Pathogenesis

POSSIBLE MECHANISMS FOR THE DEVELOPMENT OF TSP/HAM

INTRODUCTION

The cytolytic T lymphocytes (CTL) have an important role in viral infections, especially in retrovirus infections. Clones from the HTLV-I Tax 11-19 have been isolated from cytotoxic T cells specific form the HLA-A2-positives. Patients with TSP/HAM show a significant number (14%) of CD8+ lymphocyte T for peptides from the HTLV-I Tax11-19 region in the peripheral blood. Simultaneous comparisons, from the peripheral blood and from the cerebro spinal fluid (CSF) of a patient, revealed 2.5 more Tax11-19 specifics in T cells in the CSF (24 VS 9% in lymphocytes from the peripheral blood). The analysis of the HTLV-I Tax-11-19-CTL in patients with TSP/HAM showed different TNF-alpha and IFN-gamma intracellular activation signaling, depending on the gravity of the disease. The presence of the CTLs demonstrated that the HTLV-I Tax11-19 is activated and persisting during the chronic phase of the disease, while it is accumulating in the CSF (25)

Besides its lytic characteristics, the CTLs or other mononuclear cells are important sources of soluble post-inflammatory mediators, which contribute significantly to the TSP/HAM pathogenesis (26). In a study, the HTLV-I infection increase the secretion of the IL-6 in microglial cells culture in humans, but it does not show stimulus for the release of the IL-1 in monocytes or microglial cells. Consequently, TNF-alpha and IL-6 have been involved in the inflammatory process of demyelinization and gliosis, which it has been suggested that the human microglial cells and monocytes infected and activated by the HTLV-I could play a role in the TSP/HAM pathogenesis (27,28).

Another soluble factor, called Transforming Growth Factor Beta (TGF-ß) is responsible for the regeneration of damaged tissues in the spinal cord and could attract more antigens from the HTLV-I for the CSF. In fact, the proliferative response of CD8+ cells versus the culture and irradiation of the autologous CD4+ cells, which contained HTLV-I antigens, were significantly inhibited by the TGF-ß1. However, the in vitro activation of the HTLV-I was evaluated through the spontaneous proliferation of CD4+ T cells and they were not affected by the TGF-ß1. The HTLV-I intracytoplasmic antigens induction in CD4+ cells culture was facilitated by the TGF-ß1, in a dose-dependent approach. In the meantime, the TGF-ß could play a critical role in localizing the viral activation within the central nervous system (CNS) in patients with TSP/HAM (29).

The humoral system has also an important role in the pathogenesis, and the activation of the complement system classical pathway could contribute to the inflammatory process that takes place in this disease (30). The presence of IgM and high titers of IgG and IgA antibodies against HTLV-I protein, mainly the Tax protein, adding the increasing of the HTLV-I proviral DNA load, could indicate a correlation in the TSP/HAM pathogenesis (31). However, high levels of antibodies could contribute to the growth of viral load in patients with TSP/HAM, without necessarily being prejudicial or causing death.