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PubMed1996

High activated and memory cytotoxic T-cell responses to HTLV-1 in healthy carriers and patients with tropical spastic paraparesis.

The cytotoxic T-lymphocyte (CTL) response to HTLV-1 is directed mainly against the Tax protein. Circulating, activated Tax-specific CTL can be found in a majority of healthy carriers and patients with the HTLV-1-associated disease tropical spastic paraparesis (HAM/TSP). In this study we present data on the Tax-specific CTL response of 26 HTLV-1 carriers, including 10 newly recruited subjects. Rex-specific CTL were not found in any subjects investigated. Activated and memory CTL responses were determined separately in 4 healthy carriers, 3 HAM/TSP patients, and 1 "seronegative HAM/TSP." In all subjects, the mean frequency of peptide-specific memory cells per epitope (1/1307) was high. There was no significant difference in mean memory CTL frequency per epitope or in the proportion of subjects with activated CTL between healthy carriers and HAM/TSP patients. One individual with HAM/TSP had an unusually high frequency response to two peptides, suggesting immunodominance of epitope recognition in this individual. We conclude that the magnitude and components of the HLTV-1-specific CTL response do not differ between healthy carriers and HAM/TSP patients. These data do not support a specific CTL-mediated component in the pathogenesis of HAM/TSP.

Amino Acid Sequence↗

PubMed1991

Multiple sclerosis, tropical spastic paraparesis and HTLV-1 infection in Afro-Caribbean patients in the United Kingdom.

Forty four consecutive patients of Afro-Caribbean origin resident in the United Kingdom (UK) were studied, based on a provisional diagnosis of myelopathy of unknown cause, tropical spastic paraparesis (TSP) or multiple sclerosis (MS). Of 30 patients with progressive paraparesis 27 had serum antibodies to HTLV-1 and were classified as having TSP. Fourteen patients fulfilled the criteria for MS and none of 12 tested had HTLV-1 antibodies. All the TSP patients and nine of those with MS were born in the West Indies. Five of the West Indianborn MS patients had migrated to the UK after adolescence but the duration of residence in the UK before symptoms of MS developed was similar to those born in the UK (average 18 years). The features that differentiated MS from TSP patients, apart from HTLV-1 status, included clinical evidence of cranial nerve involvement, more extensive abnormalities on the brain and cervical cord MRI and asymmetry of the VEP latency increase, all of which were more frequent in the MS group. Of the three patients without a diagnosis one, born in the UK, had marked abnormalities on MRI of the brain indistinguishable from those seen in MS.

Adult↗

PubMed1995

In vivo proviral burden and viral RNA expression in T cell subsets of patients with human T lymphotropic virus type-1-associated myelopathy/tropical spastic paraparesis.

We used in situ hybridization combined with immunocytochemistry, cell sorting, and the polymerase chain reaction (PCR) to investigate clinical events in three asymptomatic carriers of human T lymphotrophic virus type-1 (HTLV-1) and ten patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The objective was to determine which T cell subset of peripheral blood mononuclear cells (PBMC), CD4 or CD8, were infected by HTLV-1 and the manner in which HTLV-1 proviral DNA was expressed at the level of the single cell. Both CD4-positive and CD8-positive cells of the PBMC from five patients with HAM/TSP were infected with HTLV-1. The proportion of HTLV-1-infected cells was 2.5-40% in the CD4-positive subset and 1.0-65% in the CD8- positive subset, when quantified by PCR using HTLV-1-infected MT2 cells as a positive standard. Proviral DNA of HTLV-1 was expressed in both CD4-positive cells and CD8-positive cells of the PBMC from six patients with HAM/TSP and three asymptomatic HTLV-1 carriers. In patients with HAM/TSP, the proportion of the cells expressing HTLV-1 proviral DNA was 0.02-0.1% in both subsets. In asymptomatic carriers, the expression of HTLV-1 proviral DNA was 0.01-0.02% in the CD4-positive subset and 0.01% in the CD8-positive subset. Therefore, HTLV-1 possessed similar in vivo cellular tropism for both CD4-positive cells and CD8-positive cells and HTLV-1 proviral DNA was expressed in vivo in both circulating T cell subsets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

[The diagnostic course in patients with hereditary ataxias and hereditary spastic paraparesis].

