RESUMO
One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS). There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.
Assuntos
Autoimunidade/fisiologia , Infecções por HTLV-I/imunologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Imunoglobulina G/análise , Mimetismo Molecular/imunologia , Doenças do Sistema Nervoso/imunologia , Anticorpos Monoclonais , Encéfalo/metabolismo , Reações Cruzadas , DNA Complementar , Infecções por HTLV-I/patologia , Infecções por HTLV-I/fisiopatologia , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas , Humanos , Imunoglobulina G/sangue , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Especificidade de Órgãos , Técnicas de Patch-Clamp , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleoproteínas/genéticaRESUMO
Multiple sclerosis (MS) patients make antibodies to heterogeneous nuclear ribonuclear protein A1 (hnRNP-A1), a nucleocytoplasmic protein. We hypothesized this autoimmune reaction might contribute to neurodegeneration. Antibodies from MS patients reacted with hnRNP-A1-'M9', its nuclear translocation sequence. Transfection of anti-M9 antibodies into neurons resulted in neuronal injury and changes in transcripts related to hnRNP-A1 function. Importantly, RNA levels for the spinal paraplegia genes (SPGs) decreased. Changes in SPG RNA levels were confirmed in neurons purified from MS brains. Also, we show molecular interactions between spastin (the encoded protein of SPG4) and hnRNP-A1. These data suggest a link between autoimmunity, clinical phenotype and neurodegeneration in MS.