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.

Macrophagic myofascitis associated with rheumatoid arthritis.

Macrophagic myofascitis (MMF) is an unusual inflammatory myopathy characterized by muscle infiltration by macrophages and lymphocytes. Here, we describe a case of MMF which is associated with rheumatoid arthritis. A 53-year-old Japanese rheumatoid arthritis (RA) patient presented with focal tenderness of lower extremities. Magnetic resonance imaging showed evidence of myofascitis involving fascias of anterior tibialis muscle. Muscle biopsy showed a unique pathological pattern of MMF. MMF is known to be associated with vaccination containing aluminum. However, our case was not related to aluminum containing vaccinations and etiologies are unknown. The possible link needs to be discussed.

[Pilomyxoid astrocytoma presenting in an elderly patient: a case report].

A 77-year-old man presented with progressive visual disturbance. MR images revealed a mass lesion mainly spreading in the left basal cistern, sylvian fissure and to the left hypothalamic region, with ventricular enlargement. To obtain precise diagnosis of the mass lesion, an open biopsy was performed. The pathological diagnosis was pilomyxoid astrocytoma (PMA). The patient was discharged without adjuvant therapy. A Ventriculoperitoneal shunt procedure was performed afterwards because his hydrocephalic symptoms progressed. PMA is a rare tumor newly added to the glioma section by the WHO classification renewed in 2007, and generally develops in infancy. To our knowledge, there are only four adult cases being reported. In those cases, the symptoms of the disease developed during the second to fourth decade of life. The onset at a more advanced age as in the present case seems to be extremely rare. The treatment strategy described in infant cases is similar to that for pilocytic astrocytoma, but there are only few reports. To establish a treatment protocol for adult patients, further more cases are needed to accumulate knowledge of this rare brain tumor.

Catastrophic transverse myelitis in a patient with systemic lupus erythematosus.

A 24-year-old Japanese woman was admitted to our hospital suffering from high fever and progressive paralysis in both legs. Magnetic resonance imaging of the spinal cord showed high-intensity signals from C5 to Th4 and from Th7 to L1 on T2-weighted images. The patient was diagnosed as having acute transverse myelitis trade mark, which was a complication of systemic lupus erythematosus based on the serological findings. Despite aggressive immunosuppressive treatments including corticosteroid pulse therapy, plasmapheresis, and intravenous cyclophosphamide, the paralysis of her lower extremities did not improve. In the catastrophic type of lupus-associated TM, which develops extensively and longitudinally along the spinal cord, the prognosis still seems to be poor despite intensive treatments.

Cytapheresis with a filter for selective removal of CD4+ T cells in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a major animal model of human multiple sclerosis (MS). CD4+ T cells are thought to play a pivotal role in the pathogenesis of EAE and MS. In order to investigate the depletion of CD4+ T cells from the systemic circulation as an effective strategy for the treatment of MS, we performed extracorporeal CD4+ T cell adsorption, using a filter to which anti-CD4+ antibody is immobilized as a ligand, in adoptively transferred EAE. Rats treated with CD4+ T cell removal filter (CD4RF) exhibited milder clinical signs of EAE and earlier recovery than those receiving sham treatment. Moreover, the thymic cells from EAE rats treated with CD4RF exhibited a suppressed proliferative response and IFN-gamma production to myelin basic protein. These results suggest that depletion of CD4+ T cells from the systemic circulation by extracorporeal treatment is a potentially useful strategy for treatment of acute phase and relapsing MS.

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.