A postal questionnaire was sent to all patients affected by hereditary ataxias and hereditary spastic paraparesis resident in the province of Turin (Italy) to study their diagnostic process. A 61% response rate was obtained. The mean time interval between onset and diagnosis was 6 years (1 to 32 years). The percentage of late diagnoses dropped from 59% before 1959 to 19% after 1970, mostly because a reduction of the interval between symptom onset and the first contact with the general practitioner. The onset with dysarthria and ataxia led to earlier neurologic consultation, but the whole time requested for the diagnosis was not modified. A reduction of the time needed for the diagnostic process may be important to address the family to an early genetic counselling.

Age Factors↗

PubMed1989

Comparison of a human T-cell lymphotropic virus type I strain from cerebrospinal fluid of a Jamaican patient with tropical spastic paraparesis with a prototype human T-cell lymphotropic virus type I.

The isolation and characterization of a human T-cell lymphotropic retrovirus related to human T-cell lymphotropic virus type I (HTLV-I) from cerebrospinal fluid of a Jamaican patient with tropical spastic paraparesis is described. The virus isolate is a typical type C retrovirus as seen by electron microscopy and is related to prototype HTLV-I isolated from patients with adult T-cell leukemia but is not identical to this prototype HTLV-I as seen by restriction enzyme mapping.

Aged↗

PubMed1990

[Familial spastic paraparesis: phenotypic variant of adrenoleukodystrophy].

Two brothers developed a slowly progressive paraparesis during adulthood, lately associated in one to primary adrenal and gonadal insufficiency but no electrophysiological evidence of peripheral nerve involvement. Both patients and an asymptomatic sister had increased plasma concentrations of very-long chain fatty acids (VLCFA). A CT-scan of the propositus was initially normal but showed at follow-up diffuse white matter hypodensities consistent with severe demyelination of the centrum semiovale. The appearance of the lesions remained unchanged for the next two years without clinical evidence of supraspinal changes in despite of progression of the paraparesis. We believe that these observations further support a link between the severe infantile variety of adrenoleukodystrophy and the more protracted adult-onset variants. Further, CT-scan in families with spastic paraparesis may be of help in detecting early evidence of an underlying diffuse white matter disorder, eventually supported by more conclusive studies as VLCFA determinations.

Adrenoleukodystrophy↗

PubMed1999

Detection of human T-lymphotropic virus type I p40tax protein in cerebrospinal fluid cells from patients with human T-lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis.

We investigated the role of viral transcripts of human T-lymphotropic virus type I (HTLV-I) in the cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs) of patients with human T-lymphotropic virus type I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). To detect the HTLV-I p40tax protein, we developed a new sensitive method of immunohistochemistry combined with tyramide signal amplification and quantitative analysis. Seven patients with HAM/TSP were examined. As controls, four patients with other neurological diseases were examined; two of these patients were infected with HTLV-I and the other two were not. Both the CSF cells and PBMCs were reacted with a monoclonal antibody, Lt-4, for p40tax protein, followed by secondary antibody labeled with horseradish peroxidase. This was visualized by fluorescein directly labeled with tyramide and the number of positive cells was quantified with a Laser Scanning Cytometer. In the samples from patients with HAM/TSP, the HTLV-I p40tax protein was successfully detected by tyramide signal amplification, but not without it. In HAM/TSP patients, 0.04-1.16% of the CSF cells and 0.02-0.54% of PBMCs were positive for the HTLV-I p40tax protein, respectively. The expression of the HTLV-I p40tax protein in the CSF cells was more frequent than that in PBMCs in both HAM/TSP patients and HTLV-I carriers, and was also more frequent in the patients with HAM/TSP of shorter duration of illness. This technique could be a powerful tool to investigate the pathogenic mechanism of diseases associated with HTLV-I.

Adult↗

PubMed2001

Human T cell leukemia virus Type I (HTLV-I) infection induces greater expansions of CD8 T lymphocytes in persons with HTLV-I-associated myelopathy/tropical spastic paraparesis than in asymptomatic carriers.

A quantitative study of the T cell receptor repertoire was performed ex vivo on CD4 and CD8 T cell subsets of human T cell leukemia virus type I (HTLV-I)-infected asymptomatic carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Indexes of oligoclonality that compiled all repertoire modifications were calculated for peripheral blood mononuclear cells and for CD4 and CD8 T cell subsets. Both patients with HAM/TSP and asymptomatic carriers had greater T lymphocyte expansions than did uninfected donors, which was independent of age and at least twice higher in the CD8 than in the CD4 cell compartment. Some expanded CD8 T cells corresponded to cytotoxic T lymphocytes directed against various epitopes of the immunodominant Tax protein. Patients with HAM/TSP had significantly higher CD8 cell expansions than did asymptomatic carriers. These results highlight the prognostic value of measuring CD8 T cell expansions during follow-up of HTLV-I infection.

