Intrathecal synthesis of human T-lymphotropic virus type 1 (HTLV-1) antibodies (Abs) represents conclusive evidence of a specific immune response in the central nervous system of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. Western blotting (WB) for HTLV Abs in serum is a confirmatory test for HTLV-1 infection. The aim of this study was to standardise the Western blot to demonstrate the intrathecal pattern of Abs against HTLV-1 proteins in HAM/TSP patients. Paired cerebrospinal fluid (CSF) and serum samples were selected from 20 patients with definite HAM/TSP, 19 HTLV-1 seronegative patients and two HTLV-1 patients without definite HAM/TSP. The presence of reactive bands of greater intensity in the CSF compared to serum (or bands in only the CSF) indicated the intrathecal synthesis of anti-HTLV-1 Abs. All definite HAM/TSP patients presented with an intrathecal synthesis of anti-HTLV-1 Abs; these Abs were not detected in the control patients. The most frequent intrathecal targets of anti-HTLV-1 Abs were GD21, rgp46-I and p24 and, to a lesser extent, p19, p26, p28, p32, p36, p53 gp21 and gp46. The intrathecal immune response against env (GD21 and rgp46-I) and gag (p24) proteins represents the most important humoral pattern in HAM/TSP. This response may be used as a diagnostic marker, considering the frequent association of intrathecal anti-HTLV-1 Ab synthesis with HAM/TSP and the pathogenesis of this neurological disease.

Immunopathogenesis and neurological manifestations associated to HTLV-1 infection / Imunopatogênese e manifestações neurológicas associadas à infecção pelo HTLV-1

The human T lymphotropic virus type-1 (HTLV-1) was the first human retrovirus identified. The virus is transmitted through sexual intercourse, blood transfusion, sharing of contaminated needles or syringes and from mother to child, mainly through breastfeeding. In addition to the well-known association between HTLV-1 and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), several diseases and neurologic manifestations have been associated with the virus. This review was conducted through a PubMed search of the terms HTLV-1, immune response and neurological diseases. Emphasis was given to the most recent data regarding pathogenesis and clinical manifestations of HTLV-1 infection. The aim of the review is to analyze the immune response and the variety of neurological manifestations associated to HTLV-1 infection. A total of 102 articles were reviewed. The literature shows that a large percentage of HTLV-1 infected individuals have others neurological symptoms than HAM/TSP. Increased understanding of these numerous others clinical manifestations associated to the virus than adult T cell leukemia/lymphoma (ATLL) and HAM/TSP has challenged the view that HTLV-1 is a low morbidity infection.

O vírus linfotrópico de células T humanas do tipo 1 (HTLV-1) foi o primeiro retrovírus humano identificado. O vírus é transmitido via relação sexual, transfusão de sangue, compartilhamento de agulhas ou seringas contaminadas ou da mãe para o filho, principalmente através da amamentação. Além da conhecida associação entre o HTLV-1 e a mielopatia associada ao HTLV-1 (HAM/TSP), várias doenças e manifestações neurológicas tem sido associadas com o vírus. Esta revisão de literatura foi conduzida através de pesquisa ao banco de dados do PubMed, com os termos HTLV-1, resposta imune e doenças neurológicas. Foram enfatizados os dados mais recentes sobre a patogênese e às manifestações clínicas na infecção pelo HTLV-1. O objetivo dessa revisão é analisar a resposta imune e a variedade de manifestações neurológicas associadas com a infecção pelo HTLV-1. Um total de 102 artigos foi analisado. A literatura mostra que grande porcentagem de indivíduos infectados pelo HTLV-1 apresenta sintomas neurológicos mesmo na ausência de HAM/TSP. Uma maior compreensão das várias manifestações clínicas associadas ao vírus, além da leucemia/linfoma de células T do adulto (ATLL) e HAM/TSP, auxilia a estabelecer que, na realidade, a infecção pelo vírus possui uma morbidade maior do que se pensava.

