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.

HTLV-1-associated infective dermatitis and probable HTLV-1- associated myelopathy in an adolescent female

Human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis (ID) is a chronic, severe and recurrent eczema occurring during childhood in patients vertically infected with HTLV-1. HTLV-1-associated myelopathy/tropical spastic paraparesia (HAM/ TSP) is slow and progressive. We report the case of an adolescent female from a non-endemic area for HTLV-1 who presents ID and, most likely, associated HAM/TSP.

Aportes y consideraciones sobre la infección por los virus linfotrópicos-T humanos tipo 1 y 2 en Argentina / Contributions to the knowledge of Human T-Cell Lymphotropic Virus Type 1 and 2 (HTLV-1/2) infections in Argentina

El virus linfotrópicos-T humanos tipo 1 (HTLV-1) es el agente etiológico de una enfermedad hematológica de mal pronóstico, la leucemia de células T del adulto (ATL) y de una enfermedad neurológica invalidante, la mielopatía asociada al HTLV-1/paraparesia espástica tropical (HAM/TSP) para las cuales no existe un tratamiento eficaz. El virus linfotrópico-T humano tipo 2 (HTLV-2) ha sido relacionado a síndromes neurológicos, aumento de infecciones y mortalidad. En Argentina, existe una restricción étnica/geográfica con una región endémica para el HTLV-1 en el Noroeste (Aymarás) y otra para el HTLV-2 en la Región Chaqueña (Tobas y Wichis). El aumento de corrientes migratorias a partir de áreas endémicas ha contribuido a la mayor circulación de estos virus en el país, hecho que plantea el desafío de poder brindar un diagnóstico final y una atención integral a los individuos. Este manuscrito comprende una revisión actualizada y la experiencia de nuestro grupo sobre estas infecciones...

HTLV-1 is the ethiologic agent of an hematologic disease with bad prognosis, Adult T-cell Leukemia (ATL) lethal in short time and a chronic and progressively invalidant neurological disease, HTLV-1 Associated Mielopathy/Tropical Spastic Paraparesis (HAM/TSP), for which no effective treatment is available. HTLV-2 has been related to neurologic syndromes, an increase in infections and mortality. In Argentina, the infection shows an ethnic/geographic restriction with an endemic regions for HTLV-1 in the Northeast (Aymaras) and for HTLV-2 in the Chaqueña Region (Tobas y Wichis). The increasing migrations from endemic areas have contributed to a major circulatin of these viruses and detection of HAM/TSP and ATL cases countrywide. This situation poses the challenge of giving a complete and final diagnosis and an integral care to infected individuals. This manuscript describes general aspects of HTLV-1/2 and the situation and experience of our group on these infections in the country...

HAM/TSP: association between white matter lesions on magnetic resonance imaging, clinical and cerebrospinal fluid findings / HAM/TSP: associação entre lesões de substância branca à ressonância magnética, achados clínicos e do líquido cefalorraquidiano

OBJECTIVE: To investigate the association between clinical data, white matter lesions and inflammatory cerebrospinal fluid (CSF) findings in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). METHOD: We studied brain and cervical spinal cord on magnetic resonance imaging (MRI) and CSF examinations of 28 Brazilian HAM/TSP patients. RESULTS: The majority of patients had severe neurological incapacity with EDSS median of 6.5 (3-8). The brain MRI showed white matter lesions (75%) and atrophy (14%). The preferential brain location was periventricular. Cervical demyelination lesions occurred in 11% of the cases, and cervical atrophy in 3.5%. One patient had enhancement lesions on T1 cervical spinal cord MRI. Cases with spinal cord lesions had signs of acute CSF inflammation. The brain white matter lesions predominated in the patients with higher age. CONCLUSION: Our data suggest that an active inflammatory process is associated with the cervical spinal cord lesions in HAM/TSP. The brain abnormalities are not related to the clinical picture of HAM/TSP.