Adult↗

PubMed2004

Polymorphism in the interleukin-10 promoter affects both provirus load and the risk of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis.

To investigate non-human leukocyte antigen candidate genes that influence the outcome of human T cell lymphotropic virus (HTLV) type I infection, we analyzed 6 single-nucleotide polymorphisms in the interleukin (IL)-10 promoter region in 280 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and 255 HTLV-I-seropositive asymptomatic carriers from an area where HTLV-I is endemic. The IL-10 -592 A allele, which shows lower HTLV-I Tax-induced transcriptional activity than the C allele in the Jurkat T cell line, was associated with a >2-fold reduction in the odds of developing HAM/TSP (P=.011; odds ratio [OR], 0.50 [95% confidence interval, 0.30-0.86]) by reducing the provirus load in the whole cohort (P=.009, analysis of variance). Given the OR and the observed frequency of IL-10 -592 A, we demonstrate that this allele prevents approximately 44.7% (standard deviation, +/-13.1%) of potential cases of HAM/TSP, which indicates that it defines one component of the genetic susceptibility to HAM/TSP in the cohort.

Alleles↗

PubMed2003

A cluster of human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis in Jujuy, Argentina.

Compared with other regions in Argentina, greater human T-cell lymphotropic virus type I (HTLV-I) seroprevalence has been reported in Jujuy Province, where it reaches 2.32% in the general population, so that a search for HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) cases deserved to be carried out. Accordingly, a clinically diagnosed and serologically confirmed cluster of cases in 1 man and 10 women, including 2 sisters, is described here. Most patients (9/11) were born in Cochinoca Department, located in an Andes highland area called Puna Jujeña, situated at more that 3400 m above sea level. No history of risk factors was disclosed, except for a single transfusion in 1 patient. In contrast to the Andean region of Bolivia, where high HTLV-I seroprevalence is in part attributable to Japanese immigrants, the Jujuy population mainly consists of aborigines, mestizos, and European descendants. Therefore, the long-term presence of virus in Jujuy natives may be taken for granted. Considering the HAM/TSP cluster described here plus previously reported isolated cases in neighboring Salta Province, we speculate that the Puna Jujeña region and regions in that vicinity would be a microepidemic focus of disease. To determine the role of possible pathogenic cofactors such as geographic, ethnic, genetic, and cultural features, further pertinent surveys are required in subtropical northwestern Argentina.

Argentina↗

PubMed1995

Adult T cell leukemia following HTLV-I-associated myelopathy/tropical spastic paraparesis: case reports and implication to the natural course of ATL.

Adult T cell leukemia (ATL) is the T cell malignancy caused by human T lymphotropic virus type I (HTLV-I), and HTLV-I is also the causative agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although HTLV-I causes both diseases, concomitant occurrence is reported to be rare. This paper describes two cases of HAM/TSP that developed into lymphoma-type ATL after the onset of HAM/TSP. In one case, the same HTLV-I infected clone could be detected by polymerase chain reaction in peripheral blood obtained when the patient was diagnosed as HAM/TSP. This finding showed that the HTLV-I clone already existed at the stage of HAM/TSP. Since frequent detection of clonal proliferation of HTLV-I infected cells has been reported previously in patients with HAM/TSP, careful follow-up is needed for patients with HAM/TSP.

Base Sequence↗

PubMedDate not supplied

HTLV-I serostatus of mothers of patients with adult T-cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis.

OBJECTIVES: It has been shown that > 90% of mothers of HTLV-I-infected children were themselves carriers of HTLV-I. This study was designed to determine the HTLV-I serostatus of mothers of patients with adult T-cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and to assess the association of age of exposure and disease outcome. STUDY DESIGN/METHODS: In a cross-sectional study of the HTLV-I serostatus of mothers of HTLV-I-seropositive patients with ATL and HAM/TSP, 36 living mothers of patients with ATL and 15 mothers of patients with TSP/HAM were traced and enrolled. RESULTS: Five of the 15 (33%) mothers of patients with HAM/TSP and 35 of the 36 (97.2%) mothers of patients with ATL were HTLV-I-seropositive. All patients were breast-fed and none received blood transfusions. CONCLUSION: This study confirms that infection with HTLV-I in early childhood can lead to ATL in later life, and that HAM/TSP can also result from early infection but more commonly results from infection acquired in adulthood. There are several reports of posttransfusion HAM/TSP, but ATL has not been reported following blood transfusion except in patients who were immunocompromised. Because the newborn infant is considered to be immunoincompetent, it seems that this is a necessary factor for the development of ATL after infection.

