Neuronal molecular mimicry in immune-mediated neurologic disease

• Published in: Annals of neurology Vol. 44; no. 1; p. 87
• Main Authors: Levin, M C, Krichavsky, M, Berk, J, Foley, S, Rosenfeld, M, Dalmau, J, Chang, G, Posner, J B, Jacobson, S
• Format: Journal Article
• Language: English
• Published: United States 01-07-1998
• Subjects: Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Blotting, Western; Brain Chemistry; Cells, Cultured; HTLV-I Infections - immunology; HTLV-I Infections - pathology; Human T-lymphotropic virus 1 - isolation & purification; Humans; Immunoglobulin G - analysis; Immunohistochemistry; Leukemia, T-Cell - immunology; Leukemia, T-Cell - pathology; Molecular Mimicry - immunology; Neurons - chemistry; Neurons - immunology; Paraparesis, Tropical Spastic - immunology; Paraparesis, Tropical Spastic - pathology; Parkinson Disease - immunology; Parkinson Disease - pathology; Reference Values
• ISSN: 0364-5134
• DOI: 10.1002/ana.410440115

Molecular mimicry is implicated in the pathogenesis of autoimmune diseases such as diabetes mellitus, rheumatoid arthritis, and multiple sclerosis (MS). Cellular and antibody-mediated immune responses to shared viral-host antigens have been associated with the development of disease in these patients. Patients infected with human T-lymphotropic virus type I (HTLV-I) develop HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an immune-mediated disorder of the central nervous system (CNS) that resembles some forms of MS. Damage to neuronal processes in the CNS of HAM/TSP patients is associated with an activated cellular and antibody-mediated immune response. In this study, IgG isolated from HAM/TSP patients was immunoreactive with uninfected neurons and this reactivity was HTLV-I specific. HAM/TSP IgG stained uninfected neurons in human CNS and cell lines but not nonneuronal cells. Neuronal western blots showed IgG reactivity with a single 33-kd band in all HAM/TSP patients tested. By contrast, no neuron-specific IgG reactivity could be demonstrated from HTLV-I seronegative controls and, more important, from HTLV-I seropositive, neurologically asymptomatic individuals. Both immunocytochemical staining and western blot reactivity were abolished by preincubating HAM/TSP IgG with HTLV-I protein lysate but not by control proteins. Staining of CNS tissue by a monoclonal antibody to HTLV-I tax (an immunodominant HTLV-I antigen) mimicked HAM/TSP IgG immunoreactivity. There was no staining by control antibodies. Absorption of HAM/TSP IgG with recombinant HTLV-I tax protein or preincubation of CNS tissue with the monoclonal antibody to HTLV-I tax abrogated the immunocytochemical and western blot reactivity of HAM/TSP IgG. Furthermore, in situ human IgG localized to neurons in HAM/TSP brain but not in normal brain. These data indicate that HAM/TSP patients develop an antibody response that targets uninfected neurons, yet reactivity is blocked by HTLV-I, suggesting viral-specific autoimmune reactivity to the CNS, the damaged target organ in HAM/TSP.