Contribution of an Anti-Neuronal Immune Response to Neurodegeneration in Multiple Sclerosis (S50.007)

OBJECTIVE: To examine whether antibodies to neurons contributed to neurodegeneration using in vitro and in vivo models of neurodegeneration. BACKGROUND: Recent data indicate that antibodies to neurons and intra-neuronal antigens are targets for autoimmune responses that contribute to the pathogenesis of neurologic disease (J Exp Med 204, 2007; Brain 133, 2010). MS patients develop antibodies to heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), an RNA binding protein overexpressed in neurons (J Neuroimmunol 235, 2011). Anti-hnRNP A1 antibodies reacted specifically with central nervous system neurons compared to systemic organs; caused decreased neuronal firing, as well as neurodegeneration and changes in gene expression related to mechanisms of neurodegeneration in neurons (J Neuroimmunol 235, 2011; Nat Med 8, 2002). DESIGN/METHODS: Anti-hnRNP A1 antibodies were incubated with SKNSH neurons, which were examined for mechanisms of cell entry and markers of neurodegeneration. Near-infrared labeled anti-hnRNP A1 antibodies were infused into SJL mice and localized with an In Vivo Imaging System (IVIS) and immunohistochemistry. Using an adoptive transfer experimental allergic encephalomyelitis (EAE) model, Th1 polarized cells were injected into mice, followed by injection of anti-hnRNP A1 and control antibodies. Brains were examined for neurodegeneration with Fluoro Jade C, a marker of degenerating neurons. RESULTS: Compared to control antibodies, anti-hnRNP A1 antibodies entered neurons more readily and co-localized within early endosomes, suggestive of endocytosis. Antibody entry was specific for clathrin-mediated endocytic pathway. Importantly, in contrast to control antibodies, anti-hnRNP A1 antibodies caused a redistribution of hnRNP A1 within neurons, apoptosis and decreased ATP levels. In vivo, anti-hnRNP A1 antibodies localized specifically to the brain and spinal cord. Compared to control animals, injection of anti-hnRNP A1 antibodies resulted in clinical worsening and increased Fluoro-Jade C staining (indicative of neurodegeneration) in an EAE model of neurodegeneration. CONCLUSIONS: Anti-hnRNP A1 antibodies target neurons and contribute to neurodegeneration in MS models of immune mediated neurologic disease. Supported by: Research Service, Department of Veterans Affairs & The MS Research Fund, University of Tennessee Health Science Center. Disclosure: Dr. Levin has received personal compensation for activities with Serono, TEVA and Biogen-Idec as a speaker and Gerson Lehman Group as a consultant. Dr. Lee has nothing to disclose. Dr. Gardner has nothing to disclose. Dr. Douglas has nothing to disclose. Dr. Shin has nothing to disclose. Dr. Sawchenko has nothing to disclose. Dr. Lalor has nothing to disclose. Dr. Segal has nothing to disclose.