Adolescent↗

PubMed1993

[Familial cases of spastic paraparesis, mental disturbance and thinning of the corpus callosum].

We reported a family in which two brothers and one sister out of five siblings were affected by a neurological disease showing the following clinical manifestations: 1) intellectual disturbance with relative preservation of memory and orientation probably developed on child food, 2) spastic paraparesis beginning at the age of about 20 years, 3) mild peripheral neuropathy and cerebellar sign. Their clinical courses were stereotyped, and so much the worse in elder patients. Two of them were investigated in detail. Laboratory findings including chromosomal analysis, amino acid analysis and thyroid function were normal. HTLV-1 antibody was negative. Several lymphocytes lysosomal enzymes including beta-hexosaminidase and arylsulfatase A and serum very long fatty acids were also within normal range. CT and MRI showed characteristic thinning of corpus callosum, dominant in anterior portion. However, changes in intensity of white matter in T2 weighted image were not so prominent. In the older patient, more mentally deteriorated, were demonstrated hypoperfusion in the fronto-parietal lobes by SPECT and slow wave bursts dominant in the same region by EEG. Therefore, we considered that the change of corpus callosum was hypoplasia, but not atrophy, and it may provoke dysfunction of relevant nervous system. Family cases of such clinical feature were rare. We could confirm only three families in literatures, all of them were Japanese.

Adult↗

PubMed1997

HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP): a chronic progressive neurologic disease associated with immunologically mediated damage to the central nervous system.

This review examines information on clinical, pathological and immunological events in the slowly progressive neurologic disorder associated with the human T lymphotropic virus type-I (HTLV-I) termed HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). The role of cellular immune responses to HTLV-I in patients with HAM/TSP and how these responses may be associated with the pathogenesis of this disorder will be discussed. While a number of immunologic responses have been shown to be abnormal in HAM/TSP patients, studies on HTLV-I specific cytotoxic T cell responses (CTL) will be specifically examined. By defining such antigen specific functional cellular host responses to HTLV-I we hope to better understand the underlying mechanisms that may be involved in the neuropathology of HTLV-I associated neurologic disease. This has led to a number of HTLV-I associated immunopathogenic models that may be operative in HAM/TSP patients. Importantly, based on these models, potential immunotherapeutic strategies for disease intervention can be devised. Moreover, such an analysis may have significant implications for our understanding of other HTLV-I associated clinical disorders and other neurological diseases in which viral etiologies have been suggested.

Adolescent↗

PubMed2005

Involvement of p38 MAPK signaling pathway in IFN-gamma and HTLV-I expression in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

We analyzed the relationship between the expression of interferon (IFN)-gamma and HTLV-I p19 antigen and activation of p38 mitogen-activated protein kinase (p38 MAPK) in two HTLV-I-infected T cell lines derived from two patients (HCT-1 and HCT-4) with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and three HTLV-I-infected T cell lines derived from three patients with adult T cell leukemia (ATL). Expression of phosphorylated (activated)-p38 MAPK was markedly increased concomitant with high levels of both IFN-gamma and HTLV-I p19 antigen expression in both HCT-1 and HCT-4 compared with cell lines derived from ATL patients. Treatment with SB203580, a specific inhibitor of p38 MAPK, suppressed IFN-gamma and HTLV-I p19 antigen expression levels in HCT-1, HCT-4 and peripheral blood CD4(+) T cells of HAM/TSP patients. These findings strongly suggest that activation of p38 MAPK signaling pathway is involved in the up-regulation of IFN-gamma expression with high HTLV-I proviral load in HAM/TSP patients.

Adult↗

PubMed2000

Hypoxanthine-guanine phosphoribosyltransferase reporter gene mutation for analysis of in vivo clonal amplification in patients with HTLV type 1-associated Myelopathy/Tropical spastic paraparesis.

