Neurofilament Light in CSF and Plasma Is a Marker of Neuronal Damage in HTLV-1-Associated Myelopathy and Correlates With Neuroinflammation.

BACKGROUND AND OBJECTIVES: To evaluate the usefulness of CSF and plasma neurofilament light (Nf-L) as a biomarker for human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM). METHODS: Nf-L, CXCL10, and neopterin were measured by ELISA in 83 CSF samples obtained from 49 individuals living with HTLV-1/2. Plasma Nf-L was also measured by single molecule array. Results were correlated with duration of disease, age, mobility, CSF cell counts, CSF protein, and HTLV-1 proviral load. RESULTS: Nf-L was detected in all CSF samples (median [range] = 575 [791.8-2,349] pg/mL) and positively correlated with markers of inflammation (CXCL10 (r = 0.733), neopterin (r = 0.499), cell count (r = 0.403), and protein levels (r = 0.693) in CSF; p < 0.0015). There was an inverse correlation between Nf-L and duration of disease (r = -0.584, p < 0.0001). Wheelchair-dependent patients had high concentrations of markers of inflammation and neuronal damage. Concentrations of CXCL10, neopterin, and Nf-L remained elevated in follow-up samples (mean follow-up 5.2 years). Nf-L in plasma correlated with concentration of Nf-L, neopterin, CXCL10, and protein in CSF. CONCLUSIONS: Nf-L in plasma and CSF has potential to be used as a biomarker of disease activity in HAM. Neuronal damage seems to be more intense early in disease but persists long term. Wheelchair-dependent patients have ongoing neuroinflammation.

Relevance of retrovirus quantification in cerebrospinal fluid for neurologic diagnosis.

Different human retroviruses, such as Human Immunodeficiency Virus (HIV) and Human T-cell Lymphotropic Virus (HTLV), can cause neurologic infection. However, a definitive diagnosis may be hampered by several factors. Quantification of the viral or proviral load in cerebrospinal fluid (CSF) may be helpful in the diagnosis of nervous system disorders due to retroviral infection and may influence the treatment approach. The present work discusses retrovirus infection and neurologic impairment, as well as the usefulness of the determination of the HIV and HTLV proviral or viral load in cerebrospinal fluid in cases of neurologic disorder, in light of recent advances in this field. This study also discusses the different molecular techniques for quantifying the proviral load (real-time quantitative PCR, droplet digital PCR, and semi-nested real-time reverse transcription PCR) that are currently available.

Digital droplet PCR (ddPCR) for the precise quantification of human T-lymphotropic virus 1 proviral loads in peripheral blood and cerebrospinal fluid of HAM/TSP patients and identification of viral mutations.

An elevated human T cell lymphotropic virus 1 (HTLV)-1 proviral load (PVL) is the main risk factor for developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-1 infected subjects, and a high cerebrospinal fluid (CSF) to peripheral blood mononuclear cell (PBMC) PVL ratio may be diagnostic of the condition. However, the standard method for quantification of HTLV-1 PVL-real-time PCR-has multiple limitations, including increased inter-assay variability in compartments with low cell numbers, such as CSF. Therefore, in this study, we evaluated a novel technique for HTVL-1 PVL quantification, digital droplet PCR (ddPCR). In ddPCR, PCR samples are partitioned into thousands of nanoliter-sized droplets, amplified on a thermocycler, and queried for fluorescent signal. Due to the high number of independent events (droplets), Poisson algorithms are used to determine absolute copy numbers independently of a standard curve, which enables highly precise quantitation. This assay has low intra-assay variability allowing for reliable PVL measurement in PBMC and CSF compartments of both asymptomatic carriers (AC) and HAM/TSP patients. It is also useful for HTLV-1-related clinical applications, such as longitudinal monitoring of PVL and identification of viral mutations within the region targeted by the primers and probe.

Positive feedback loop via astrocytes causes chronic inflammation in virus-associated myelopathy.

Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare neurodegenerative disease characterized by chronic inflammation in the spinal cord. We hypothesized that a positive feedback loop driven by chemokines may be responsible for the chronic inflammation in HAM/TSP. We aimed to determine the identity of these chemokines, where they are produced, and how they drive chronic inflammation in HAM/TSP. We found that patients with HAM/TSP have extraordinarily high levels of the chemokine CXCL10 (also known as IP-10) and an abundance of cells expressing the CXCL10-binding receptor CXCR3 in the cerebrospinal fluid. Histological analysis revealed that astrocytes are the main producers of CXCL10 in the spinal cords of patients with HAM/TSP. Co-culture of human astrocytoma cells with CD4+ T cells from patients with HAM/TSP revealed that astrocytes produce CXCL10 in response to IFN-γ secreted by CD4+ T cells. Chemotaxis assays results suggest that CXCL10 induces migration of peripheral blood mononuclear cells to the central nervous system and that anti-CXCL10 neutralizing antibody can disrupt this migration. In short, we inferred that human T-lymphotropic virus type 1-infected cells in the central nervous system produce IFN-γ that induces astrocytes to secrete CXCL10, which recruits more infected cells to the area via CXCR3, constituting a T helper type 1-centric positive feedback loop that results in chronic inflammation.

Accumulation of human T-lymphotropic virus type I (HTLV-I)-infected cells in the cerebrospinal fluid during the exacerbation of HTLV-I-associated myelopathy.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive, inflammatory disease of the central nervous system (CNS). We report a patient with transverse myelitis, who exhibited acute onset and rapid progression of the disease and whose symptoms resembled those observed in multiple sclerosis with spinal cord presentation. During neurological exacerbation of the condition, the HTLV-I proviral load in the cerebrospinal fluid (CSF) increased to 10 times that in the peripheral blood. This suggests that the accumulation of HTLV-I-infected cells in the CNS contributes to neurological exacerbation. Based on the increased proviral load in the CSF, we diagnosed the disease as acute progressive HAM/TSP. The measurement of the HTLV-I proviral load in the CSF is useful for the diagnosis of HAM/TSP and for monitoring its progression.

Incidence and clinical significances of human T-cell lymphotropic virus type I-associated myelopathy with T2 hyperintensity on spinal magnetic resonance images.

OBJECTIVE: To clarify the incidence and clinical significance of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) showing T2 hyperintensity in the spinal cord on magnetic resonance images (MRI). PATIENTS AND METHODS: We reviewed the spinal cord MRI of 38 HAM/TSP patients and analyzed them in relation to clinical and laboratory findings. Analyzed data were: age at onset, disease duration, disability status, responsiveness to interferon therapy, brain abnormalities on MRI, serum anti-HTLV-I titers, and cerebrospinal fluid (CSF) findings. RESULTS: MRI findings of the spinal cord were classified into 3 types, "normal" (n=22, 57.9%), "atrophy" (n=13, 34.2%) and "T2-hyperintensity" (n=3, 7.9%). Patients in the normal and atrophy types showed slowly progressive paraparesis. Significant differences were not found between the normal and atrophy types in any clinical or laboratory data, including disease duration, disability status and responsiveness to interferon-alpha therapy. Meanwhile, all patients showing T2-hyperintensity had severe paraparesis of a rapid progressive nature, with CSF IgG elevation. CONCLUSION: HAM/TSP with T2-hyperintensity on spinal MRI shows a rapid progressive clinical course with severe motor impairment. The incidence of this malignant form of HAM/TSP is estimated to be around 7.9%.

Clinicopathological and virological analyses of familial human T-lymphotropic virus type I--associated polyneuropathy.

