Association of Tuberculosis Status with Neurologic Disease and Immune Response in HTLV-1 Infection
Anselmo SouzaNatália B. CarvalhoYuri Costa Sarno NevesSilvane Braga SantosMaria de Lourdes BastosSérgio ArrudaEduardo Martins NettoMarshall J. GlesbyEdgar M. Carvalho
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The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected individuals have increased susceptibility to Mycobacterium tuberculosis infection but the influence of tuberculosis (TB) on the course of HTLV-1 infection is unknown. The aim of this study was to evaluate the influence of TB on immunological, virologic, and neurologic features of HTLV-1 infection. This is a retrospective analysis of individuals enrolled in a cohort study from an HTLV-1 clinic who were evaluated for past or latent tuberculosis (LTB) and classified clinically as HTLV-1 carriers, probable HAM/TSP and definite HAM/TSP. Spontaneous cytokine production (interferon-gamma [IFN-γ], tumor necrosis factor [TNF], and interleukin[IL]-10), serum chemokines (CXCL9 and CXCL10) and HTLV-1 proviral load were evaluated. Of 172 participants, 64 did not have histories of TB (TB- group), 81 had LTB and 27 had TB in the past (TB+ group). In the TB+ group, there was a higher frequency of HAM/TSP patients (35%) than in HTLV-1 carriers (10%) (OR = 3.8, p = .0001). HAM/TSP patients with histories of TB had higher IFN-γ/IL-10 and TNF/IL-10 ratios when compared with HAM/TSP patients without histories of TB. There were no differences in serum chemokine production and proviral load across TB groups stratified on HTLV-1 clinical status. In conclusion, TB may influence the development of HAM/TSP, and patients with these two diseases have an impairment in the modulation of immune response.Keywords:
Tropical spastic paraparesis
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ABSTRACT: We report the clinical and laboratory findings of six Canadian patients with progressive myelopathy associated with HTLV-1 infection. The diagnosis was suspected on clinical grounds and supported by serological studies and positive gene amplification. Only five had emigrated from an area endemic for HTLV-1 infection. Tropical spastic paraparesis should be considered in all patients with myelopathy, even those without standard serological markers of HTLV-1 infection. The pathogenesis of this condition and the serological and molecular biological means by which this diagnosis can be made are reviewed.
Tropical spastic paraparesis
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Recent studies of tropical spastic paraparesis have confirmed the existence of human T-cell leukemia virus type-1 (HTLVI) in several tropical areas of the world. In order to determine the role of HTLVI as an etiologic agent of myelopathies in Salvador, we conducted a clinical and serological study in 43 patients with non-traumatic and non-tumoral myelopathies. We found 9 patients with HTLVI associated myelopathy (HAM) which points to a new endemic area of HAM.
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Recent reports have demonstrated that human T lymphotropic virus type 1 (HTLV-1) is associated with other neurological abnormalities in addition to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It has been well established that high HTLV-1 proviral loads are associated with the development of HAM/TSP. We now demonstrate, for the first time, to our knowledge, that HTLV-1 proviral loads in patients with other neurological abnormalities are also significantly higher than in asymptomatic HTLV-1 carriers.
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Human T-cell virus-1 associated myelopathy/Tropical Spastic Paraparesis is a chronic progressive neurological disorder with dominant features affecting the pyramidal tract and posterior column. It has of recent been unequivocally linked to a viral infection, Human Lymphotropic T Virus infection is estimated to infect about 10-20million people worldwide. Its geographical distribution varies with area of high prevalence in the Caribbean, southern Japan and Africa. Human T-cell lymphtropic virus-1 associated myelopathy/tropical spastic paraparesis is more common in thetropics and present as a non-compressive, slowly progressive symmetrical paraparesis of the lower extremities with signs of pyramidal tract involvement. We reviewed the clinical features and the management of two cases of Human T-cell lymphtropic virus-1 associated myelopathy/tropical spastic paraparesis. A literature review of Human T-Cell virus-1 associated myelopathy / tropical spastic paraparesis.
