Nature communications · 2025
Anti-CV2/CRMP5 autoantibodies as drivers of sensory neuron excitability and pain in rats.
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Martin Laurent, Stratton Harrison J, Salih Lyuba Y, Dumaire Nicolas LA, Gomez Kimberly, Do Le Duy, Loya-Lopez Santiago, Tang Cheng, Calderon-Rivera Aida, Ran Dongzhi, Nunna Venkatrao, Bellampalli Shreya S, François-Moutal Liberty, Luo Shizhen, Porreca Frank, Ibrahim Mohab, Rogemond Véronique, Honnorat Jérôme, Khanna Rajesh, Moutal Aubin
Аннотация
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.