ABSTRACT
HTLV-1-infected individuals may develop a neurologic inflammatory condition known as HTLV-1-associated myelopathy (HAM/TSP), in which the high production of TNF is observed. These patients exhibit higher proviral loads, enhanced production of proinflammatory cytokines and lymphocyte proliferation in comparison to asymptomatic HTLV-1 carriers and those presenting overactive bladder (OAB-HTLV-infected). Metalloproteinases (MMPs) are known to degrade the components of the blood-brain barrier, favoring the migration of infected cells into the central nervous system. Moreover, the unbalanced production of MMPs and their inhibitors (TIMPs) has also been associated with tissue damage. The present work studied the production of MMP-9 and TIMPs in HTLV-1-infected individuals with and without neurological manifestations. HAM/TSP patients presented higher concentrations of MMP-9 in peripheral blood mononuclear cell (PBMC) culture supernatants, as well as a higher MMP-9/TIMP-3 ratio when compared to the other groups studied. MMP-9 levels positively correlated with proviral load and TNF in OAB-HTLV-infected individuals, and the in vitro neutralization of TNF significantly decreased MMP-9 levels in PBMC culture supernatants. Our findings indicate an association between MMP-9 production and the proinflammatory state associated with HTLV-1 infection, as well as HAM/TSP.
Subject(s)
Human T-lymphotropic virus 1 , Paraparesis, Tropical Spastic , Humans , Leukocytes, Mononuclear , Matrix Metalloproteinase 9 , Proviruses , Viral LoadABSTRACT
BACKGROUND: While bladder dysfunction is observed in the majority of patients with human T cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM), it is also observed in patients who do not fulfill all diagnostic criteria for HAM. These patients are classified as having possible or probable HAM/TSP. However, it remains unclear whether the severity and progression of bladder dysfunction occurs similarly between these two groups. OBJECTIVE: Compare the severity and evolution of bladder dysfunction in HTLV-1-infected patients with possible and definite HAM/TSP. METHODS: The present prospective cohort study followed 90 HTLV-1 patients with possible HAM/TSP and 84 with definite HAM/TSP between April 2011 and February 2019. Bladder dysfunction was evaluated by bladder diary, overactive bladder symptoms scores (OABSS) and urodynamic studies. Bladder dysfunction progression was defined as the need for clean self-intermittent catheterization (CIC). RESULTS: At baseline, nocturia, urgency and OABSS scores were worse in definite compared to possible HAM/TSP patients. The main urodynamic finding was detrusor overactivity, present in 77.8% of the patients with definite HAM/TSP versus 58.7% of those with possible HAM/TSP (P = 0.05). Upon study conclusion, the cumulative frequency of patients requiring CIC increased in both groups, from 2 to 6 in possible HAM/TSP and from 28 to 44 in definite HAM/TSP patients. The estimated time to need for CIC was 6.7 years (95%CI 6.5-7.0) in the possible HAM/TSP group compared to 5.5 years (95%CI 4.8-6.1) in the definite HAM/TSP group. CONCLUSIONS: Although both groups showed similarities in bladder dysfunction and tended to progress to requiring CIC over time, patients with possible HAM/TSP presented less severe manifestations at baseline and progressed more slowly than those with definite HAM/TSP.
Subject(s)
Disease Progression , HTLV-I Infections/complications , Paraparesis, Tropical Spastic/complications , Urinary Bladder Diseases/complications , Adult , Cohort Studies , Female , Human T-lymphotropic virus 1 , Humans , Intermittent Urethral Catheterization/statistics & numerical data , Male , Middle Aged , Prospective Studies , UrodynamicsABSTRACT
A high proviral load (PVL) is recognized as a risk factor for human T cell leukemia virus-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but there is a lack of prospective studies evaluating whether or not HTLV-1 carriers with high PVL are at risk of developing HAM/TSP or other HTLV-1-related diseases. Here, we compare the incidence of clinical manifestations and the cytokine levels in 30 HTLV-1 carriers with high (> 50,000 copies/106 PBMC) and an equal number of subjects with low proviral load. Participants were followed for 3 to 16 years (median of 11 years). The PVL, IFN-γ, TNF, and IL-10 levels were quantified at entry and at the end of the follow-up. Among the self-reported symptoms in the initial evaluation, only the presence of paresthesia on the hands was more frequent in the group with high PVL (p < 0.04). The production of IFN-γ was higher in the group with high PVL group (median of 1308 versus 686 pg/ml, p < 0.011) when compared with the control group in the first assessment. There was no difference in the occurrence of urinary symptoms or erectile dysfunction, periodontal disease, Sicca syndrome, and neurologic signs between the two groups during the follow-up. The observation that none of the HTLV-1 carriers with high PVL and with exaggerated inflammatory response progressed to HAM/TSP indicates that other factors in addition to the PVL and an exaggerated immune response are involved in the pathogenesis of HAM/TSP.
Subject(s)
Carrier State/immunology , HTLV-I Infections/immunology , Human T-lymphotropic virus 1/immunology , Leukocytes, Mononuclear/immunology , Proviruses/immunology , Adult , Aged , Carrier State/diagnosis , Carrier State/virology , Erectile Dysfunction/diagnosis , Erectile Dysfunction/genetics , Erectile Dysfunction/immunology , Erectile Dysfunction/virology , Female , Gene Expression , HTLV-I Infections/diagnosis , HTLV-I Infections/genetics , HTLV-I Infections/virology , Human T-lymphotropic virus 1/growth & development , Humans , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Leukocytes, Mononuclear/virology , Longitudinal Studies , Male , Middle Aged , Nocturia/diagnosis , Nocturia/genetics , Nocturia/immunology , Nocturia/virology , Proviruses/growth & development , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/genetics , Sjogren's Syndrome/immunology , Sjogren's Syndrome/virology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Viral Load/immunologyABSTRACT
BACKGROUND: HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is related with high proviral load, high proinflammatory cytokine levels, and passage of infected cell from the blood to the central nervous system. We aimed to evaluate the participation of chemokines and adhesion molecules in HAM/TSP pathogenesis. METHODS: CXCL9, CXCL10, sICAM-1, and sVCAM-1 were determined by ELISA in serum and cerebrospinal fluid (CSF) of HTLV-1 infected individuals. The frequency and median fluorescence intensity (MFI) of lymphocytes and monocytes expressing ligands of adhesion molecules (CD11a and CD49d) and a chemokine receptor (CXCR3) were analyzed by flow cytometry. RESULTS: The levels of CXCL9 and CXCL10 in serum of definite HAM/TSP were higher than in serum of probable HAM/TSP and HTLV-1 carriers. Considering the production of chemokines by patients with definite HAM/TSP, CXCL9 levels were higher in serum than in CSF, and CXCL10 production was higher in CSF than in serum. Levels of adhesion molecules in serum and CSF of HTLV-1 infected individuals did not differ. The MFI of CD11a on CD4+, CD8+ and CD14+ cells was lower in definite HAM/TSP than in HTLV-1 carriers and did not differ from probable HAM/TSP and healthy subjects (HS). The frequency of lymphocytes expressing CXCR3 was lower in definite HAM/TSP than in cells of probable HAM/TSP and did not differ from carrier and HS. CONCLUSION: These data point to the participation of proinflammatory chemokines, especially CXCL10, in the pathogenesis of definite HAM/TSP.
