Autoimmunity due to molecular mimicry as a cause of neurological disease

Abstract

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 1,2 . This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS) 1-4 . 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 -7 ). HAM/TSP patients develop antibodies to neurons 8 . 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 7 . 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. To test for molecular mimicry between an environmental agent and the central nervous system (CNS), we isolated immunoglobulin G (IgG) from the serum of patients with human Tlymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and tested it for reactivity with human tissues (Fig. 1a). There was intense staining of neurons in brain and no staining of glia, dorsal root ganglion (peripheral nervous system) or systemic organs. A monoclonal antibody to HTLV-1-tax (tax mAb) mimicked IgG staining of neurons. To identify the protein, cortical neurons were isolated, proteins extracted and subjected to SDS-PAGE and western-blot analysis. The IgG recognized a band of approximately 33 kD (Fig. 1b), whereas IgG isolated from controls did not. Importantly, the tax mAb that stained CNS neurons reacted with the antigen. All patients with HAM/TSP (13/13) developed antibodies recognizing the neuronal antigen 8 . Nine of ten HTLV-1-seropositive patients without neurological symptoms and 12 HTLV-1-seronegative controls showed no reactivity (P < 0.0001 versus HAM/TSP) 8 . Clinically, the HAM/TSP patients presented with progressive neurological disease in which corticospinal tract damage (weakness, spasticity and pathological reflexes) predominated 6 . Many of our patients were originally diagnosed with MS. In fact, one of our patients was diagnosed with MS for 20 years before HTLV-1 testing 10 .To establish a direct link between the immune response to HTLV-1 and the neurological...

Identification of pyruvate kinase as an antigen associated with Tourette syndrome

“…Antibodies to neuronal targets have been implicated in the pathology of several neurological disorders including Sydenham's chorea (Kirvan et al, 2003), GuillainBarre syndrome (Ang et al, 2004) and multiple sclerosis (MS) (Gran et al, 1999;Levin et al, 2002). Furthermore, antibodies to the intracellular heterogeneous nuclear ribonuclear protein-A1 have been shown to cause a neurological disease related to MS (Levin et al, 2002), and a recent study has shown an increase in serum levels of the cytokines IL-12 and TNFα in TS .…”

PANDAS: current status and directions for research

“…[46][47][48][49] There is also evidence for a genetic predisposition as the rates of tic disorders and OCD in first-degree relatives of children in the PANDAS subgroup are higher than those in the general population, and similar to those previously reported for tic disorders and OCD. 50 Several groups have reported the presence of antineuronal antibodies among patients with childhood-onset OCD and/or tic disorders.…”

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

“…Para definir de manera más precisa el proceso autoinmune observado en la paraparesia espástica tropical de la costa pacífica colombiana, es importante determinar el tipo de citocinas producidas diferencialmente por las poblaciones de sus linfocitos T ayudadores (Th (17), quienes identificaron una proteína de aproximadamente 35 kDa en neuronas de corteza cerebral normal humana, la cual reacciona en forma cruzada con un anticuerpo monoclonal para la proteína tax del HTLV-I. Sin embargo, un punto importante de nuestro trabajo es que expande el proceso de reacción cruzada de anticuerpos antitaxp40 no sólo al cerebro sino a regiones de la médula espinal, como la lumbar y la sacra, que jugarían un papel importante en el fisiopatología de la enfermedad en estos pacientes.…”

“…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).…”