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Abstract Details

Contribution of an Anti-Neuronal Immune Response to Neurodegeneration in Multiple Sclerosis
MS and Related Diseases
S50 - (-)
007
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).
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.
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.
Anti-hnRNP A1 antibodies target neurons and contribute to neurodegeneration in MS models of immune mediated neurologic disease.
Authors/Disclosures
Michael C. Levin, MD, FAAN (University of Saskatchewan)
PRESENTER 		Dr. Levin has received personal compensation for serving as an employee of Merck. Dr. Levin has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Levin has received research support from CIHR.
No disclosure on file
Lidia Gardner, PhD, EMBA (Novartis Pharmaceutical Corporation) Dr. Gardner has stock in EMD Serono.
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Benjamin M. Segal, MD (University of Michigan) Dr. Segal has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bloom, Inc. Dr. Segal has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lily. The institution of Dr. Segal has received research support from NIH. Dr. Segal has received intellectual property interests from a discovery or technology relating to health care. Dr. Segal has received intellectual property interests from a discovery or technology relating to health care. Dr. Segal has received personal compensation in the range of $5,000-$9,999 for serving as a Expert talks moderator; writer/ commentator with Ology Medical 好色先生, Inc/ Neurodiem.
No disclosure on file