Human T-cell leukaemia/lymphoma virus Type-1 associated myeloneuropathies: a caribbean perspective / Mieloneuropatías asociadas con el virus humano de células tipo 1 de la leucemia/linfoma: una perspectiva caribeña

This review follows the contributions of researchers from the Caribbean in improving the understanding of the disease mechanisms, clinical features and aetiology of neurological syndromes manifesting as diseases of the spinal cord and peripheral nerves. The evolution from the initial descriptions of neuropathies of presumed nutritional aetiology and later the recognition of two distinct subgroups, an ataxic neuropathy and a spastic myelopathy, are highlighted. The link between the natural history of human T-cell leukaemia/lymphoma virus type-1 (HTLV-1) infection and the immunopathogenesis of tropical spastic paraparesis is explored.

Este examen sigue las contribuciones de investigadores del Caribe encaminadas a mejorar la comprensión de los mecanismos de la enfermedad, rasgos clínicos y la etiología de los síndromes neurológicos que se manifiestan como enfermedades de la médula espinal y los nervios periféricos. El trabajo resalta la evolución de las descripciones iniciales de las neuropatías de etiología nutricional presuntiva y el posterior reconocimiento de dos subgrupos claramente distintos: la neuropatía atáxica, y la mielopatía espástica. Se explora el vínculo entre la historia natural de la infección por el virus humano de células tipo 1 (HTLV-1) en la leucemia/linfoma, y la inmunopatogénesis de la paraparesia espástica tropical.

Diagnóstico laboratorial da mielopatia associada ao HTLV-I: métodos para análise do líquido cefalorraquidiano / Laboratorial diagnosis of HTLV-I associated myelopathy: methods for the cerebrospinal fluid analysis

O vírus linfotrópico de células T humanas do tipo I (HTLV-I) pode causar uma doença neurológica inflamatória, crônica e incapacitante, que acomete a medula espinhal, denominada mielopatia associada ao HTLV-I/paraparesia espástica tropical (PET/MAH). A verificação de anticorpos da classe G (IgG) anti-HTLV-I no soro e no líquido cefalorraquidiano (LCR) representa importante parâmetro para o diagnóstico laboratorial da PET/MAH. OBJETIVO: Avaliação crítica dos métodos utilizados para verificação da presença e da produção intratecal de anticorpos totais e anti-HTLV-I no LCR para o diagnóstico de PET/MAH. MÉTODO: Realizou-se uma revisão sistemática de artigos da literatura médica, usando-se palavras-chave da língua inglesa como cerebrospinal fluid, intrathecal synthesis of antibodies, HTLV-I, HAM/TSP. As bases de dados utilizadas incluíram Pubmed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), MEDlars onLINE (Medline) e Cochrane Library. RESULTADO: Foram selecionados 14 artigos: cinco relacionados com a presença do anticorpo IgG específico no LCR; nove sobre síntese intratecal de anticorpos totais (IgG ou IgG/IgA/IgM) e específicos anti-HTLV-I (IgG ou IgM). DISCUSSÃO: O estudo isolado da presença de anticorpo IgG anti-HTLV-I no LCR não discrimina a fração produzida no sistema nervoso central (SNC), possui baixa especificidade (40 por cento) para o diagnóstico de PET/MAH. A demonstração da síntese intratecal de anticorpos IgG anti-HTLV-I possui maior relevância por suas elevadas especificidade (89 por cento) e sensibilidade (83 por cento). Entre os métodos para a avaliação da síntese intratecal de anticorpo específico, destaca-se o índice de IgG anti-HTLV-I, segundo Reiber e Felgenhauer(18), o qual se baseia no teste do ensaio imunossorvente ligado à enzima (ELISA), com análise simultânea do LCR e do soro. Outros estudos utilizam pequenas amostragens e não demonstram sensibilidade e especificidade no teste do LCR...

