Work

Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis 9119

Year: 2025

Type: article

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)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.2566