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Plasma proteome analysis in HTLV-1-associated myelopathy/tropical spastic paraparesis.

ABSTRACT: Human T lymphotropic virus Type 1 (HTLV-1) causes a chronic inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM) which resembles chronic spinal forms of multiple sclerosis (MS). The pathogenesis of HAM remains uncertain. To aid in the differential diagnosis of HAM and to identify pathogenetic mechanisms, we analysed the plasma proteome in asymptomatic HTLV-1 carriers (ACs), patients with HAM, uninfected controls, and patients with MS. We used surface-enhanced laser desorption-ionization (SELDI) mass spectrometry to analyse the plasma proteome in 68 HTLV-1-infected individuals (in two non-overlapping sets, each comprising 17 patients with HAM and 17 ACs), 16 uninfected controls, and 11 patients with secondary progressive MS. Candidate biomarkers were identified by tandem Q-TOF mass spectrometry.The concentrations of three plasma proteins--high [?2-microglobulin], high [Calgranulin B], and low [apolipoprotein A2]--were specifically associated with HAM, independently of proviral load. The plasma [?2-microglobulin] was positively correlated with disease severity.The results indicate that monocytes are activated by contact with activated endothelium in HAM. Using ?2-microglobulin and Calgranulin B alone we derive a diagnostic algorithm that correctly classified the disease status (presence or absence of HAM) in 81% of HTLV-1-infected subjects in the cohort.

SUBMITTER: Kirk PD

PROVIDER: S-EPMC3210102 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Plasma proteome analysis in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Kirk Paul D W PD Witkover Aviva A Courtney Alan A Lewin Alexandra M AM Wait Robin R Stumpf Michael P H MP Richardson Sylvia S Taylor Graham P GP Bangham Charles R M CR

Retrovirology 20111012

<h4>Background</h4>Human T lymphotropic virus Type 1 (HTLV-1) causes a chronic inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM) which resembles chronic spinal forms of multiple sclerosis (MS). The pathogenesis of HAM remains uncertain. To aid in the differential diagnosis of HAM and to identify pathogenetic mechanisms, we analysed the plasma proteome in asymptomatic HTLV-1 carriers (ACs), patients with HAM, uninfected con ...[more]

PMID: 21992623

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Project description:BACKGROUND:As human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neurological disease, large scale studies to collect continuous clinical data have been difficult to conduct. Therefore, the incidence of comorbidities and drug utilization data remain unknown. When conducting trials to develop new drugs in rare disease such as HAM/TSP, historical control data obtained from registry studies would be useful, as cohorts in rare disease tend to be small. Long-term follow-up of patients with a chronic disease can also be challenging. In this study, we addressed the following two goals using registry data on patients (n?=?486) enrolled in the Japanese HAM/TSP patient registry "HAM-net" from 2012 to 2016: 1) to clarify the epidemiological information of HAM/TSP such as the incidence of comorbidities and drug utilization and 2) to provide the real-world data on changes in lower limb motor dysfunction. RESULTS:In HAM-net-registered patients, common comorbidities were fractures, herpes zoster, and uveitis, with incidences of 55.5, 10.4, and 6.5, respectively, per 1000 person-years. Every year, oral steroid treatment was administered in 48.2-50.7% of the HAM-net-registered patients and interferon-? treatment was used in 2.6-3.5% of patients. The median dose of oral prednisolone was low at 5.0?mg/day. The incidence of fractures and herpes zoster tended to be higher in the steroid-treated group than in the untreated group (fractures: 61.0 vs. 48.3, herpes zoster: 12.7 vs. 8.8, per 1000 person-years). The analysis of chronological change in Osame motor disability score (OMDS) indicated that the mean change in OMDS was +?0.20 [95% confidence intervals (CI): 0.14-0.25] per year in the one-year observation group (n?=?346) and?+?0.57 (95% CI: 0.42-0.73) over four years in the four-year observation group (n?=?148). Significant deterioration of OMDS was noted in all subgroups with varying steroid use status. CONCLUSIONS:This study revealed the incidence of comorbidities and drug utilization data in patients with HAM/TSP using registry data. Furthermore, this study provided real-world data on chronological changes in lower limb motor dysfunction in patients with HAM/TSP, indicating the utility of these data as historical controls.