The human T-cell lymphotropic virus type I (HTLV-I) may cause HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP), an incapacitating chronic inflammatory disease of the spinal cord. The detection of IgG anti-HTLV-I antibodies in the serum and cerebrospinal fluid (CSF) has been an important parameter for the laboratorial diagnosis of HAM/TSP. OBJECTIVE: critical evaluation of the methods applied to detect the presence and intrathecal production of total antibodies and anti-HTLV-I in the CSF for the diagnosis of HAM/TSP. METHODS: We performed a systematic review of medical articles by using the key words: "cerebrospinal fluid, intrathecal synthesis of antibodies, HTLV-I associated myelopathy, HTLV-I, HAM/TSP". The used databases included: PubMed, Lilacs, Medline and Cochrane Library. RESULTS: A total of 14 articles were selected: five studies were related to the presence of specific IgG antibody in the CSF and nine studied the intrathecal synthesis of total antibodies (IgG or IgG/IgA/IgM) and specific anti-HTLV-I (IgG or IgM). DISCUSSION: The isolated study of the presence of IgG antibody anti-HTLV-I in the CSF does not show the fraction produced in the central nervous system, which represents low specificity (40 percent) for the diagnosis of HAM/TSP. The demonstration of the intrathecal synthesis of IgG anti-HTLV-I antibodies is more relevant due to its high specificity (89 percent) and sensibility (83 percent). According to Reiber & Felgenhauer (1987), the index IgG anti-HTLV-I, which is based on ELISA test with simultaneous CSF and serum analysis, stands out from the other methods applied to evaluate the intrathecal synthesis of specific antibody. Other studies use small samples and do not demonstrate the sensibility and specificity of the test in the CSF. Only one study shows statistical analysis. CONCLUSION: The immunological diagnosis of the CSF in HAM/TSP requires the standardization of methods, which should be based...

T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1): high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM)

INTRODUCTION: HIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event. OBJECTIVE: To study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells. MATERIAL AND METHODS: Since 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV), as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases "Emílio Ribas", São Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB) or polymerase chain reaction (PCR). All subjects were evaluated by two neurologists, blinded to the patient's HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO) classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC) classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event. RESULTS: A total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688) cells/mm³ and 89 (53-196) cells/mm³ for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036). Eight of 27 co-infected subjects (30 percent) were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event. DISCUSSION: Our results indicate that...

INTRODUÇÃO: A possibilidade que a co-infecção pelo vírus da leucemia de células T humana do tipo 1 (HTLV-1) em indivíduos infectados pelo vírus da imunodeficiência humana do tipo 1 poderia falsamente elevar o número de linfócitos T CD4+ no momento do evento definidor de aids, inferindo que essa contagem poderia ser um marcador laboratorial incompleto nos pacientes com a co-infecção HIV-1/HTLV-1. OBJETIVO: Estudar a interação entre o HIV-1 e a co-infecção como o HTLV-1. MATERIAL E MÉTODO: Desde 1997, nosso grupo tem seguido uma coorte de pacientes para estudar a interação entre HIV e/ou vírus da hepatite C (HCV), como também pacientes assintomáticos ou com TSP/HAM. 150 pacientes infectados pelo HTLV-1, encaminhados à clínica de HTLV do Instituto de Infectologia Emilio Ribas, São Paulo, Brasil, foram estudados. Vinte e sete deles estavam co-infectados pelo HIV-1 e HTLV-1, usando dois ELISAs e confirmados tipados pelo WB ou PCR. Todos os pacientes foram avaliados por dois neurologistas, cegos para o status de HTLV e o diagnóstico de TSP/HAM foi baseado na classificação da Organização Mundial de Saúde, 1988. A primeira contagem de células T disponível antes da terapia anti-retroviral foi mostrada para comparar com os pacientes infectados pelo HIV no momento do evento definidor de aids de acordo com Classificação do Centro de controle de Doenças, 1988. RESULTADOS: Um total de 27 HIV-1/HTLV-1 co-infectados foram identificados na coorte, 15 já apresentavam aids e 12 permaneceram sem evento de aids. A mediana de células T CD4 foi de 189 (98-688) células/mm³ e 89 (53-196) células/mm³ nos co-infectados que tinham evento definidor de aids e naqueles com a infecção somente pelo HIV, respectivamente (p = 0,036). Oito dos 27 co-infectados (30 por cento) foram diagnosticados tendo TSP/HAM símile, e três deles mostraram elevada contagem de células T CD4 e apresentaram infecções oportunistas no momento do evento definidor de aids. DISCUSSÃO: Nossos resultados...