Human T-lymphotropic virus type I (HTLV-I) is known to be the causative agent of the chronic myelopathy, HTLV-I--associated myelopathy (HAM), and on rare occasions infection is also associated with the development of polyneuropathy. Here the authors present an HTLV-I--positive family of whom four members developed a chronic demyelinating polyneuropathy without HAM. Four female patients in a family from Hokkaido in Japan developed distal dominant paresthesia and muscle weakness in the second and third decades of their life. Neurological findings at ages ranging from 50 to 65 years included mild painful sensorimotor disturbances with atrophy of the distal parts of the extremities but without pyramidal signs or hyperactive tendon reflexes. Magnetic resonance imaging (MRI) findings of brain and spinal cord were unremarkable. Serum HTLV-I antibody levels were elevated at 1:8192 to 1:32,768, whereas those in cerebrospinal fluid were low at 1:4 to 1:8. Electrophysiological studies revealed polyphasic compound muscle action potentials with denervation potentials on nerve conduction studies and neurogenic patterns by electromyography, which were consistent with signs of chronic motor dominant demyelinating polyneuropathy. Sural nerve biopsy showed decreased myelinated fibers, occurrence of globule formation, myelin ovoid and remyelinated fibers, and an infiltration of CD68-positive macrophages with occasional CD4-positive T cells in the nerve fascicles. The polyneuropathy was responsive to steroid therapy. Analyses of serological human leukocyte antigen (HLA) types indicated that none of the patients possessed a high-risk HLA type known to be associated with adult T-cell leukemia (ATL), whereas they did have high responsive alleles to HTLV-I env similar to that observed in HAM. Nucleotide sequence analysis of the HTLV-I tax region demonstrated the B subgroup in all patients. This study suggests that HTLV-I infection can result in the development of a familial form of polyneuropathy that is associated with distinct HLA class I alleles, which might possibly involve a distinct virus subtype.

Extracellular matrix protein expression in cerebrospinal fluid from patients with tropical spastic paraparesis associated with HTLV-I and Creutzfeldt-Jakob disease.

The cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the CNS, thus biochemical processes in the CNS could potentially be reflected in the CSF. Changes in extracellular matrix (ECM) proteins can be studied through their analysis in the CSF. ECM plays an essential role in CNS homeostasis and several proteins such as laminin (LN), fibronectin (FN), thrombospondin (TS) and heparan sulphate proteoglycan (HS, perlecan) form part of its structure. Possible changes in the levels of these proteins were investigated in two different pathologies--tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) (n=25) and Creutzfeldt-Jakob disease (CJD) (n=19)--and compared with those in a control group with or without neurological disease (n=25). CSF analyses were carried out using monoclonal or monospecific polyclonal antibodies. In comparison with the control group, it was found that TSP/HAM patients presented significantly higher levels of LN, TS and HS, while in CJD patients the levels of FN, TS and HS were increased. In CJD patients the HS level was almost double that of the TSP/HAM patients. These results suggest a distinct pattern of ECM proteins in CSF in relation to the type of neurological disease. TSP/HAM is a chronic motor disease that affects the white matter of the spinal cord, while CJD is a subacute dementia that affects cerebral neurons and their synapsis.

Detection of myelin basic protein in cerebrospinal fluid and serum from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis.

BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) is a chronic inflammatory disease that primarily affects the spinal cord and may be a neurological syndrome that is clinically similar to multiple sclerosis (MS). Myelin basic protein (MBP) in the cerebrospinal fluid (CSF) of MS patents is generally measured by radioimmunoassay. We have recently established a sensitive enzyme-linked immunosorbent assay (ELISA) and measured the MBP concentrations in CSF and serum of HAM/TSP patients. METHODS: A sensitive two-site ELISA capable of measuring MBP at a concentration as low as 30 pg/mL in serum and CSF samples was used. RESULTS: Significantly higher CSF MBP concentrations were detected in 61% of HAM/TSP patients than in patients with non-neurological diseases. Serum MBP concentrations were also higher in 9% of HAM/TSP patients compared with patients with non-neurological diseases or healthy controls. CONCLUSIONS: Using our ELISA system, we detected MBP in CSF and serum not only in patients with central active demyelination as in MS, but also in patients with spinal cord demyelination as in HAM/TSP.

Tissue inhibitor of metalloproteinase 3, matrix metalloproteinase 9, and neopterin in the cerebrospinal fluid: preferential presence in HTLV type I-infected neurologic patients versus healthy virus carriers.

