Abstract
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 (hnRNPA1). 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 hnRNPA1 protein in neuronal cells. These findings indicate that anti-hnRNPA1 antibodies might contribute to the pathogenesis of MS.
Highlights
Antibodies have been implicated in the pathogenesis of a number of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), paraneoplastic syndromes, multiple sclerosis (MS), and human T-lymphotropic virus type 1(HTLV1) associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1,2,3,4,5,6,7,8,9]
We have shown that antibodies to hnRNP A1-M9 are capable of penetrating SK-N-SH neuronal cells through clathrin-mediated endocytosis
Anti-hnRNP A1-M9 antibodies added directly into the media penetrated near the efficiency rate seen previously through transfection methods of anti-hnRNP A1-M9 antibodies into the SK-N-SH neuronal cells [9]
Summary
Antibodies have been implicated in the pathogenesis of a number of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), paraneoplastic syndromes, multiple sclerosis (MS), and human T-lymphotropic virus type 1(HTLV1) associated myelopathy/tropical spastic paraparesis (HAM/TSP) (a viral model of MS) [1,2,3,4,5,6,7,8,9]. In neurological disease previous data suggested that only neuronal surface antigens were reliable targets for pathogenic autoimmune responses [12,13]. Autoantibodies to enolase, a cytoplasmic glycolytic enzyme, were shown to penetrate neurons and alter the function of enolase [14] Another example is present in a model of stiff man syndrome in which anti-amphiphysin antibodies entered neurons and co-localized with presynaptic markers and altered gamma-aminobutyric acid (GABA) release in vivo [15]. To better understand the contribution of immune responses to intra-neuronal antigens in the pathogenesis of immune-mediated neurological diseases, more information is required
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