Postdoctoral Fellow La Jolla Institute for Immunology La Jolla, California, United States
Disclosure(s):
Emil Johansson, PhD: No financial relationships to disclose
Introduction/Rationale: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron loss and eventual paralysis. While autoimmune mechanisms have long been suspected to contribute to ALS pathology, disease-associated antigen targets have remained elusive.
Methods: We analyzed if ALS was associated with increased autoreactive T cell responses towards TDP-43, SOD1, and C9orf72, compared to healthy controls. Peptide megapools consisting of 15 amino acid peptides overlapping by 10 residues spanning the entire sequence was synthesized for each protein. Fluorospot assays were used to measure T cell responses to the peptide pools by measuring release of interferon-γ (IFNγ), interleukins 5 (IL-5) and 10 (IL-10).
Results: We demonstrate that the ALS-associated protein C9orf72 is a major antigenic target in ALS. Epitope mapping revealed multiple immunogenic regions across the C9orf72 protein. While the reactivity was found broadly in ALS subjects, the responses were particularly high ALS donors who carried the C9orf72 hexanucleotide repeat expansion mutation in the non-coding regions of the gene. Importantly, IL-10-mediated responses were significantly higher in individuals with longer predicted survival, suggesting a regulatory and potentially protective influence on disease progression.
Conclusion: Together, these findings identify the first defined target of autoreactive T cell responses in ALS, and support the hypothesis that disease trajectory is in part shaped by the balance of inflammatory and counter-inflammatory T cell activity.