Avaliação do desempenho de parâmetros imunológicos como indicadores de progressão clínica da infecção crônica pelo HTLV-1 / Evaluation of the performance of immunological parameters as indicators for clinical progression of chronic HTLV-1 infection

Neste estudo, foi avaliado o desempenho isolado e combinado de parâmetros laboratoriais, percentual de linfócitos B ( por centoLB), a razão entre células T/B e o por centoCD8+HLA-DR+/CD8+, na identificação de indivíduos assintomáticos-AS ou portadores de HAM/TSP-HT numa população de casos soropositivos para HTLV-1. índices expressos em porcentagem demonstram que cada parâmetro, isoladamente, apresenta desempenho moderado, com co-negatividade=83 por cento e 91 por cento para por centoLB e razão entre células T/B, respectivamente e co-positividade=78 por cento para por centoCD8+HLA-DR+/CD8+. A análise combinada ( por centoCD8+HLA-DR+/CD8+ e razão T/B) não revelou ganho significativo no desempenho (co-positividade=75 por cento, co-negatividade=74 por cento). A análise das razões de verossimilhança em diferentes faixas de valores, para os parâmetros isolados, revelou que um indivíduo soropositivo para HTLV-1 com por centoLB<7 por cento, razão entre células T/B>11 e por centoCD8+HLA-DR+/CD8+>70 por cento possui, respectivamente, 11, 19 e quase 10 vezes mais chances de pertencer ao grupo HT. Portanto, recomenda-se o uso desses indicadores fenótipos na propedêutica laboratorial complementar de monitoração da progressão clínica da infecção crônica pelo HTLV-1.

This study evaluated the performance of single and combined laboratory parameters, B-lymphocyte percentages ( percentLB), T/B cell ratio and percentCD8+HLA-DR+/CD8+, to differentiate asymptomatic cases (AS) from HAM/TSP patients (HT) within a population of HTLV-1 seropositive cases. Percentage indices demonstrated that each parameter alone presented moderate performance, with co-negativity of 83 and 91 percent for percentLB and T/B cell ratio, respectively, and co-positivity of 78 percent for percentCD8+HLA-DR+/CD8+. Combined analysis ( percentCD8+HLA-DR+/CD8+ and T/B cell ratio) did not show any substantial performance enhancement (co-positivity = 75 percent and co-negativity = 74 percent). Likelihood ratio analysis using different value ranges for the separate parameters revealed that HTLV-1 seropositive cases with percentLB<7 percent, T/B cell ratio>11 and percentCD8+HLA-DR+/CD8+>70 percent would have, respectively, 11, 19 and 10 times greater chance of belonging to the HT group. Therefore, use of these phenotypic indicators as complementary laboratory methods for monitoring the clinical progression of chronic HTLV-1 infection is recommended.

Association of cytokines, neurological disability, and disease duration in HAM/TSP patients

OBEJETIVO: Identificar marcadores clínicos e imunológicos associados com a mielopatia associada ao HTLV-I/paraparesia espástica tropical (MAH/PET). MÉTODO: 237 indivíduos infectados pelo HTLV-I foram clinicamente avaliados. Eles foram classificados de acordo com a escala expandida do estado de incapacidade de Kurtzke (EDSS) e escala de incapacidade motora de Osame (OMDS). Níveis de citocinas foram determinados nos indivíduos. RESULTADOS: 37 pacientes tinham MAH/PET. Houve correlação entre os graus de incapacidade pelas escalas. Houve também correlação entre a duração da MAH/PET e o grau da incapacidade pelas escalas. Níveis elevados de IFN-g foram detectados em células mononucleares de sangue periférico (CMSP) não estimuladas de pacientes com MAH/PET quando comparados com indivíduos HTLV-I positivos assintomáticos. CONCLUSÃO: Os dados demonstram a validade das escalas neurológicas para classificar o grau de incapacidade neurológica em portadores do HTLV-I e sugerem o comportamento progressivo da MAH/PET. Este estudo também demonstra que os níveis de IFN-g em sobrenadante de CMSP são marcadores da MAH/PET.

