TY - JOUR
T1 - Anti-CV2/CRMP5 autoantibodies as drivers of sensory neuron excitability and pain in rats
AU - Martin, Laurent
AU - Stratton, Harrison J.
AU - Salih, Lyuba Y.
AU - Dumaire, Nicolas L.A.
AU - Gomez, Kimberly
AU - Do, Le Duy
AU - Loya-Lopez, Santiago
AU - Tang, Cheng
AU - Calderon-Rivera, Aida
AU - Ran, Dongzhi
AU - Nunna, Venkatrao
AU - Bellampalli, Shreya S.
AU - François-Moutal, Liberty
AU - Luo, Shizhen
AU - Porreca, Frank
AU - Ibrahim, Mohab
AU - Rogemond, Véronique
AU - Honnorat, Jérôme
AU - Khanna, Rajesh
AU - Moutal, Aubin
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen, with approximately 80% of these patients experiencing painful neuropathies. Here we investigate the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain and find that patient-derived CV2/CRMP5-Abs bind to their target on rat dorsal root ganglia (DRG) and superficial laminae of the spinal cord, to induce DRG neuron hyperexcitability and mechanical hypersensitivity. These effects from patient-derived Abs are recapitulated in rats immunized with a DNA vaccine for CRMP5, in which therapeutic treatment with anti-CD20 depleting B cells ameliorates autoimmunity and neuropathy. Our data thus reveal a mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes and implicates CV2/CRMP5-Abs as a potential target for treating paraneoplastic neurological syndromes.
AB - Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen, with approximately 80% of these patients experiencing painful neuropathies. Here we investigate the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain and find that patient-derived CV2/CRMP5-Abs bind to their target on rat dorsal root ganglia (DRG) and superficial laminae of the spinal cord, to induce DRG neuron hyperexcitability and mechanical hypersensitivity. These effects from patient-derived Abs are recapitulated in rats immunized with a DNA vaccine for CRMP5, in which therapeutic treatment with anti-CD20 depleting B cells ameliorates autoimmunity and neuropathy. Our data thus reveal a mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes and implicates CV2/CRMP5-Abs as a potential target for treating paraneoplastic neurological syndromes.
UR - https://www.scopus.com/pages/publications/105012742754
UR - https://www.scopus.com/pages/publications/105012742754#tab=citedBy
U2 - 10.1038/s41467-025-62380-y
DO - 10.1038/s41467-025-62380-y
M3 - Article
C2 - 40775229
AN - SCOPUS:105012742754
SN - 2041-1723
VL - 16
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 7311
ER -