Upregulation of hsa-miR-125b in HTLV-1 asymptomatic carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis patients

The retrovirus human T lymphotropic virus type 1 (HTLV-1) promotes spastic paraparesis, adult T cell leukaemia and other diseases. Recently, some human microRNAs (miRNAs) have been described as important factors in host-virus interactions. This study compared miRNA expression in control individuals, asymptomatic HTLV-1 carriers and HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis patients. The proviral load and Tax protein expression were measured in order to characterize the patients. hsa-miR-125b expression was significantly higher in patients than in controls (p = 0.0285) or in the HAM group (p = 0.0312). Therefore, our findings suggest that miR-125b expression can be used to elucidate the mechanisms of viral replication and pathogenic processes.

In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4+CD25+ T cells of patients with human T-lymphotropic virus type 1-associated myelopathy

HTLV-1 Tax expression exerts an inhibitory effect on the Foxp3 transcription factor in CD4+CD25+ T-regulatory cells (Treg). For a better understanding of the role of Tax mRNA in the gene expression of cellular markers we measured Tax, Foxp3, CTLA-4, GITR, TGF-β, and IL-10 mRNA in Treg cells of 50 patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP; 27 women and 23 men; mean age: 56.7 years). The control group consisted of 23 non-infected subjects (12 women and 11 men) with a mean age of 51.3 years. Real-time PCR was used to measure mRNA of Tax proteins and several cellular markers of Treg function. Determinations revealed a high level of Tax mRNA in HAM/TSP (124.35 copies/100 CD4+CD25+ T cells). Foxp3, GITR, and CTLA-4 mRNA levels were lower in HAM/TSP patients (mean ± SD, 22.07 ± 0.78, 9.63 ± 0.36, and 4.54 ± 0.39, respectively) than in non-infected controls (47.15 ± 12.94, 22.14 ± 1.91, and 21.07 ± 2.31). Both groups had similar levels of TGF-β and IL-10. An inverse relationship was found between Tax levels and Foxp3, CTLA-4, and GITR levels. Conversely, there was a direct correlation between levels of Foxp3, GITR, and CTLA-4. Disease severity and evolution time did not correlate with Tax or Foxp3 levels. The present results suggest that Tax and Foxp3 mRNA vary with the same degree of disease severity in HAM/TSP patients. Tax fluctuations may affect CTLA-4 and GITR expression via the Foxp3 pathway, causing virus-induced dysfunction of CD4+CD25+ T cells in HAM/TSP patients.

Método de reação em cadeia por polimerase para a pesquisa de retrovírus em casos de linfomas não-Hodgkin de células T periféricas e paraparesias crurais espásticas / PCR methods for retrovirus search in cases of non-Hodgkin lynphoma of peripheral T-cells and crural spastic paraparesis

Partindo de dois oligonucleotídeos degenerados derivados de uma fração conservada da região pol de retrovírus conhecidos, foi pesquisada a presença de agente viral exógeno ou de uma seqüência endógena similar as retrovirais (ERV). A partir da amplificação do DNA pela técnica de PCR, foram testadas células mononucleares periféricas de 33 portadores de paraparesia crural espática de evolução crônica sem agente etiológico conhecido, produzindo um fragmento de aproximadamente 500 bp em 8 destas amostras...

Incremento de la actividad metaloproteinásica y de sus inhibidores en el líquido cefalorraquídeo, en pacientes con paraparesia espástica tropical / Increased activity of matrix metalloproteinases and their tissue inhibitors in cerebrospinal fluid of patients with HTLV-1 associated tropical spastic paraparesis

Background: Proteolytic modifications of neuronal surfaces and the surrounding extracellular matrix are very important in neuronal development and regeneration. Increased activity of matrix metalloproteinases (MMPs) and their tissue inhibitors, due to secretion by macrophages and lymphocytes, occur in inflammatory processes that disrupt the blood brain barrier. However, neurons and microglia can also secrete these enzymes. Aim: To identify the type of MMP present in the cerebrospinal fluid (CSF) and changes in the expression of tissue inhibitors of metalloproteinases (TIMPs) in patients with HTLV-1 associated tropical spastic paraparesis. Patients and methods: CSF samples from 12 patients with HTLV-1 associated tropical spastic paraparesis and 12 healthy controls were obtained by an atraumatic lumbar puncture. The presence of MMPs was measured by zymography and the relative amounts of TIMPs were measured by immunowestern blot. Results: In the CSF of both controls and patients, a similar gelatinolytic band corresponding to proMMP-2 (latent form) was observed. In 83.3 percent of patients with HTLV 1 associated tropical spastic paraparesis, the MMP-9 was also present. TIMP-1, TIMP-2 and TIMP-3 were elevated 2.24 ñ 0.72, 3.85 ñ 1.38 and 5.89 ñ 3.4 fold, respectively, in the CSF of patients as compared to controls. Conclusions: Patients with HTLV-1 associated tropical spastic paraparesis have elevated activity of MMP-9 and levels of TIMPs in the CSF, when compared to healthy controls

Infección por HTLV-I, leucemia de células T del adulto y factor con actividad de parathormona

La infección por el virus linfotrópico humano tipo I (HTLV-I) se ha asociado a la paraparesia espástica tropical (PET) y a la leucemia/linfoma de células T del adulto (ATL). Recientemete se demostró que los desordenes del metabolismo del calcio que acompañan la ATL son debidos a la secreción de un factor con actividad de parthormonas producido por los linfocitos infectados por el HTVL-I. Se presenta el caso de una paciente con anticuerpos contra el HTVL-I, anormalidades en el metabolismo del calcio y con parámetros que la clasifican en uno de los subtipos de ATL.