Role of Integrin Signaling Activation on the Development of Human T Cell Leukemia Virus-1 (HTLV-1)-Associated Myelopathy/Tropical Spastic Paraparesis: Its Relationship to HTLV-1-Infected CD4+ T Cell Transmigrating Activity into the Tissues.

The main clinical feature of human T cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is slowly progressive spastic paraparesis with bladder dysfunction. HAM/TSP is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by the interaction between infiltrated Th1-like, HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ cytotoxic T cells (CTL), is probably critical for the induction of chronic inflammation. Although the HTLV-1-infected CD4+ T cells in HAM/TSP appear to play a crucial role in the initial pathogenesis of HAM/TSP, the exact mechanisms of how these cells acquire their function as the first responders in the pathogenesis of HAM/TSP still remain unresolved. Herein, we propose the importance of the activation of both outside-in signals from integrin signaling and inside-out signals for integrin signaling in the HTLV-1-infected CD4+ T cells of HAM/TSP patients.

Increased sialyl Lewis(x) antigen-positive cells mediated by HTLV-1 infection in peripheral blood CD4(+) T lymphocytes in patients with HTLV-1-associated myelopathy.

Sialyl Lewis(x) antigen-positive (sLe(x+)) cells play an important role in the first step of transmigration of T lymphocytes through vascular endothelial cells into tissues. We compared the proportion of sLe(x+) cells in peripheral blood CD4(+) T lymphocytes between patients with HTLV-1-associated myelopathy (HAM) and control patients, by using flow cytometry. The percentage of sLe(x+) cells in peripheral blood CD4(+) T lymphocytes was significantly higher in HAM patients compared to control patients. Interferon-gamma (IFN-gamma), but not interleukin-4 (IL-4), production by the sLe(x+) cell population of peripheral blood CD4(+) T lymphocytes was significantly higher in HAM patients than in control patients. In addition, comparison of the HTLV-1 proviral load between sLe(x+) and sLe(x-) cells in peripheral blood CD4(+) T lymphocytes of HAM patients showed that the HTLV-1 proviral load was significantly higher (two- to eight-fold), concomitant with enhanced IFN-gamma production, in the sLe(x+) than in the sLe(x-) cell population. Our findings indicate that the sLe(x+) cell population, which has features of activated Th1 cells with up-regulated expression of E- and P-selectin ligands mediated by HTLV-1 infection, is increased in peripheral blood CD4(+) T lymphocytes in HAM patients, suggesting their involvement in transmigration of peripheral T lymphocytes from the peripheral blood into tissues.

Up-regulation of interleukin-12 receptor expression in peripheral blood mononuclear cells of patients with HTLV-I-associated myelopathy/tropical spastic paraparesis.

We previously reported elevated levels of serum interleukin-12 (IL-12) in association with increased interferon-gamma (IFN-gamma) levels in patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The interaction between IL-12 and IL-12 receptor (IL-12R) plays an important role in differentiation of the T helper type 1 (Th1) phenotype. In this study, we further examined the IL-12/IL-12R axis by investigating the expression of IL-12R and CD40 ligand (CD40L) in peripheral blood mononuclear cells (PBMC) of 18 HAM/TSP patients, and comparing the levels with those in 25 patients with other neurological disorders, including 4 anti-HTLV-I-seropositive carriers as controls. Two-color analysis by flow cytometry revealed a significantly high percentage of IL-12R beta1+ cells in CD4+ T lymphocytes in HAM/TSP patients compared to the control. Furthermore, IL-12R beta2 mRNA expression in PBMC was detected by reverse-transcriptase polymerase chain reaction in 6 of 18 HAM/TSP patients, but not in any control patients. In contrast, there was no significant difference between the percentage of CD40L+ cells in CD4+ T lymphocytes in HAM/TSP and control patients. Our results suggest Th1 immune activation in patients with HAM/TSP, which leads to chronic inflammation in the spinal cord, mediated by dysregulation of the IL-12/IL-12R axis rather than of the CD40/CD40L interaction.