OBJETIVO: Analisar a associação entre aspectos clínicos, lesões de substância branca e reação inflamatória aguda no líquido cefalorraquidiano (LCR) na mielopatia associa ao HTLV-1 (HAM/TSP). MÉTODO: Foram estudadas ressonâncias magnéticas (RM) do encéfalo/medula espinhal cervical e exame do LCR de 28 pacientes com HAM/TSP. RESULTADOS: A maioria dos pacientes apresentava grave incapacidade neurológica, com EDSS 6,5 (3-8). A RM revelou lesões da substância branca (75%) com predominância periventricular e atrofia cortical (14%). Lesões desmielinizantes cervicais ocorreram em 11% dos casos e atrofia em 3,5%. Um paciente apresentou lesão cervical na T1 com captação de contraste. Sinais de inflamação aguda no LCR ocorreram em situações de lesão da medula espinhal cervical. As alterações de substância branca do encéfalo predominaram nos indivíduos com maior faixa etária. CONCLUSÃO: Nossos achados sugerem que processo inflamatório com atividade clínica na HAM/TSP está associado a lesões da medula espinhal cervical. As anormalidades da substância branca encefálicas não são relacionadas ao quadro clínico de HAM/TSP.

Motor behavioral abnormalities and histopathological findings of Wistar rats inoculated with HTLV-1-infected MT2 cells

The objective of the present study was to describe motor behavioral changes in association with histopathological and hematological findings in Wistar rats inoculated intravenously with human T-cell lymphotropic virus type 1 (HTLV-1)-infected MT2 cells. Twenty-five 4-month-old male rats were inoculated with HTLV-1-infected MT2 cells and 13 control rats were inoculated with normal human lymphocytes. The behavior of the rats was observed before and 5, 10, 15, and 20 months after inoculation during a 30-min/rat testing time for 5 consecutive days. During each of 4 periods, a subset of rats was randomly chosen to be sacrificed in order to harvest the spinal cord for histopathological analysis and to obtain blood for serological and molecular studies. Behavioral analyses of the HTLV-1-inoculated rats showed a significant decrease of climbing, walking and freezing, and an increase of scratching, sniffing, biting, licking, and resting/sleeping. Two of the 25 HTLV-1-inoculated rats (8 percent) developed spastic paraparesis as a major behavioral change. The histopathological changes were few and mild, but in some cases there was diffuse lymphocyte infiltration. The minor and major behavioral changes occurred after 10-20 months of evolution. The long-term observation of Wistar rats inoculated with HTLV-1-infected MT2 cells showed major (spastic paraparesis) and minor motor abnormalities in association with the degree of HTLV-1-induced myelopathy.

Paraparesia espástica progresiva asociada a HTLV-I en Chile: estudio y seguimiento de 121 pacientes por diez años / Progresive spastic paraparesis associated to HTLV-I in Chile

Revision is made to 121 Chilean patients with progressive adult spastic paraparesis (PSPs) associated to HTLV-I. Epidemiologic, clinical, diagnosis and associated illnesses aspects are analyzed as well as the pathogenesis. The follow-up of patients during several years allowed defining the evolutional profile, establishing the causes of death and studying the virus' behavior. Pathogenesis hypothesis arose from the neuropathological search to define the mechanisms of damage supported on immunohystochemical studies. It was confirmed that the CNS illness is a degenerative process linked to a central axonopathy which expresses flaws in the axoplasmic transport, particularly affecting the corticospinal tracts, although there is a more extended myeloencephalic involvement. Furthermore, the virus is capable of producing a multisystemic illness that may simultaneously involve the nervous system; the hematological system; the exocrine glands; the hepatic, lung, muscular and bone parenchymas.

Se revisan las paraparesias espásticas progresivas del adulto (PEPAs) producidas por el HTLV-I, en 121 pacientes chilenos. Se analizan los aspectos epidemiológicos, clínicos, diagnósticos, las enfermedades asociadas, y la patogenia. El seguimiento de los pacientes durante varios años permitió definir el perfil evolutivo, establecer las causas de muerte y estudiar el comportamiento del virus. De los casos con anatomía patológica surgieron hipótesis, que han permitido definir mecanismos de daño, sustentados en estudios inmunohistoquímicos. Se pudo confirmar que la enfermedad del SNC es un proceso degenerativo, vinculado a una axonopatía central que expresa fallas del transporte axoplásmico, que afecta particularmente la vía corticoespinal, aunque existe un compromiso más extenso mielo-encefálico. Además, el virus es capaz de producir una enfermedad multisistémica, que puede comprometer simultáneamente el sistema nervioso, el sistema hematológico, las glándulas exocrinas, el parénquima hepático, pulmonar, muscular y óseo.

