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CC BY-NC-ND V4.0, Open Access
Journal article
Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis
Nature (London)
2025
PMID: 41034581
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons. Neuroinflammation is apparent in affected tissues, including increased T cell infiltration and activation of microglia, particularly in the spinal cord
. Autoimmune responses are thought to have a key role in ALS pathology, and it is hypothesized that T cells contribute to the rapid loss of neurons during disease progression
. However, until now there has been no reported target for such an autoimmune response. Here we show that ALS is associated with recognition of the C9orf72 antigen, and we map the specific epitopes that are recognized. We show that these responses are mediated by CD4
T cells that preferentially release IL-5 and IL-10, and that IL-10-mediated T cell responses are significantly greater in donors who have a longer predicted survival time. Our results reinforce the previous hypothesis that neuroinflammation has an important role in ALS disease progression, possibly because of a disrupted balance of inflammatory and counter-inflammatory T cell responses
. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells
, and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.
Details
- Title
- Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis
- Authors/Creators
- Tanner Michaelis - La Jolla Institute for ImmunologyCecilia S Lindestam Arlehamn - Center for Vaccine Research, Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, DenmarkEmil Johansson - La Jolla Institute for ImmunologyApril Frazier - La Jolla Institute for ImmunologyJames D Berry - Massachusetts General HospitalMerit Cudkowicz - Massachusetts General HospitalNamita A Goyal - University of California, IrvineChristina Fournier - Emory UniversityAllison Snyder - University of PennsylvaniaJustin Y Kwan - National Institute of Neurological Disorders and StrokeJody Crook - National Institute of Neurological Disorders and StrokeElizabeth J Phillips - Vanderbilt University School of Medicine, Nashville, TN, USASimon A Mallal - Vanderbilt University School of Medicine, Nashville, TN, USAJohn Ravits - University of California San DiegoKaren S Marder - Columbia University Irving Medical CenterJohn Sidney - La Jolla Institute for ImmunologyDavid Sulzer - Research NetworkAlessandro Sette - La Jolla Institute for Immunology
- Publication Details
- Nature (London)
- Publisher
- Springer Nature
- Number of pages
- 26
- Identifiers
- 991005821349907891
- Copyright
- © The Author(s) 2025
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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Source: InCites
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.52 Neurodegenerative Diseases
- 1.52.765 ALS Mechanisms
- Web Of Science research areas
- Neurosciences
- ESI research areas
- Neuroscience & Behavior