Neuronal molecular mimicry in immune-mediated neurologic disease.
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.
Levin
M C
MC
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, USA.
Krichavsky
M
M
Berk
J
J
Foley
S
S
Rosenfeld
M
M
Dalmau
J
J
Chang
G
G
Posner
J B
JB
Jacobson
S
S
D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology*; D015153:Blotting, Western; D001923:Brain Chemistry; D002478:Cells, Cultured; D015490:HTLV-I Infections / Q000276:immunology / Q000473:pathology*; D015368:Human T-lymphotropic virus 1 / Q000302:isolation & purification; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis*; D007150:Immunohistochemistry; D015458:Leukemia, T-Cell / Q000276:immunology / Q000473:pathology*; D018716:Molecular Mimicry / Q000276:immunology*; D009474:Neurons / Q000737:chemistry* / Q000276:immunology; D015493:Paraparesis, Tropical Spastic / Q000276:immunology / Q000473:pathology; D010300:Parkinson Disease / Q000276:immunology / Q000473:pathology*; D012016:Reference Values
D007074:Immunoglobulin G