Pathogenesis

POSSIBLE MECHANISMS FOR THE DEVELOPMENT OF TSP/HAM

INTRODUCTION

It was observed that 32% of the patients with TSP/HAM who produced allolymphotropic antibodies in the peripheral blood (mainly in the T cells, as well as the B cells), which belongs to the IgM class, reacted in different temperature conditions, and showed specificity for multiple HLA antigens, especially HLA A2, A26, A33, B7, B27, B35, B48, B61, and Cw3. Therefore, it could be suggested that any class of anti-HLA antigen produce a cross-reaction with the HLA present. Low specificity cytotoxity antibodies were detected in 14% of the serum from asymptomatic carriers. The cells infected by the HTLV-I express altered HLA antigens and could have a response to this stimulation (33,34). However, in another study (35), individuals who expressed HLA-A*02+ could prevent 28% of the TSP/HAM cases, and the HTLV-I asymptomatic carriers had one third less of proviral load than the individuals with the disease but without the presence of this haplotype. These findings show that a strong response, at restrict level, from the CTL benefits the host to reduce the viral load.

Table 1 show some TSP/HAM and ATL characteristics, whereas Figure 1 illustrate the TSP/HAM possible mechanisms. The activation of the CTL and the HTLV-infected cells provides a migration to the CNS, infecting the neural cells. Some cytolytic CD8+ cells could recognize viral antigens in the CNS cells infected by the HTLV-I, causing a demyelinization. However, there is not a specific action available against the CNS cells. Consequently, the presence of IFN-g release in the HTLV-I-infection and its recognition by the CD8+ cells, induced by the cytokines secreted by the microglia, such as the TNF-a and IL-6, are toxic to the myelin (35,36). Self-immune mechanisms could be present with the occurrence of: a) a self-activation of the T cells with the CNS antigens, or b) infection in the T cells resulting in a self-reactivation of the CNS T cells. This, in turn, is activated, expanding, and migrating to the CNS, where it finds its antigens with the consequential occurrence of a specific immune response and demyelinization. The presence of a genetic inheritance, such as the presence of some HLA haplotypes (31-35), could have some implication in the susceptibility of the host.

Finally, the CTL low response for the HTLV-I helps to develop a high proviral load as a result of the chronic infection activation spread through the T cells (36). Therefore, an immune deregulation with high production of the IL-2 receptor by the T cells could attract more cells, producing stimulants from other cytokines, such as the IFN-g or, on the other hand, a great expression of adhesion molecules could have an important role in the TSP/HAM (37,38). In contrast, our preliminary observations showed that the PBMC obtained from 2 patients with TSP and with patients co-infected by the HIV-1/HTLV-I have shown high levels of IL-10, low levels of IL-2, and levels of IFN-g compared to HTVL-I asymptomatic carriers. These findings could indicate that a change in the Th2 predominant pattern had been observed in TSP/HAM with the HIV-1 and the HTLV-I infections (39,40).

Concluding, the TSP/HAM pathogenesis is a phenomenon of multivariable activation of the immune system, especially the IFN-g against the presence of HTLV-I antigens, which leads to a chronic inflammatory process and demyelinization in the spinal cord of some HTLV-I carriers.