Abstract

Summary: NEUROPATHOGENY OF TROPICAL SPASTIC PARAPARESIS The histopathological characteristics of the Tropical Spastic Paraparesis (HAM/TSP) indicate that the lesions seen in the spinal cord correspond to an essentially degenerative axonal entity (axonopathy) of the corticospinal tracts from the distal to the proximal zone. HTLV-1 enters the central nervous system (CNS) through the recruitment of HTLV-1 infected T cells that pass through the brain blood barrier presenting alterations in its permeability by cytokine release, metalloproteinases (MMPs) and increased expression of adhesion proteins by the activated lymphocytes themselves and/or astrocytes. These lymphocytes exhibit increased migratory activity due to changes in their cytoskeleton involving phosphorylated proteins as CRMP-2 (Collapsin response-mediator protein 2) and release of sSEMA-4D (Semaphorin-4D soluble), which represents a signal of chemoattraction together with other chemoattractant signals secreted by astrocytes. Once inside the CNS, infected lymphocytes mainly undergo clonal expansion and can infect cells by virological synapses. The cerebrospinal fluid of some MMPs and their tissue inhibitors (TIMPs) can alter the proteins of the extracellular matrix, participate in the destruction of myelin and increase the permeability of brain blood barrier. MMPs come from infected lymphocytes and glial cells. MMP-2, MMP-3 and MMP-9, and only TIMP-2, TIMP-3, and TIMP-4 were elevated in HAM/TSP patients, meaning that MMP-3 and MMP-9 would not be counteracted. Astrocytes are the cells that initially respond to CNS damage, being the producers of proteins of the extracellular matrix, neurotrophic factors, cytokines, chemokines and adhesion proteins. The increase in the CSF of proteins of the extracellular matrix like laminin, thrombospondin and heparan sulfate proteoglycan compared to controls may have a regenerative function. Since neurons are not HTLV-1 virus infection, there is a consensus that this axonopathy should be a consequence of the chronic extracellular action of secreted viral proteins from HTLV-1-infected lymphocytes found in the CNS, such as Tax protein. Viral protein Tax has been detected in the CSF and plasma of patients with HAM/TSP and comes from the secretion of infected lymphocytes via a canonical pathway along with the chaperone calreticulin with which it interacts. Tax protein has been found modified with two molecules of Ubiquitin. Axonal damage, from distal to proximal, selective to the longest axons of the CNS, ie corticospinal tracts, suggests that it may be a causal factor of neurodegeneration in HAM/TSP because of its special sensitivity to alterations in its transport. This central axonopathy could be caused by the alteration of axoplasmic transport based on the presence of deposits of amyloid precursor protein (β-APP) in the axons. Analysis of Tau protein in the CSF and the use of neuronal models has demonstrated an increase in kinase activity such as CDK5 that participates in the phosphorylation of protein associated with the axonal cytoskeletons such as Tau and CRMP-2. In the CSF of patients with HAM/TSP there is hyperphosphorylation of threonine 181 in Tau and in infected T lymphocytes is that of serine 522 of CRMP-2. In both cases, it is possible to alter microtubule cytoskeletal and actin filaments. These phosphorylations play a role in signaling pathways associated with neurodegeneration. There is a cross-talk between the immune system through the SEMA-4D semaphorin. In patients with HAM/TSP both membrane-bound SEMA-4D (in lymphocytes) and soluble sSEMA-4D (released into the lymphocyte culture medium by proteolysis with MMPs) are significantly increased compared to healthy carriers and controls. A chemoattractant effect of sSEMA-4D on CD4+Tax+ cells of HAM/TSP patients with a high content of phosphorylated serine 522 CMRP-2 was demonstrated. In plasma and PBMC (peripheral blood mononuclear cells) culture media the Tax viral protein interacts with sSEMA-4D, suggesting that its neurotoxic effect is translated through its association with SEMA-4D triggering the Plexin 1B signaling pathway that could account for the central axonopathy found in HAM/TSP including, depolymerization of the actin filament and microtubule cytoskeletons.