Inmunohistoquímica de los cambios degenerativos del sistema nervioso central en paraparesias esp sticas asociadas al virus linfotrópico humanoTtipol(HTLV-l) / Immunohistochemistry of degenerative changes in the central nervous system in spastic paraparesis associated to human T lymphotropic virus type I (HTLV-I)

Background: Human T lymphotropic virus type I is associated with tropical spastic paraparesis, that is a chronic and progressive disease which damages specially the cortiespinal tracts. The pathogenesis of this degenerative process remains unknown. Aim: To identify histopathological aspects that could suggest a pathogenic hypothesis we studied immunohistochemical features in spinal cords obtained from patients that died due to progressive spastic paraparesis. Patients and Methods: Five males and five females, who died between 1990 and 2000, with a mean age of 52 years and mean disease duration of 8.6, were studied. All had a complete clinical and virological diagnosis. Samples were obtained from the frontal motor cortex and spinal cord (cervical, dorsal and lumbar segments), were fixed in formol (10 percent), included in paraffin, and stained with Haematoxylin and Luxol-fast-blue. Immunohistochemical study was made with anti-neurofilament antibodies 1:100 (M0762, DAKO), anti-APP 1:20 (Rabbit Pre Amyloid protein 51-2700 ZYMED), anti-tau 1:100 (A0024DAKO) and anti-ubiquitine 1:50 (NCL UBIQm Novocastra). Results: All cases had demyelinization and axonal loss in the cortico-spinal tracts; distal and segmental demyelinization of Goll tract; axonal thickening, amyloid precursor protein deposits in the white matter; tau protein aggregation in the spinal cord oligodendrocytes; axonal ubiquitination of sensitive and motor tracts, and subcortical white matter. Neurona! injury was absent. Conclusions: The systematic damage of motor and sensitive tracts of the spinal-cord and the absence of neurona! damage, defines a degenerative process limited to axons. This central axonopathie could be caused by a disturbance of axoplasmic transport.

Resonancia Magnética de médula espinal y cerebro en el correlato clínico de la paraparesia espástica progresiva que se asocia al virus humano linfotrópico tipo-I (HTLV-I) / Brain and spinal cord magnetic resonance imaging in spastic paraparesis associated to human T-lymphotropic virus

Background: The spastic paraparesis associated to HTLV-1 causes degenerative pyramidal tract lesions of the spinal cord and affects cortical-nuclear connections in the brain. Aim: To report the findings of magnetic resonance imaging in patients with spastic paraparesis. Material and methods: A magnetic resonance imaging of the brain and spinal cord was performed in 30 patients (24 females), mean age and evolution of 56 and 12 years respectively, with a clinical and virological diagnosis of tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). Results: No patient had abnormal signals in the spinal cord parenchyma. However, an atrophy of the dorsal segment was observed in 87 percent of patients. Patients with the highest degree of atrophy showed a higher degree of functional impairment. Eleven patients had spinal cord conus atrophy, associated to neurogenic bladder or impotency. In 80 percent of patients, hyperintense subcortical white matter images in DP, T2 and Flair, mostly bi frontal, were detected. In half of them, small rounded and isolated images were observed. In the other half, eight or more images, generally larger and occasionally confluent, were found. Ten of 12 patients with confluent brain lesions showed different degrees of cognitive impairment. No patient had lesions in the corpus callosus, periventricular white matter, pons, medulla oblongata or cerebellum. Conclusions: Most patients with tropical spastic paraparesis have alterations in brain or spinal cord magnetic resonance imaging. The magnetic resonance lesions are concordant with functional impairment. The characteristics of the imaging in TSP/HAM patients can be helpful in the differential diagnosis of patients with paraparesis.

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.

Multiple clinical manifestation of HTLV1 infection in a single patient

HTLV-1 infection is endemic in the Caribbean and several publications have reported the clinical disease entities seen in this population of patients. This case report is an account of a patient admitted to Kingstown General Hospital, St Vincent and the Grenadines, who had severe infective dermatitis, tropical spastic paraparesis (TSP) and Non-Hodgkin's Lymphoma (NHL). As far as we are aware, all three diseases have not been described in a single patient

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.

