Autoimmunity and molecular mimicry in tropical spastic paraparesis/human T-lymphotropic virus-associated myelopathy

Abstract

Viruses share antigenic sites with normal host cell components, a phenomenon known as molecular mimicry. It has long been suggested that viral infections might trigger an autoimmune response by several mechanisms including molecular mimicry. More than 600 antiviral monoclonal antibodies generated against 11 different viruses have been reported to react with 3.5% of cells specific for uninfected mouse organs. The main pathological feature of tropical spastic paraparesis/ human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (TSP/HAM) is a chronic inflammation of the spinal cord characterized by perivascular cuffing of mononuclear cells accompanied by parenchymal lymphocytic infiltration. We detected the presence of autoantibodies against a 98-to 100-kDa protein of in vitro cultured human astrocytes and a 33-to 35-kDa protein from normal human brain in the serum of HTLV-I-seropositive individuals. The two cell proteins exhibited molecular mimicry with HTLV-I gag and tax proteins in TSP/HAM patients, respectively. Furthermore, the location of 33-to 35-kDa protein cross-reaction correlated with the anatomical spinal cord areas (in the rat model) in which axonal damage has been reported in several cases of TSP/HAM patients. Our experimental evidence strongly suggests that the demyelinating process occurring in TSP/ HAM may be mediated by molecular mimicry between domains of some viral proteins and normal cellular targets of the spinal cord sections involved in the neurodegeneration.

Pathogenic mechanisms of neurodegeneration based on the phenotypic expression of progressive forms of immune-mediated neurologic disease

“…[12][13][14]132 The cross-reactivity between HTLV-1 tax monoclonal antibodies with a 33 kDa brain-derived protein was replicated independently. 134 Taken together, these data suggest that HAM/TSP patients develop a highly specific antibody response to neurons that is biologically active and potentially contributory to the pathogenesis of this immune-mediated neurologic disease. 12,13 Because of similarities between the chronic, progressive nature and pathology of HAM/TSP and progressive forms of MS, we hypothesized that MS patients would also develop antibodies to hnRNP A1.…”

Molecular mimicry in neurological disease: what is the evidence?

“…There is little evidence that direct infection of neural elements with HTLV-1 causes HAM/TSP [120,121,123,131]. Instead, data indicate that immune-mediated mechanisms, including molecular mimicry, play a significant role [9,10,13,120,121,123,127,131,141]. HAM/TSP patients make immune responses to a number of viral targets including HTLV-1-tax, -env and -gag, which separates them from control populations [121, 142 -145].…”

Síndrome autoinmune en la paraparesia tropical espástica/ mielopatía asociada a la infección por el virus linfotrópico humano tipo I de la costa pacífica colombiana

“…Este proceso, que no es más que la reacción cruzada ocurrida entre los anticuerpos generados como parte de la respuesta inmune a un agente infeccioso y autoantígenos, ha sido confirmado en el complejo sida/demencia (15) y se ha sugerido recientemente para otras enfermedades degenerativas del sistema nervioso central como la esclerosis múltiple (16) y la misma paraparesia espástica tropical (17,18).…”

“…Se utilizó el anticuerpo monoclonal LT4 (anti-taxp40) (18)(19)(20). Se emplearon los sueros policlonales para la proteína acídica fibrilar el IgG-anti-GFAP (N-18) (Santa Cruz Biotechnology.…”