The human retrovirus HTLV-I is responsible for the chronic progressive myelopathy, TSP/HAM, characterized by the presence of infiltrated T lymphocytes, cytokines, and matrix metalloproteinases (MMPs) within spinal cord lesions. MMPs have been associated with several neurological diseases, and we previously reported the specific presence of the extracellular matrix-degrading protease, MMP-9, in the cerebrospinal fluid of TSP/HAM patients. Nevertheless, previous studies have not yet shown whether the expression of MMP-9 is associated with HTLV-I infection per se, or with neurological symptoms following infection. In the present work, the presence of tissue inhibitors of metalloproteinases 1 and 3 (TIMP-1 and TIMP-3) and of MMP-9 in the CSF of HTLV-I-infected individuals was compared in TSP/HAM patients versus HTLV-I carriers without neurological symptoms. TIMP-3, a regulator of MMP activity and cell survival, was detected with a significantly higher frequency in the TSP/HAM group and paralleled the increased levels of MMP-9 and neopterin, a sensitive indicator of cellular immune activation. These data may reflect the intense cell remodeling that occurs intrathecally in inflamed tissue. Changes in MMP, TIMP, and neopterin expression were not related to age at onset of disease, grade of motor disability, progressor status, or duration of disease, presumably indicating that TSP/HAM patients are continuously subjected to viral and immunological pressure. All these observations suggest that TIMPs and MMPs may contribute to the pathogenesis of TSP/HAM, and hence a new therapeutic strategy targeting the MMP/TIMP balance is needed. These observations also suggest that MMP-9 and TIMP-3 in CSF may be useful markers in the follow-up of the efficacy of therapeutic trials in TSP/HAM patients.

Human T lymphotropic virus type I (HTLV-I) infection in neurological patients in Salvador, Bahia, Brazil.

HTLV-I infection represents a major health concern in endemic areas throughout the world, such as Salvador, the main city of Bahia State, with socio-demographic characteristics similar to sub-Saharan African cities, located in the Northeast of Brazil. In order to provide an estimate of the frequency distribution, and range of neurological manifestations potentially related to HTLV-I infection in this city, we conducted a cross-sectional clinical-epidemiological study to determine the prevalence of this infection in patients with neurological diseases. Patients exhibiting vascular diseases, tumoral diseases or trauma were excluded. Over a period of 16 months, we studied 322 consecutive patients with chronic neurological diseases, who attended the neurological clinics of two major hospitals in Salvador. Overall, the prevalence of HTLV-I infection among the patients was 20.9% (67/320). However, the prevalence among the 104 patients with chronic myelopathy was 50.0% (52/104). It was observed that the major prevalence of HTLV-I was between the ages of 40 and 60 years with a female predominance. Our data indicate that, in Salvador city, HTLV-I is associated with chronic myelopathies or myeloneuropathies, which seem to be the only neurological diseases associated with HTLV-I.

Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in HTLV-I-associated myelopathy.

Matrix metalloproteinases (MMPs) have been reported to be involved in inflammatory disorders of the central nervous system (CNS). However, little is known about the role of MMPs in the pathogenesis of HTLV-I-associated myelopathy (HAM)/Tropical spastic paraparesis (TSP). To address this issue, we examined the tissue expression and localization of MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) in the spinal cord lesions of HAM/TSP using immunohistochemistry. In addition, the blood and cerebrospinal fluid (CSF) levels of MMPs and TIMPs of the patients with HAM/TSP were determined using sandwich enzyme immunoassays (SIA) and gelatin zymography. Immunohistochemical studies revealed that collagen IV and decorin immunoreactivity on the basement membrane of CNS parenchymal vessels was partially disrupted where inflammatory mononuclear cells infiltrated in active-chronic lesions of HAM/TSP. In these lesions, MMP-2 (gelatinase A) was immunostained mainly on the surface of foamy macrophages and lymphocytes, whereas MMP-9 (gelatinase B) expression was positive in the intravascular and perivascular mononuclear cells but not on foamy macrophages. In contrast, inactive chronic lesions of the spinal cords of the HAM/TSP contained fewer MMP-2-positive or MMP-9-positive mononuclear cells than active-chronic lesions. Many parenchymal vessels had thickened vascular walls which showed increased immunoreactivity to decorin. SIA revealed that production levels of MMP-2 and MMP-9 in both blood and CSF were higher in the patients with HAM/TSP than those in non-inflammatory other neurological disease controls (ONDs). Using zymography, proMMP-9 was detected more frequently in the CSF of patients with HAM/TSP than those in ONDs. Taken together, our data indicate that MMP-2 and MMP-9 may play an important role in the blood-brain barrier breakdown and tissue remodeling in the CNS of HAM/TSP.