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Paired cerebrospinal fluid (CSF) and serum samples from 52 Italian patients affected by myelopathy of unknown origin (MUO) were tested for the presence of antibodies to human T cell lymphotrophic virus type I (HTLV-I) by an enzyme-linked immunosorbent assay, in an attempt to demonstrate a common retroviral origin of MUO, tropical spastic paraparesis (TSP) and HTLV-I-associated myelopathy (HAM). All the patients complained of weakness to the legs, while weakness to the arms, mild sensory disturbances, impaired bladder and bowel functions, and impotence were present in different percentages. All CSF and serum samples were devoid of HTLV-I antibodies. The possible relations between MUO, TSP and HAM are discussed.
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We studied 57 patients with congenital muscular dystrophy (CMD) and among them 40 were assessed for 5-laminin chains (alfpha-1, alpha-2, beta-1, beta-2, and gamma-1) by immunohistochemistry on the muscular biopsy, and 7 only for alpha-2 laminin (merosin).Of the 47 patients assessed for merosin, 22 were merosin-deficient and 25 merosin-positive, including two typical cases of Walker-Warburg syndrome with "cobblestone" lissencephaly, hydrocephalus, severe mental retardation, microphthalmia and other ocular abnormalities.A subgroup of 7 patients with merosin deficiency showed only a partial reduction that was detected by both antibodies for alpha-2 80 kDa and alpha-2 300 kDa in 6 and only by the antibody for alpha-2 300 kDa in one, thus demonstrating that the antibody for alpha-2 300 kDa offers a more precise immunohistochemical detection of the partially deficient type of CMD.Twenty-one merosin-deficient patients had abnormal T2 sequence signal of white matter on magnetic resonance imaging (MRI) and one had hypodensity of brain white matter on computerized tomography (CT) scanning; no patient in this group achieved independent walking except one with partial deficiency who after a period of independent walking lost it at the end of the first decade of life.Among the remaining patients with partial deficiency of merosin we observed that three patients with complete absence of one merosin fragment and reduction of the other showed a more severe clinical phenotype than other three who had a partial expression of both fragments.The immunohistochemical pattern of the remaining merosin chains in 19 merosin-deficient patients who had complete immunohistochemical analysis of laminin chains on muscle biopsy was characterized by overexpression of alpha-1 chain in 100% and weakly reduced expression of beta-1, beta-2 and gamma-1 chains in 89.5%, 73.7% and 57.9%, respectively.Excluding the two cases with Walker-Warburg syndrome, in addition to the remaining 23 merosinpositive patients we included 5 familiar cases without biopsy whose phenotype was identical to the respective siblings.Of the last 5 patients without any immunohistochemical analysis, three had abnormal white matter on brain MRI and severe muscle involvement and were included within the merosin-deficient group and two had respectively mild and moderate clinical phenotype, one of them with no abnormalities of brain white matter on CT scanning, while the other did not perform neuroimaging examination.Both patients were included among merosin-positive group.In the total group of 30 merosin-positive patients, 70% achieved independent walking and among 19 who had a complete immunohistochemical analysis of laminin chains, 31.6%showed alpha-1 overexpression, and 26.3%, 21.1% and 21.1% showed a slight reduction of expression of beta-1, beta-2 and gamma-1 laminin chains, respectively.Considering the total amount of patients with and without immunohistochemical study, we observed homogeneous clinical severity in the merosin-deficient group (25 cases) and strong clinical heterogeneity in the merosin-positive group (30 cases), that included 5 cases with associated central nervous system involvement (brain cortical atrophy in one and mental retardation in 4, two of them also with cataracts), two possible cases of rigid spine syndrome and one possible case of hypotonic-sclerotic type of CMD.Statistical analysis between the two groups was done and there was a significant difference regarding many different parameters.In relation to clinical phenotype -age of onset, poor sucking and respiratory distress at birth, degree of congenital hypotonia, maximal motor capacity, muscular weakness, facial involvement, facial dysmorphism, creatine kinase level, and type of clinical course -showed statistical significance and pointed to a prognosis much more severe in merosin-deficient patients.In relation to muscle biopsy -lipomatosis, endo-perimysial fibrosis, and variation in fiber size -were significantly higher in the merosin deficien group.Finally, also the results of the immunohistochemical analysis showed that both -the overexpression of alpha-1 chain, and the slight reduction of beta-1, beta-2 and gamma-1 chains expression -were significantly more marked in the merosin-deficient type of CMD.