Project description:BackgroundAlthough human T-lymphotropic virus type 1 (HTLV-1) infection is a prerequisite for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), specific provirus mutations in HAM/TSP have not yet been reported. In this study, we examined whether HAM/TSP patients had the disease-specific genomic variants of HTLV-1 by analyzing entire sequences of HTLV-1 proviruses in these patients, including familial cases. In addition, we investigated the genetic variants of host restriction factors conferring antiretroviral activity to determine which mutations may be related to resistance or susceptibility to HAM/TSP.ResultsThe subjects included 30 patients with familial HAM/TSP (f-HAM/TSP), 92 patients with sporadic HAM/TSP (s-HAM/TSP), and 89 asymptomatic HTLV-1 carriers (ACs). In all 211 samples, 37 samples (18%) were classified into transcontinental subtype and 174 samples (82%) were classified as Japanese subtype. Among three groups, the percentage of transcontinental subtype in f-HAM/TSP, s-HAM/TSP and ACs was 33, 23 and 7%, respectively. The frequency of transcontinental subtype was significantly higher in both f-HAM/TSP (p < 0.001) and s-HAM/TSP (p < 0.001) than in ACs. Fifty mutations in HTLV-1 sequences were significantly more frequent in HAM/TSP patients than in ACs, however, they were common only in transcontinental subtype. Among these mutations, ten common mutations causing amino acid changes in the HTLV-1 sequences were specific to the transcontinental subtype. We examined host restriction factors, and detected a rare variant in TRIM5α in HAM/TSP patients. The patients with TRIM5α 136Q showed lower proviral loads (PVLs) than those with 136R (354 vs. 654 copies/104 PBMC, p = 0.003). The patients with the 304L variant of TRIM5α had significantly higher PVLs than those with 304H (1669 vs. 595 copies/104 PBMC, p = 0.025). We could not find any HAM/TSP-specific mutations of host restriction factors.ConclusionsTranscontinental subtype is susceptible to HAM/TSP, especially in familial cases. Ten common mutations causing amino acid changes in the HTLV-1 gene were specific to the transcontinental subtype. TRIM5α polymorphisms were associated with PVLs, indicating that TRIM5α could be implicated in HTLV-1 replication.

Project description:BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP.Methodology/principal findingsPeripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined "deteriorating HAM/TSP" as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS)) over four years and "stable HAM/TSP" as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set.Conclusions/significanceAs the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials.

Project description:BackgroundUrinary dysfunction is one of the main features of human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive assessment of the severity is difficult because a standardized assessment measure is unavailable. Therefore, this study aimed to develop a novel symptom score for the assessment of urinary dysfunction in HAM/TSP. We interviewed 449 patients with HAM/TSP using four internationally validated questionnaires for assessment of urinary symptoms (27 question items in total): the International Prostate Symptom Score; the International Consultation on Incontinence Questionnaire-Short Form; the Overactive Bladder Symptom Score; and the Nocturia Quality-of-Life questionnaire. We developed a symptom score based on the data of 322 patients who did not use urinary catheters by selecting question items from questionnaires focused on descriptive statistics, correlation analysis, and exploratory factor analysis. The score distribution, reliability, and validity of the developed score were evaluated.ResultsFirst, 16 questions related to quality of life, situations, or subjective assessment were omitted from the 27 questions. Exploratory factor analysis revealed that the remaining 11 questions pertained to three factors: frequent urination, urinary incontinence, and voiding symptoms. Three questions, which had similar questions with larger factor loading, were deleted. Finally, we selected eight question items for inclusion in the novel score. The score distribution exhibited no ceiling or floor effect. The Cronbach's alpha (0.737) demonstrated reliable internal consistency. The new score comprised two subscales with acceptable factorial validity (inter-factor correlation coefficient, 0.322): storage symptoms (frequent urination plus urinary incontinence) and voiding symptoms. The correlation between each item and the subscales suggested acceptable construct validity.ConclusionsWe developed a novel score, the HAM/TSP-Bladder Dysfunction Symptom Score, and demonstrated its reliability and validity. The applicability of this score to patients using catheters should be examined in future research.

Project description:BackgroundOX40 is a member of the tumor necrosis factor receptor family that is expressed primarily on activated CD4+ T cells and promotes the development of effector and memory T cells. Although OX40 has been reported to be a target gene of human T-cell leukemia virus type-1 (HTLV-1) viral transactivator Tax and is overexpressed in vivo in adult T-cell leukemia (ATL) cells, an association between OX40 and HTLV-1-associated inflammatory disorders, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), has not yet been established. Moreover, because abrogation of OX40 signals ameliorates chronic inflammation in animal models of autoimmune disease, novel monoclonal antibodies against OX40 may offer a potential treatment for HTLV-1-associated diseases such as ATL and HAM/TSP.ResultsIn this study, we showed that OX40 was specifically expressed in CD4+ T cells naturally infected with HTLV-1 that have the potential to produce pro-inflammatory cytokines along with Tax expression. We also showed that OX40 was overexpressed in spinal cord infiltrating mononuclear cells in a clinically progressive HAM/TSP patient with a short duration of illness. The levels of the soluble form of OX40 (sOX40) in the cerebrospinal fluid (CSF) from chronic progressive HAM/TSP patients or from patients with other inflammatory neurological diseases (OINDs) were not different. In contrast, sOX40 levels in the CSF of rapidly progressing HAM/TSP patients were higher than those in the CSF from patients with OINDs, and these patients showed higher sOX40 levels in the CSF than in the plasma. When our newly produced monoclonal antibody against OX40 was added to peripheral blood mononuclear cells in culture, HTLV-1-infected T cells were specifically removed by a mechanism that depends on antibody-dependent cellular cytotoxicity.ConclusionsOur study identified OX40 as a key molecule and biomarker for rapid progression of HAM/TSP. Furthermore, blocking OX40 may have potential in therapeutic intervention for HAM/TSP.

Dataset Information

Plasma proteome analysis in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Publications

Plasma proteome analysis in HTLV-1-associated myelopathy/tropical spastic paraparesis.

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