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

Ressonância magnética na mielopatia associada ao HTLV-I. leucoencefalopatia e atrofia medular / Magnetic ressonance in HTL-I associeted myelopathy. Leukoencephalopathy and spinal cord atrophy

Lesöes na substância branca cerebral e atrofia medular têm sido descritas em pacientes com mielopatia associada ao HTLV-I (MAH). A frequência e a importância clínica destes achados ainda näo säo totalmente conhecidas. Vinte e nove pacientes foram estudados por ressonância magnética (RM) do crânio e da coluna. Imagens com hipersinal em T2 na substância branca, de diâmetro igual ou superior a 3 mm foram consideradas anormais. O tamanho da medula foi avaliado usando índice por nós denominado "índice medular". Os achados neurorradiológicos foram correlacionados às características clínicas da mielopatia. Lesöes na substância branca cerebral ocorreram em 52 por cento dos pacientes e atrofia medular ocorreu em 74 por cento. Näo houve correlaçäo entre os achados neurorradiológicos e as características clínicas estudadas. Os resultados sugerem que a RM é um método útil na detecçäo de anormalidades cerebrais e medulares em pacientes com MAH. As lesöes de substâncias branca näo apresentaram correlaçäo com idade ou com fatores de risco cardiovasculares e podem estar associadas à infecçäo pelo vírus HTLV-I.

Mielopatía HTLV-I positivo

La mielopatía HTLV-I positivo es una enfermedad de origen viral, caracterizada por comienzo lento, dolor lumbar y trastornos de la marcha; puede presentar diversos grados de compromiso, desde las formas asintomáticas hasta cuadros severos crónicos con postración total al lecho, Después de muchas especulaciones de tipo nutricional, neurotóxico, bacteriano, etc., hoy se conoce que sus agentes causales son retrovirus HTVL-I y HTVL-II. Las manifestaciones clínicas una vez instalado el cuadro patológico son sificultad para la marcha, notable disminución de la líbido, compromiso de esfinteres y una lenta y progresiva incapacidad para sostenerse en pie. La enfermedad afecta por igual a hombres y mujeres, a veces con carácter familiar, y la mayoría de los pacientes están alrededor de 30 - 35 años. La evolución en promedio es de unos 3-5 años, aunque hay pacientes cuya enfermedad tiene 10 a 20 años de duración. Ningún paciente fallece por causa de la enfermedad. Presentamos una relación de los casos observados en el área de influencia de nuestro Hospital Universitario San José

Paraparesia espástica tropical en el Ecuador: Comunicación preliminar

La paraparesia espastica tropical (PET) es una mieloneuropatía endémica en regiones insulares o costeras cercanas a la línea ecuatorial, que ha sido tradicionalmente considerada como secundaria a factores tóxicos, nutricionales o infecciosos. Recientemente, se ha sugerido que la infección crónica con el virus linfotrófico-T humano tipo I (HTLV-I) juega un papél fundamental en la etiología de esta entidad. En el presente trabajo se reportan los primeros 10 pacientes con PET diagnosticados en el Ecuador. Siete de los pacientes fueron mujeres y 3 fueron hombres, con edad promedio de 61 años. En todos los pacientes se encontró un cuadro de paraparesia espástica de larga evolución, acompañado en algunos casos de discretas alteraciones sensitivas. Una paciente presentó un cuadro de atrofia muscular asociado a la paraparesia espástica, simulando una esclerosis lateral amiotrófica. La detección de anticuerpos anti HTLV-I mediante ELISA fue positiva en los 10 pacientes con PET y en 2 de 26 controles sanos o con otro tipo de enfermedades neurológicas. Los estudios de Western Blot corroboraron la positividad de las reacciones de ELISA en 9 de los 10 pacientes con PET. En los dos controles con Elisa positivo, El Western Blot fue negativo. La mayoría de los pacientes con PET provenían o residían en islas o puertos tropicales de la provincia de Esmeraldas, cercanas a la frontera con Colombía. En esta comunicación preliminar se confirma la existencia de PET en el Ecuador y su posible relación con el HTLV-I. Futuros estudios epidemiológicos son necesarios para establecer la incidencia y prevalencia de esta entidad en nuestro país y para evaluar sus consecuencias en la población general.