Human T-cell lymphotropic virus type I (HTLV-I) proviral DNA viral load among asymptomatic patients and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis

To evaluate the human T-cell lymphotropic virus type I (HTLV-I) proviral DNA load among asymptomatic HTLV-I-infected carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), real time PCR using TaqMan probes for the pol gene was performed in two million peripheral blood mononuclear cells (PBMC). The albumin gene was the internal genomic control and MT2 cells were used as positive control. The results are reported as copies/10,000 PBMC, and the detection limit was 10 copies. A total of 89 subjects (44 HAM/TSP and 45 healthy HTLV-I-infected carriers) followed up at the Institute of Infectious Diseases "Emilio Ribas" and in the Neurology Division of Hospital of Clínicas were studied. The asymptomatic HTLV-I-infected carriers had a median number of 271 copies (ranging from 5 to 4756 copies), whereas the HAM/TSP cases presented a median of 679 copies (5-5360 copies) in 10,000 PBMC. Thus, HAM/TSP patients presented a significantly higher HTLV-I proviral DNA load than healthy HTLV-I carriers (P = 0.005, one-way Mann-Whitney test). As observed in other persistent infections, proviral DNA load quantification may be an important tool for monotoring HTLV-I-infected subjects. However, long-term follow-up is necessary to validate this assay in the clinical setting.

Autoimmunity and molecular mimicry in tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy

Viruses share antigenic sites with normal host cell components, a phenomenon known as molecular mimicry. It has long been suggested that viral infections might trigger an autoimmune response by several mechanisms including molecular mimicry. More than 600 antiviral monoclonal antibodies generated against 11 different viruses have been reported to react with 3.5 percent of cells specific for uninfected mouse organs. The main pathological feature of tropical spastic paraparesis/human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (TSP/HAM) is a chronic inflammation of the spinal cord characterized by perivascular cuffing of mononuclear cells accompanied by parenchymal lymphocytic infiltration. We detected the presence of autoantibodies against a 98- to 100-kDa protein of in vitro cultured human astrocytes and a 33- to 35-kDa protein from normal human brain in the serum of HTLV-I-seropositive individuals. The two cell proteins exhibited molecular mimicry with HTLV-I gag and tax proteins in TSP/HAM patients, respectively. Furthermore, the location of 33- to 35-kDa protein cross-reaction correlated with the anatomical spinal cord areas (in the rat model) in which axonal damage has been reported in several cases of TSP/HAM patients. Our experimental evidence strongly suggests that the demyelinating process occurring in TSP/HAM may be mediated by molecular mimicry between domains of some viral proteins and normal cellular targets of the spinal cord sections involved in the neurodegeneration.

Consequências clínicas e imunológicas da co-infecção HTLV-1 e helmintos / Clinical and immunological consequences of co-infection HTLV-1 and helminth

Estudos prévios têm mostrado que a infecção pelo HTLV-I pode resultar em uma ativação e proliferação linfocitária, e uma exacerbada resposta imune Th1 com níveis altos de IFN-y. A infecção por helmintos está relacionada com produção de IgE e citocinas com um perfil Th2. Neste trabalho foi caracterizada a resposta imune de portadores de HTLV-1 e de pacientes com mielopatia asssociada ao HTLV-1 e a influência da infecção pelo HTLV-I no curso clínico e na resposta imune de pacientes com estrongiloidíase e esquistossomos. Adcionalmente, foi avaliada a influência da infecção por he1mintos na resposta imune (determinação de citocinas em sobrenadante e análise por FACS) e na carga proviral de indivíduos infectados pelo HTLV-I. Foi observado que indivíduos com mielopatia apresentaram níveis de citocinas pro-inflamatórias, especificamente o IFN-y, bem mais altos do que portadores assintomáticos, porém neste último grupo houve uma variação nestes níveis e 40% destes indivíduos tiveram níveis semelhantes aos pacientes com mielopatia. Além disso, os pacientes com mielopatia apresentaram maior proliferação linfocitária e maior freqüência de células T CD8+. Quando foi avaliada a influência do HTLV-1 na resposta imune ao S. stercoralis, foi documentado que pacientes com estrongiloidíase quando co-infectados pelo HTLV-1 apresentaram níveis mais baixos de IL-5, IL-13 e níveis mais altos de IFN-y do que pacientes que apresentavam somente estrongiloidíase. Estes achados podem justificar o fato de que pacientes co-infectados pelo HTLV-1 e S. stercoralis desenvolvam formas disseminadas da doença e menor resposta terapêutica a drogas anti-helmínticas. Achados imunológicos semelhantes foram observados em relação à co-infecção com HTLV-1 e S. mansoni. Os pacientes dualmente infectados pelo HTLV-1 e S. mansoni produziram mais IFN-y e menos IL-5, IL-10 e IgE específica para S. mansoni do que pacientes apenas com infecção pelo S. mansoni. A despeito de pacientes com HTLV-1 e...