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

The immunopathogenesis of the HTLV-I associated myelopathy (HAM) may be studied by the CSF evaluation. The mechanism of this myelopathy remains unknown. The disturbs of the cellular and humoral immune response observed in HAM patients suggest that the immunological derangement may contribute to the disease mechanisms. For hypothesis, the migration of infected lymphocytes through the blood-brain barrier could have a main role at the pathogenesis of HAM. An increase of the production of cytokines as tumor necrosis factor alpha (TNF alpha) contributes to the migration of lymphocytes through the expression of the intercellular adhesion molecule on the surface of the endothelial cells. On the other side, new knowledges suggest that the imbalance between the production of TNF alpha and its soluble receptor (sTNF-R) could result in the lesive effects of this cytokine in the central nervous system.

Immunological features of HTLV-I myelopathy in Rio de Janeiro, Brazil, and in vitro effects of cyclosporin A.

Brazilian patients with HTLV-1 myelopathy present a significant spontaneous lymphocyte proliferation (SLP), and an increased response to IL-2 exogenous stimulation, in both peripheral blood lymphocytes and in whole blood proliferative assays, when compared to the control group. High antibody titers against HTLV-I antigens were also observed in comparison to healthy seropositive individuals. IL-6 was detected in cerebrospinal fluid (CSF) of 50% of the patients (10 out of 20) and TNF-alpha in four out of nineteen individuals. No correlation was found between the presence of levels of cytokines IL-6 and TNF-alpha and duration or severity of disease. The addition of cyclosporin A (CsA) significantly inhibited SLP suggesting that this therapeutic agent should be studied in HTLV-1 myelopathy. Brazilian patients with HTLV-I myelopathy present the same immunological abnormalities described in other endemic regions. The whole blood assay reflects the same results of separated blood cells and, due to its rapid execution may be used as an assay to follow clinical trials.

HTLV-I associated uveitis, myelopathy, rheumatoid arthritis and Sjogren's syndrome

Uma mulher branca de 62 anos foi internada apresentado história de paraparesia lentamente progressiva durante 10 anos. Dois meses antes da internaçao ela apresentou uveíte anterior nao granulomatosa bilateral. Poucos anos após início dos sintomas neurológicos, ela desenvolveu artrite migratória com edema dos joelhos e dor à palpaçao dos joelhos e dedos dos pés, boca, pele e olhos secos. Ao exame físico foi observado paraparesia espástica com sinal de Babisnski positivo, sensibilidade diminuída abaixo de L3, diminuiçao da sensaçao de vibraçao nas extremidades inferiores, e tremor postural dos membros superiores. Apresentou testes positivos para o HTVL-I no sangue. O estudo da velocidade da conduçao dos nervos foi normal. Este caso mostra a associaçao de uveíte, artrite e síndrome de Sjö em uma paciente com paraparesia espástica tropical (HTLV-I) associada a mielopatia (TSP/HAM), ilustra o largo espectro das manifestaçoes clínicas que podem acompanhar a infecçao por este vírus.

Soluble E-selectin in the serum and cerebrospinal fluid of patients with multiple sclerosis and human T-lymphotropic virus type 1-associated myelopathy.

To evaluate the activation of endothelial cells of the brain and the spinal cord, we investigated the presence of soluble endothelial leukocyte adhesion molecule-1 (sE-selectin) in the serum and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and those with human T-lymphotropic virus type 1-associated myelopathy (HAM). There were significantly higher levels of sE-selectin found in the serum of patients with relapsing-remitting MS during an exacerbation (p < 0.001) and those with chronic progressive MS (p < 0.01) compared with controls. Serum levels of sE-selectin in patients with HAM did not differ significantly from serum levels in controls or non-HAM carriers. We also found sE-selectin in the CSF of eight patients during an exacerbation of relapsing-remitting MS. These results suggest that an active immune reaction involving E-selectin production that is indicative of endothelial cell damage occurs in the CNS of patients during an exacerbation of relapsing-remitting MS. Thus, sE-selectin may be useful in monitoring disease activity in patients with relapsing-remitting MS.

HTLV-1 and myelopathy in Salvador (northeastern Brazil): a case control study.

