Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis 9119

Abstract Description Amyotrophic lateral sclerosis (ALS), like many neurodegenerative disorders, features cytoplasmic inclusion of proteins, with the most prominent component identified being TDP-43. Neuroinflammation is also apparent in affected tissues, including elevated T cell infiltration and enhanced expression of HLA Class I and II by microglia. However, the role of T cells in ALS is still largely unknown. We have previously found that a subset of individuals with Parkinson’s disease (PD) have increased frequencies of T cells recognizing alpha-synuclein, a protein found in Lewy body aggregates in PD patients. We therefore hypothesized that autoreactive T cells could also play a role in ALS pathology. We generated 15-mer peptide pools spanning the three ALS-related proteins TDP-43, SOD1, and C9orf72. Cytokine production (IFNγ, IL-5, IL-10) against these proteins was measured by the fluorospot assay, using PBMCs collected from ALS patients and age- and sex-matched healthy controls (HCs). Intriguingly, we found that ALS patient have significantly elevated T cell responses towards C9orf72 compared to HCs, particularly IL-5 mediated T cell responses. We further found IL-5-mediated responses to be associated with higher ALS Functional Rating Scale (ALSFRS), raising the possibility that these responses exert a regulatory and protective influence on disease manifestations. Importantly, these are the first findings of autoreactive T cells playing a role in ALS pathology. Funding Sources Supported by Kyowa Kirin, Inc. (KKNA-Kyowa Kirin North America) Topic Categories Neuroimmunology (NEUR)