We tested a surrogate selection approach utilizing mutation at a reporter gene [hypoxanthine-guanine phosphoribosyltransferase (hprt)] as a probe for in vivo cell division, for detection of clonal T cell expansion in human T lymphotropic (HTLV-1) carriers. Peripheral blood samples from HTLV-1-infected individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) were tested to determine the hprt mutant frequency (Mf). Wild-type and hprt mutant T cell clones were isolated, and clonal identity determined by multiplex PCR and DNA sequencing of T cell receptor (TCR) variable region beta-chain (TCR BV) and third complementarity determining regions (CDR3). Seven samples from HAM/TSP patients were tested, and Mfs were within the normal range for adults (mean 11.3 x 10(-6), max 22.4 x 10(-6), min 5.6 x 10(-6)). The frequency of HTLV-1 infection in wild-type and hprt mutant T cells from HAM/TSP patients was determined to identify enrichment in the mutant fraction of cells. This analysis was performed on 196 isolates from 6 individuals with HAM/TSP. In each case, there is enrichment for virally infected cells in the hprt mutant fraction of isolates. Ten mutant and eight wild-type isolates from sample LS42A (Mf 8.4 x 10(-6)) were tested for clonality by TCR BV PCR and sequencing. Of the 10 hprt mutants, there were two in vivo-expanded clones (four isolates with two identical TCRs, or 80% unique TCR sequences). These studies may provide new insights into the precise mechanism of HTLV-1 leukemogenesis, and aid in the study of mutator phenotypes generated by a combination of Tax-mediated in vivo expansion and mutagenesis.

Clone Cells↗

PubMed1998

Cognitive impairment in families with pure autosomal dominant hereditary spastic paraparesis.

In the course of a study of a large family with pure autosomal dominant hereditary spastic paraparesis (AD-HSP), mild cognitive impairment was found in older family members. In order to determine if cognitive impairment occurred more frequently in families with pure AD-HSP than normally expected, a case control study of cognitive function in HSP was undertaken. Thirty-one patients, from 12 kindreds with pure AD-HSP, matched with 31 healthy control subjects for age, sex and years of education, were assessed for evidence of cognitive impairment using the Cambridge Cognitive Examination (CAMCOG). Twenty unaffected siblings matched with twenty healthy control subjects were similarly assessed. The total CAMCOG score in the affected group (mean 89.26/107, SD 11.08, 95% confidence interval 85.2-94.49) compared with the control group (mean 96.52/107, SD 5.52, 95% confidence interval 94.49-98.54) was significantly reduced (P = 0.0003). There were also significant abnormalities in three out of the nine subsets including memory (P = 0.0002), language comprehension (P = 0.0166) and language expression (P = 0.0025). The differences between the groups were due to cognitive impairment appearing after the age of 50 years in patients with AD-HSP; CAMCOG scores before this age were similar to control scores. There was also a minor non-significant difference in total CAMCOG score for the unaffected siblings (mean 93.7/107, SD 8.54, 95% confidence interval 89.70-97.70) compared with the control group (mean 97.9/107, SD 4.61, 95% confidence interval 95.7-100.1) (P < 0.02). This study demonstrates that mild cognitive impairment develops after the age of 50 years in patients with pure AD-HSP and is further evidence of degeneration in other systems in this disorder.

Adult↗

PubMed1996

The association of antibodies against human T cell lymphotropic virus type I (HTLV-I) pX gene mutant products with HTLV-I-associated myelopathy/tropical spastic paraparesis.

Antibodies specific for the products of the human T cell lymphotropic virus type I (HTLV-I) pX frame-shift mutants were studied by ELISA. The serum IgG antibodies to the synthetic peptide corresponding to one nucleotide insertion at position 7784 were significantly more common in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients than in HTLV-I carriers who had neither HAM/TSP nor adult T cell leukemia (39% vs. 5%). The seropositivities to the other synthetic peptides, which corresponded to the one nucleotide deletion at position 7475 and the internal deletion of nt 7754-7819 and nt 7853-7936, were rare. A genetic study confirmed the presence of the responsible mutation of the pX gene in peripheral blood mononuclear cells and central nervous system tissue from HTLV-I-infected subjects with and without HAM/TSP. These results suggest that HTLV-I pX frame-shift mutants are expressed in vivo in HTLV-I carriers; they also induce antibodies. especially in those with HAM/TSP.

Adult↗