Pathogenesis

POSSIBLE MECHANISMS FOR THE DEVELOPMENT OF TSP/HAM

It has been proposed that the infection by the HTLV-I could be the result of the expression of a single sequence called pX with the proviral genome (11). The pX is a trans-activator known as Tax, which it is demonstrated through an induction of a variety of host cellular genes, including the interleukine-2 (IL-2) and its receptor in vitro. Changing the regulation of the cellular genes through the trans-activation of the element pX, it starts a process of activation of the T cells and the proliferation with subsequent events, which leads to an inflammation in the nervous system in TSP/HAM or a malign transformation in ATL (11).

Recently, researchers have suggested that the immune activation could contribute to the histopathological changes in the TSP/HAM. Inflammatory processes, with the presence of mononuclear and lymphocytes cells, have been observed in the central nervous system (CNS) (12,13). This has demonstrated that the state of the cellular immune activation in the TSP/HAM is driven towards the concomitant expression of the HTLV-I pX mRNA, and self-regulation of the IL-2 and IL-2Ra, in these patients. Thus, patients with TSP/HAM and HTLV-I asymptomatic carriers could represent an autocrine of the HTLV-I-infection, where the activity of the tax gene induces the IL-2 production and this receptor, leading to the polyclonal proliferation of the T cells. In contrast, there is no evidence of the tax or the IL-2 transcription, or spontaneous proliferation in patients with ATL, despite very high levels of IL-2Ra and IL-2R soluble expression in these patients (12).

In fact, it is estimated that the HTLV-I integration is present in 3 to 15% in the mononuclear cells (MNC) of patients with TSP/HAM. A high relation associated to CD4/CD8, with the presence of activated T cells and with high level of expression in the DR haplotype, was observed in the majority of the patients. For this purpose, it was shown that the proviral DNA from the HTLV-I and the high frequency of the virus in the MNC are greater in individuals with TSP/HAM or it is related to the HTLV-I-carriers. These data confirm the idea that the HTLV-I viral load plays an important role for the manifestation of neurological symptoms (14,16). This hypothesis could be tested with the use of anti-retroviral therapy against the human immunodeficiency virus (HIV-I), which has helped to improve the conditions of some patients with TSP, who were co-infected with the HIV-1/HTLV-I (Casseb J and Penalva-de-Oliveira AC, unpublished data).

The self-immunity phenomenon could contribute to the TSP/HAM pathogenesis. Taken into consideration that the proviral DNA from the HTLV-I was only detected in the lymphocytes nucleus which infiltrated the spinal medulla. However, none of the proviral DNA was amplified in any neuronal cell, including brain and glia cells. This indicates that the HTLV-I demyelinization in the spinal cord is unlikely to be the result of the oligodendrocytes or neuronal cells viral infection. These findings suggest that the self-immune mechanism in the TSP/HAM (17) and the neurological process could be associated to the cellular activator and with the immune response mediated by antibodies in some patients.