Estudo da regulação molecular da apoptose ex vivo e in vitro em pacientes com mielopatia associada ao HTLV-I/Paraparesia espástica tropical / Study ex vivo and in vitro of molecular regulation of apoptosis in HTL-I-associated myelopathy/tropical spastic paraparesis patients

O vírus linfotrópico de células T humano - tipo I (HTLV-I) é o agente etiológico da Leucemia/Linfoma de células T no adulto (ATL), da Mielopatia Associada ao HTLV-I/Paraparesia Espástica Tropical (HAM/TSP), e de outras patologias. Os IFN-α e IFN-β foram recentemente introduzidos no tratamento de ATL e HAM/TSP, embora seus mecanismos de ação ainda estejam pouco esclarecidos. A presença da iNOS e seu recém-descoberto papel anti-apoptótico na ATL iniciou novas perspectivas terapêuticas. Considerando a correlação entre a linfoproliferação induzida pelo HTLV-I e as patologias associadas, buscamos estudar a regulação molecular da linfoproliferação e da apoptose ex vivo e in vitro em indivíduos soropositivos assintomáticos e pacientes com HAM/TSP. A expressão ex vivo do mRNA das moléculas pró-apoptóticas Fas, FasL e pró-caspase-3 foi maior nos indivíduos assintomáticos quando comparados aos pacientes com HAM/TSP, sugerindo que uma diminuição da morte celular programada poderia ter influência no processo patológico. O aumento do mRNA da iNOS nos assintomáticos foi correlacionado a inibição da linfoproliferação in vitro pelo L-NMMA (inibidor da iNOS). Por outro lado, apenas o IFN-β mostrou atividade anti-proliferativa significante, mas não pró-apoptótica in vitro em células mononucleares de pacientes com HAM/TSP. Porém, as células mostraram-se sensíveis ao estímulo com anti-CD3 na indução da apoptose. A estimulação com o IFN-β ou anti-CD3 não diminuiu a expressão do mRNA da proteína viral Tax, sugerindo que os efeitos antiproliferativos e pró-apoptóticos ocorrem independente da transcrição viral. De acordo com nossos resultados, o uso combinado de IFN-β_e outras drogas antivirais ou pró-apoptóticas poderia ser considerado em futuros ensaios terapêuticos.

Expression of interleukin-2R alpha chain [CD25] on peripheral blood lymphocytes in HTLV-1 associated myelopathy/tropical spastic paraparesis patients

Mashhad, a city in northern Iran, is a newly recognized endemic area for a retrovirus, the Human T-cell Lymphotropic Virus type I [HTLV-I]. This virus is the causative agent of a chronic slowly progressive cord syndrome called HTLV-I associated with Human T-cell virus type I-associated myelopathy or/tropical spastic paraparesis [HAM/TSP] and has tropism for CD4+ T- cells, which results in T-cell activation that escape the autocrine pathway. The purpose of this study was to determine the immuno-phenotypic features of peripheral blood lymphocytes of HAM/TSP patients, especially differential expression of interleukin-2 receptor

The pathogenesis of tropical spastic paraparesis/human T-cell leukemia type I-associated myelopathy