The principal aim of the study was to determine the degree of association between cerebrospinal fluid (CSF) that is positive for HTLV-1 and myelopathy in Salvador, Brazil. From the same hospital, twenty-eight cases of myelopathy and twenty-eight cases showing no neurological disorder were studied using blind selection matched 1:1 by age and sex. The twenty-eight pairs underwent HTLV-1 serology tests. In those with a positive result, anti-HTLV-1 antibodies were investigated in the CSF. The ELISA method was used, complemented by the Western-blot test. Myelopathy was considered associated with HTLV-1 only when the CSF was positive indicating neurotropism of the virus. The mean age of the cases was 44.6 +/- 15.6 years and the control group was 43.5 +/- 16.0 (p > 0.05). An OR of 9.0 was detected with a reliability interval (95%) of 1.652-48.866 and chi-square significant at the 0.02 level. Despite a strong degree of association and considering the low level of precision, there is a need for analytical studies with larger samples which besides improving the precision will allow for greater control of the confounding variables.

HTLV-1 and myelopathy in Salvador (Northeastern Brazil): a case control study

Procurou-se determinar a magnitude da associçäo entre positividade do líquido cefalorraqueano (LCR) para HTL-1 e mielopatias em Salvador. Foram estudados 28 casos de mielopatias e 28 casos sem doença neurológica, todos procedentes de um único hospital. A seleçäo foi de modo cego, com pareamento 1:1, por idade e sexo. Os 28 pares realizaram sorologia para HTLV-1 e, nos casos com mielopatia, foram pesquisados anticorpos para HTLV-1 no LCR. Na investigaçäo dos anticorpos foram utilizados os métodos ELISA e Western-blot. Os casos tiveram média de idade de 44,6 ñ 15,6 anos e os controles de 43,5 ñ 16,0 (p > 0,05). Observamos um OR=9,0 com intervalo de confiança 95 por cento de 1,652-48,866 e qui-quadrado significante a 0,02. Apesar do grande nível de associaçäo encontrado, estudos analíticos com associaçöes mais amplas säo necessários com o objetivo de melhorar a precisäo e o controle de variáveis intervenientes

HTLV-I-specific cytotoxic T lymphocytes in the cerebrospinal fluid of patients with HTLV-I-associated neurological disease.

Recently, it has been shown that in patients with human T-cell lymphotropic virus type I (HTLV-I)-associated neurological disease, high levels of HTLV-I-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood. These CTLs predominantly recognized products of the pX region of HTLV-I, had a CD8+ phenotype, and were human leukocyte class I restricted. Moreover, these responses were not detected in asymptomatic, HTLV-I-seropositive individuals. This implied a role for these CTLs in the pathogenesis of the neurological disorder associated with HTLV-I. We have extended these observations by demonstrating HTLV-I-specific CTLs directly from lymphocytes obtained from the cerebrospinal fluid of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Uncultured cerebrospinal fluid lymphocytes were used directly as effectors on a variety of targets expressing HTLV-I. These cells were lysed in a virus-specific and HLA class I-restricted manner. Moreover, the cerebrospinal fluid lymphocytes were sorted into purified CD8+ populations, cloned by limiting dilution, and assayed for CTL activity. An exceedingly high proportion of these resultant lines were shown to be cytolytic and precursor frequency analysis indicated that as many as 1 in 500 cells were HTLV-I-specific CTLs. The majority of these CTL lines recognized HTLV-I gene products encoded within the pX region of HTLV-I. The significance of these HTLV-I-specific CTLs in the central nervous system of patients with HTLV-I-associated neurological disease is discussed with regard to the potential role of CTLs in the pathogenesis of this disease.

Neopterin concentrations in serum and cerebrospinal fluid in HTLV-I infected individuals.

The concentration of neopterin was measured in serum samples taken from individuals infected with HTLV-I: 5 from asymptomatic individuals, 1 from a patient with adult T-cell leukaemia and 30 from patients with tropical spastic paraparesis (TSP). In addition, cerebrospinal fluid (CSF) was available from 22 of the TSP patients and neopterin concentrations were determined in these. Elevated levels of neopterin were found in only 3 of the 36 HTLV-I-positive serum samples, all from TSP patients, but significantly elevated neopterin levels were observed in 12 of the 22 CSF samples. The localisation of the elevated neopterin concentrations to the CSF of patients with TSP suggests a marked degree of activation of the cell-mediated immune system intrathecally. This provides further evidence in favour of powerful immune mechanisms operating centrally in the pathogenesis of TSP.