Multiple sclerosis (MS) is an autoimmune disease that is increasingly being recognized as a neurodegenerative disorder. Patients with MS produce autoantibodies to heterogenous nuclear ribonucleoprotein A1 (hnRNP A1). A multitude of studies indicate that T-lymphocytes, B-lymphocytes and macrophages contribute to MS pathogenesis. However, a direct autoantibody impact on neuronal cells has received limited attention. This could be explained by the general belief that autoantibodies lack the ability to penetrate neurons. hnRNP A1 is an intracellular RNA binding protein that exports RNA from the nucleus to the cytoplasm. In this study, we investigated possible mechanisms of antibody penetration into neuronal cells. Our results show that anti-hnRNP A1 antibodies and control IgG penetrate SK-N-SH neuronal cells through clathrin-mediated endocytosis. In contrast to control antibodies, anti-hnRNP A1 antibodies produced deleterious effects on the neuronal cells including altered ATP levels and increased caspase 3/7 levels (leading to apoptosis). Remarkably, anti-hnRNP A1 antibodies that targeted the hnRNP A1 M9 domain (its nuclear export/localization sequence) caused redistribution of endogenous hnRNP A1 protein in neuronal cells. These findings indicate that anti-hnRNP A1 antibodies might contribute to the pathogenesis of MS.

For years, investigators have sought to prove that myelin antigens are the primary targets of autoimmunity in multiple sclerosis (MS). Recent experiments have begun to challenge this assumption, particularly when studying the neurodegenerative phase of MS. T-lymphocyte responses to myelin antigens have been extensively studied, and are likely early contributors to the pathogenesis of MS. Antibodies to myelin antigens have a much more inconstant association with the pathogenesis of MS. Recent studies indicate that antibodies to non-myelin antigens such as neurofilaments, neurofascin, RNA binding proteins and potassium channels may contribute to the pathogenesis of MS. The purpose of this review is to analyze recent studies that examine the role that autoantibodies to non-myelin antigens might play in the pathogenesis of MS.

Considering there are no treatments for progressive forms of multiple sclerosis (MS), a comprehensive understanding of the role of neurodegeneration in the pathogenesis of MS should lead to novel therapeutic strategies to treat it. Many studies have implicated viral triggers as a cause of MS, yet no single virus has been exclusively shown to cause MS. Given this, human and animal viral models of MS are used to study its pathogenesis. One example is human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Importantly, HAM/TSP is similar clinically, pathologically, and immunologically to progressive MS. Interestingly, both MS and HAM/TSP patients were found to make antibodies to heterogeneous nuclear ribonucleoprotein (hnRNP) A1, an RNA-binding protein overexpressed in neurons. Anti-hnRNP A1 antibodies reduced neuronal firing and caused neurodegeneration in neuronal cell lines, suggesting the autoantibodies are pathogenic. Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies revealed novel pathways of neurodegeneration related to alterations of RNA levels of the spinal paraplegia genes (SPGs). Mutations in SPGs cause hereditary spastic paraparesis, genetic disorders clinically indistinguishable from progressive MS and HAM/TSP. Thus, there is a strong association between involvement of SPGs in neurodegeneration and the clinical phenotype of progressive MS and HAM/TSP patients, who commonly develop spastic paraparesis. Taken together, these data begin to clarify mechanisms of neurodegeneration related to the clinical presentation of patients with chronic immune-mediated neurological disease of the central nervous system, which will give insights into the design of novel therapies to treat these neurological diseases.

BackgroundNeurodegeneration is believed to be the primary cause of permanent, long-term disability in patients with multiple sclerosis. The cause of neurodegeneration in multiple sclerosis appears to be multifactorial. One mechanism that has been implicated in the pathogenesis of neurodegeneration in multiple sclerosis is the targeting of neuronal and axonal antigens by autoantibodies. Multiple sclerosis patients develop antibodies to the RNA-binding protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), which is enriched in neurons. We hypothesized that anti-hnRNP A1 antibodies would contribute to neurodegeneration in an animal model of multiple sclerosis.MethodsFollowing induction of experimental autoimmune encephalomyelitis (EAE) by direct immunization with myelin oligodendrocyte glycoprotein, mice were injected with anti-hnRNP A1 or control antibodies. Animals were examined clinically, and the central nervous system (CNS) tissues were tested for neurodegeneration with Fluoro-Jade C, a marker of degenerating neural elements.ResultsInjection of anti-hnRNP A1 antibodies in mice with EAE worsened clinical disease, altered the clinical disease phenotype, and caused neurodegeneration preferentially in the ventral spinocerebellar tract and deep white matter of the cerebellum in the CNS. Neurodegeneration in mice injected with hnRNP A1-M9 antibodies compared to control groups was consistent with “dying back” axonal degeneration.ConclusionsThese data suggest that antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in immune-mediated disease of the CNS.

Multiple sclerosis (MS) is a complex autoimmune disease that impairs the central nervous system (CNS). The neurological disability and clinical course of the disease is highly variable and unpredictable from one patient to another. The cause of MS is still unknown, but it is thought to occur in genetically susceptible individuals who develop disease due to a nongenetic trigger, such as altered metabolism, a virus, or other environmental factors. MS patients develop progressive, irreversible, neurological disability associated with neuronal and axonal damage, collectively known as neurodegeneration. Neurodegeneration was traditionally considered as a secondary phenomenon to inflammation and demyelination. However, recent data indicate that neurodegeneration develops along with inflammation and demyelination. Thus, MS is increasingly recognized as a neurodegenerative disease triggered by an inflammatory attack of the CNS. While both inflammation and demyelination are well described and understood cellular processes, neurodegeneration might be defined by a diverse pool of any of the following: neuronal cell death, apoptosis, necrosis, and virtual hypoxia. In this review, we present multiple theories and supporting evidence that identify common biological processes that contribute to neurodegeneration in MS.