Tropical spastic paraparesis/human T-cell leukemia type I-associated myelopathy (TSP/HAM) is caused by a human T-cell leukemia virus type I (HTLV-I) after a long incubation period. TSP/HAM is characterized by a chronic progressive paraparesis with sphincter disturbances, no/mild sensory loss, the absence of spinal cord compression and seropositivity for HTLV-I antibodies. The pathogenesis of this entity is not completely known and involves a multivariable phenomenon of immune system activation against the presence of HTLV-I antigens, leading to an inflammatory process and demyelination, mainly in the thoracic spinal cord. The current hypothesis about the pathogenesis of TSP/HAM is: 1) presence of HTLV-I antigens in the lumbar spinal cord, noted by an increased DNA HTLV-I load; 2) CTL either with their lytic functions or release/production of soluble factors, such as CC-chemokines, cytokines, and adhesion molecules; 3) the presence of Tax gene expression that activates T-cell proliferation or induces an inflammatory process in the spinal cord; 4) the presence of B cells with neutralizing antibody production, or complement activation by an immune complex phenomenon, and 5) lower IL-2 and IFN-gamma production and increased IL-10, indicating drive to a cytokine type 2 pattern in the TSP/HAM subjects and the existence of a genetic background such as some HLA haplotypes. All of these factors should be implicated in TSP/HAM and further studies are necessary to investigate their role in the development of TSP/HAM

El gen tax del virus linfotrópico humano tipo I en la identificación etiológica de la paraparesia espástica tropical: estudio clínico, serológico y de polimerasa en cadena en 72 pacientes / HTLV-I tax gene on the etiological identification of tropical spastic paraparesis: a clinical, serological and polymerase chain reaction study in 72 patients

Background: Tropical spastic paraparesis (TSP) is an endemic disease in Chile. In most countries, only 50 percent of patients are seropositive to HTLV-I. However, new studies suggest that seronegative TSP is also associated with HTLV-I. Aim: To describe clinical and virological features of seronegative patients with TSP. Patients and methods: seventy two chilean patients with TSP, studied by clinical, radiological and laboratory methods during 1998, are reported. The determination of antibodies to HTLV-I was accomplished by ELISA, immunofluorescence and western-blot analysis. Polymerase chain reaction for tax and 5'Ltr genes was made using primers SK 43-44, LTR1 and LTR6. Results: Thirty one patients were HTLV-I positive and 41 were negative. No clinical, radiological or laboratory differences were observed between both groups. In seropositive patients, tax and 5'ltr viral gene sequences of the HTLV-I provirus were detected in DNA of peripheral blood mononuclear cells. In seronegative cases, sequences of tax gene were detected, exclusively, in 18 of 41 patients. Conclusions: These results confirm an association with HTLV-I infection in 43,9 percent of the TSP seronegative patients. These findings support the hypothesis that a defective provirus infects peripheral blood mononuclear cells in seronegative cases of TSP. The importance tax gene in the diagnosis of the TSP is also emphasized

Análise do líquido cefalorraqueano e neuropatogênese da infecçäo pelo HTLV-I / Cerebrospinal fluid analysis and the pathogenesis of central nervous system infection by HTLV-I

O mecanismo da mielopatia associada a infeccao pelo HTLV-I (HAM), como ocorre o dano da medula espinhal e finalmente a destruicao da mielina assim como do oligodendrocito nao esta definido. Por hipotese, a passagem delinfocitos infectados atraves da barreira hemato-encefalica atuaria como pedra alvo na patogenese da HAM. Um aumento da producao de citoquinas tais como o fatorde necrose tumoral alfa (TNF alfa), potente imunomodulador, facilida a migracao de linfocitos atraves da expressao de fatores de adesao molecular na superficiede celulas endoteliais. Por outro lado, a recente demonstracao da elevada sinteseintratecal do receptor soluvel para o TNF (sTNF-R) em pacientes com HAM tem contribuido para melhor compreensao dos mecanismos da neuropatogenise da infeccao pelo HTLV-I. Os novos conhecimentos sugerem que os efeitos deleterios do TNF alfa no sistema nervoso central podem ser o resultado do desequilibrio entre a producao desta citoquina e do seu receptor inibidor (sTNF-R).

Paraparesia Espástica Tropical / Tropical Spastic paraparesis: a case report

A paraparesia espástica tropical é uma doença de evoluçäo lenta, causada por comprometimento do sistema nervoso central (especialmente medula espinhal), cuja etiologia pode relacionar-se à infecçäo pelo vírus T-linfotrópico tipo 1 (HTLV-1), observada predominantemente nos trópicos. As alteraçöes características da doença incluem deficiência motora e sensitiva dos membros inferiores, frequentemente associadas a distúrbios miccionais. Relata-se a experiência dos autores com um caso de paraparesia espástica tropical ocorrido na regiäo de Passo Fundo, RS