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Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis

Michaelis, Tanner ; Lindestam Arlehamn, Cecilia S. ; Johansson, Emil LU orcid ; Frazier, April ; Berry, James D. ; Cudkowicz, Merit ; Goyal, Namita A. ; Fournier, Christina ; Snyder, Allison and Kwan, Justin Y. , et al. (2025) In Nature 647(8091). p.970-978
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 cord1,2. 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 progression3,4. 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... (More)

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 cord1,2. 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 progression3,4. 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 responses4. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells5, and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
647
issue
8091
pages
9 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:41034581
  • scopus:105017654789
ISSN
0028-0836
DOI
10.1038/s41586-025-09588-6
language
English
LU publication?
yes
id
2a9d8460-b3f7-4a71-bead-d9156beb4292
date added to LUP
2025-12-08 11:38:59
date last changed
2025-12-08 11:39:32
@article{2a9d8460-b3f7-4a71-bead-d9156beb4292,
  abstract     = {{<p>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<sup>1,2</sup>. 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<sup>3,4</sup>. 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<sup>+</sup> 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<sup>4</sup>. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells<sup>5</sup>, and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.</p>}},
  author       = {{Michaelis, Tanner and Lindestam Arlehamn, Cecilia S. and Johansson, Emil and Frazier, April and Berry, James D. and Cudkowicz, Merit and Goyal, Namita A. and Fournier, Christina and Snyder, Allison and Kwan, Justin Y. and Crook, Jody and Phillips, Elizabeth J. and Mallal, Simon A. and Ravits, John and Marder, Karen S. and Sidney, John and Sulzer, David and Sette, Alessandro}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  number       = {{8091}},
  pages        = {{970--978}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis}},
  url          = {{http://dx.doi.org/10.1038/s41586-025-09588-6}},
  doi          = {{10.1038/s41586-025-09588-6}},
  volume       = {{647}},
  year         = {{2025}},
}