Pathogenesis of human T‐lymphotropic virus type 1‐associated myelopathy/tropical spastic paraparesis

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus that preferentially infects CD4+ lymphocytes in vivo. The virus causes a hematological malignancy known as adult T-cell leukemia, and an inflammatory disease in the central nervous system (CNS) called HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). Approximately 0.3% of HTLV-1-infected individuals develop HAM/TSP. HAM/TSP patients show spastic paraparesis and sphincter dysfunction, as well as sensory disturbance of the lower extremities, which corresponds to pathological lesions in the spinal cord. Although the majority of HAM/TSP patients progress slowly, this disease progresses rapidly in some patients. An increased HTLV-1 proviral load is more common in HAM/TSP patients than in asymptomatic HTLV-1 carriers, and is considered to be a strong risk factor for HAM/TSP development. A prominent cellular immune response in HAM/TSP patients is a significantly elevated number of HTLV-1 Tax-specific CD8+ cytotoxic T lymphocytes (CTL) in peripheral blood mononuclear cells compared with asymptomatic HTLV-1 carriers. Additionally, CD4+ and CD8+ lymphocytes accumulate in the perivascular areas of spinal cords in HAM/TSP patients. Viral DNA, mRNA and proteins are detected only in infiltrating CD4+ T cells, but not in neural cells. A high proportion of HTLV-1-specific CTL infiltrates the CNS. Furthermore, some neural cells surrounding the CTL, predominantly oligodendrocytes, undergo apoptosis. These findings suggest the pathogenesis that the HTLV-1-specific inflammation induced by the interaction of HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ CTL causes bystander damage in the CNS. In the present review, a more exact pathogenesis of HAM/TSP is discussed based on virology, immunology and neuropathology.

HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I

“…Tropical spastic paraparesis/HTLV-1-associated myelopathy/ (TSP/HAM) is an insidious neuroinflammatory condition resulting in demyelination of the spinal cord [14]. Though HAM/TSP pathogenesis is not completely understood, evidence suggests that anti-HTLV-1 cytotoxic T-cells (CTLs) target infected lymphocytes that have crossed the blood-brain barrier, resulting in increased pro-inflammatory cytokine production and damage to the surrounding nervous tissue [15]. Adult T-cell leukemia (ATL) is a highly aggressive lymphoproliferative disorder for which there are no effective treatments [16, 17].…”

Human T-lymphotropic virus type 1 (HTLV-1) and cellular immune response in HTLV-1-associated myelopathy/tropical spastic paraparesis

“…HTLV-1-specific CTL infiltrate the CNS and play a role in HAM/TSP pathogenesis (Kubota 2017 ). Activated HTLV-1-specific CTL is markedly increased in the periphery of patients with HAM/TSP.…”

Neuromyelitis optica and human T‐cell lymphotropic virus type 1‐associated myelopathy/tropical spastic paraparesis: Pathogenesis and emerging therapies

“…This issue of Clinical and Experimental Neuroimmunology contains two articles on neuroimmunological disorders affecting the spinal cord. Ryuji Kubota from Kagoshima University contributed a Review Article on the pathogenesis of T‐cell lymphotropic virus type 1 (HTLV‐1) associated myelopathy/tropical spastic paraparesis (HAM/TSP), covering virology, immunology and pathogenesis of this disease . Manabu Araki and myself wrote a comprehensive review on the pathogenesis of neuromyelitis optica (NMO) and emerging therapies .…”