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HTLV-I—associated myelopathy/tropical spastic paraparesis (HAM/TSP) is endemic in the Caribbean basin and Japan. Because of the close proximity of the United States to the Caribbean and the presence of HTLV-I-seropositive persons in the United States, we sought reports of patients who were HTLV-I-seropositive and had a slowly progressive myelopathy. Over a 2-year period, there were 25 patients reported, 19 of whom were black and 12 of whom had been born in the United States. All patients except two had become symptomatic while living in the United States. Six patients had no apparent risk factor for acquiring HTLV-I. These data demonstrate that HAM/TSP is occurring in the United States and that the diagnosis of HAM/TSP should be considered in patients with a slowly progressive myelopathy regardless of risk factors for acquiring HTLV-I.
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Human T-lymphotropic Virus type 1 (HTLV-1) is associated with a myelopathy (namedHTLV-associated myelopathy/Tropical Spastic Paraparesis–HAM/TSP). Thrombospondin-1 (TSP-1) is a matrix protein which interferes with cell adhesion, motility, and proliferation. The expression levels of the mRNA for this protein were evaluated in HTLV-1 infected individuals: 11 asymptomatic, 18 with myelopathy or oligosymptomatic, and 13 non-infected participants. RNA from peripheral blood mononuclear cells was submitted to TSP-1 RT-PCR analysis. The number of individuals expressing thrombospondin-1 was more frequent in the symptomatic group (14/18, p=0.007). In general, a tendency to higher values of the protein´s mRNA was observed in the HTLV-1-infected group (p=0.062). The highest mRNA TSP-1 expression levels were detected at the beginning of the clinical symptoms of myelopathy. Additional studies with larger sample sizes are deemed to further elucidate the role of this matrix protein in the inflammatory network related to the HTLV-associated myelopathy/Tropical Spastic Paraparesis.
Tropical spastic paraparesis
Asymptomatic carrier
Human T-lymphotropic virus
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Abstract Using the polymerase chain reaction, we quantitated the amount of human T‐lymphotropic virus type I (HTLV‐I) proviral DNA in peripheral blood mononuclear cells from 18 patients with HTLV‐I–associated myelopathy/tropical spastic paraparesis; 17 HTLV‐I carriers without HTLV‐I–associated myelopathy/tropical spastic paraparesis, with or without other autoimmune or inflammatory diseases; and 19 seronegative control subjects. The HTLV‐I proviral DNA was 10‐ to 100‐fold higher in the patients and in the HTLV‐I carriers without HAM/TSP who had autoimmune or inflammatory diseases than in the carriers without autoimmune or inflammatory diseases. The patients who had had onset of myelopathy at a younger age (15 to 39 years) had an extremely high level of HTLV‐I proviral DNA in the early phase, as compared with findings in those with a late onset of myelopathy (at 44 to 61 years). The large increase in HTLV‐I proviral DNA in peripheral blood mononuclear cells is presumably closely related to the development of autoimmune or inflammatory processes in HTLV‐I carriers, including HTLV‐I–associated myelopathy/tropical spastic paraparesis.
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HTLV-I (Human T-lymphotropic virus type I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immunomediated myelopathy induced by the HTLV-I. Some patients, specially those from Japan, seem to have a good response to steroid treatment. However, this has not been found in other regions of the world. High dose intravenous methylprednisolone has been used with success in patients with relapses of multiple sclerosis (MS), another autoimmune disease of the central nervous system. To test the effectiveness of methylprednisolone in patients with HAM/TSP, we devised an open trial in 23 patients. We found a very limited benefit of this form of treatment in these patients. Only one patient, who had the shortest disease duration (five months) in the whole group, showed a sustained benefit. We speculate that those patients with a shorter history, with presumably less demyelination and more inflammatory lesions, would show a better response to immunosuppressive treatments.
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