Molecular mimicry in neurological disease: what is the evidence?

Abstract

Autoimmune diseases are a leading cause of disability and are increasing in incidence in industrialized countries. How people develop autoimmune diseases is not completely understood, but is related to an interaction between genetic background, environmental agents, autoantigens and the immune response. Molecular mimicry continues to be an important hypothesis that explains how an infection with an environmental agent results in autoimmune disease of the nervous system and other target organs. Although molecular mimicry has yet to be unequivocally proven, in the past several years there has been a sharpening of its definition with better experimental data implicating it as a cause of neurological disease in humans.

Antibodies to Heterogenous Nuclear Ribonucleoprotein A1 Penetrate Neurons Leading to Multiple Downstream Effects Resulting in Neurodegeneration

“…Molecular mimicry is one mechanism that explains the association between an autoimmune response to an environmental agent acting as a contributor to the pathogenesis of MS. [87][88][89][90][91][92] The hypothesis of molecular mimicry describes the molecular consequences of immunological cross reactivity: when T-cells or antibodies specific for an environmental agent (such as a virus) cross react with a host antigen, resulting in target cell and organ damage. Previously it has been shown that patients with HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), an HTLV-1 virus induced spastic paraparesis clinically similar to MS, produce autoantibodies to the RNA binding protein hnRNP A1.…”

“…[112][113][114] In addition, antibodies to hnRNP A1, B2 (hnRNP A1/B2) were present in CSF of MS and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, but not in normal controls. 12,[92][93][94]97,98,115 hnRNPs are RNA-binding proteins that play a major role in adjustment of pre-mRNA splicing through various factors. 116 They also participate in mRNA stability, NF-k-ß dependent transcription and telomerase activity.…”

“…For example, patients with MS and HAM/TSP have been shown to produce autoantibodies to the M9 epitope of the protein hnRNP A1. 11,12,[92][93][94][95]97,98,125 Other autoimmune disorders have also implicated various autoantibodies specific to certain diseases. Anti-recoverin antibodies were found to be present in patients with cancer associated retinopathy (CAR).…”

“…[130][131][132] Importantly, MS patients have been shown to develop autoantibodies to the RBP hnRNP A1. 11,12,92,94,95,97,98,125 Epitope analyses has shown that the antibody response in MS patients is specific for the 'M9' region of hnRNP A1. M9 is hnRNP A1's nuclear export sequence/nuclear localization sequence (NES/NLS) which is required for hnRNP A1's transport into and out of the nucleus.…”

“…M9 is hnRNP A1's nuclear export sequence/nuclear localization sequence (NES/NLS) which is required for hnRNP A1's transport into and out of the nucleus. 12,[92][93][94][95]97,98,125,126 Previous studies have shown that anti-hnRNP A1-M9 antibodies transfected into neuronal cells cause neurodegeneration and alter the RNA expression of the spinal paraplegia genes (SPG4 (spastin), SPG7 (paraplegin), and SPG20 (spartin)). 12,125,126 Mutations in the SPGs (of which spastin is the most common) result in hereditary spastic paraparesis (HSP), which is clinically indistinguishable from progressive MS. 12,126,133 It appears there may be a potential link between anti-hnRNP A1, M9 specific antibodies, produced in MS patients and the alterations in the SPGs expression levels which could be a possible contributing factor to the neurodegeneration seen in MS.…”