Correlation between clinical symptoms and peripheral immune response in HAM/TSP
Introduction
Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects 10 to 20 million people worldwide [1], [2], [3], [4], [5]. Most infected individuals remain asymptomatic. However, approximately 3–5% of infected subjects develop adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disease of the central nervous system (CNS) [2], [6], [7]. CD4+ T cells are the main reservoir of this virus, but other cells such as CD8+ T cells may also be infected [8], [9], [10], [11].
HTLV-1-infected CD4+ T cells and HTLV-specific CD8+ T cells play an important role in HAM/TSP pathogenesis [8], [12], [13]. These cells usually infiltrate the CNS [3], [14], and they are responsible for producing neurotoxic cytokines (TNF-α, IFN-γ, and IL1-β [14]. In addition, studies have shown that these neurotoxic cytokines in peripheral blood are important mediators of tissue injury in HAM/TSP [8], [15], [16], [17], [18]. Studies showed that, not just TH1 response is higher, but TH2 response is diminished presenting low levels of IL-4 [19], [20], [21]. Studies focused on the role of T regulatory cells in HTLV-1 infection presenting reduction in its function. Patients that developed HAM/TSP had decreased FOXP3 expression and production of the IL-10 and TGF-b, which are cytokines responsible for suppression of the immune response [11], [20], [21], [22], [23]. Pathological descriptions of HAM/TSP indicate involvement of the lower thoracic spinal cord, which is characterized by the loss of myelin and axons [18], [24], [25], [26], [27], [28]. Inflammation of the spinal cord, in turn, causes weakness and spasticity of the lower limbs, gait disturbances, paresthesia, bladder/bowel dysfunction, and erectile dysfunction in men [15], [24], [26], [28], [29], [30].
This study aimed to compare the gene expression of IFN-γ, IL-4 and IL-10 in peripheral blood between HAM/TSP and asymptomatic HTLV-1 infected patients. Also the gene expression of IFN-γ, IL-4 and IL-10 in peripheral blood was correlated with the clinical symptoms seen in HAM/TSP patients.
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Materials and methods
Eight HAM/TSP and 20 asymptomatic HTLV-1 patients were studied. They were recruited from the outpatient clinic of the Tropical Medicine Institute, Pará Federal University, Brazil. For HTLV-1 detection, ELISA exam was performed and confirmed by PCR reaction. The diagnosis of HAM/TSP was based on WHO criteria [31]. Spasticity was evaluated using the Modified Ashworth Scale [32], and the degree of walking aid was classified on a progressive scale (Table 1).
Five mL of peripheral blood was collected
Results
The asymptomatic HTLV-1 group had 17 women and 3 men (Mean age of 49.2 years). Among the HAM/TSP group were 5 women and 3 men (Mean age of 50 years).
Only the left plantar flexors showed higher spasticity degree. The others muscles showed lower spasticity degree (Fig. 1). Seven patients with HAM/TSP required the use of walking aid (Table 1).
The gene expression showed higher expression of Th1 cytokine in all patients. In HAM/TSP patients, expression levels were higher for IFN-γ when compared to
Discussion
Several aspects of the pathogenesis of HAM/TSP remain to be elucidated. Studies suggest that the balance between inflammatory and regulatory cytokines play a major role in the development of this disease. An imbalance in the Th1/Th2 system in HAM/TSP patients, characterized by a higher expression of Th1 cytokines, may cause chronic inflammation of the spinal cord. This process, in turn, may result in neural damage which are responsible for the neurological symptoms [15], [24], [29], [30].
Conclusions
These results show that HTLV-1 infected patients have an IFN-γ overexpression, which is higher in HAM/TSP patients. This inflammatory response is correlated to development and progression of HAM/TSP, which is evidenced by the correlation of IFN-γ levels and use of walking aid. New studies are warranted to look into more specific mechanisms that could help to design novel medications to improved clinical outcome.
Ethical approval
The project has been given ethical approval from the Nucleus of Tropical Medicine Committee on Human Research (Protocol No. 038/2010) and informed written consent was obtained from each patient.
Funding
This study was supported by CNPQ and Immunophathology Laboratory – University of Pará- Brazil.
Competing interests
None declared.
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