Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain

Martin, L.; Stratton, H. J.; Gomez, K.; Do, L.; Loya-lopez, S.; Tang, C.; Calderon-rivera, A.; Ran, D.; Nunn, V.; Bellampalli, S. S.; Francois-Moutal, L.; Dumaire, N. L. A.; Salih, L.; Luo, S.; Porreca, F.; Ibrahim, M.; Rogemond, V.; Honnorat, J.; Khanna, R.; Moutal, A.

doi:10.1101/2024.05.04.592533

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bioRxiv · 10.1101/2024.05.04.592533

Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain

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Abstract

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. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.

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Martin, L., Stratton, H. J., Gomez, K., Do, L., Loya-lopez, S., Tang, C., Calderon-rivera, A., Ran, D., Nunn, V., Bellampalli, S. S., Francois-Moutal, L., Dumaire, N. L. A., Salih, L., Luo, S., Porreca, F., Ibrahim, M., Rogemond, V., Honnorat, J., Khanna, R., Moutal, A.. 2024-05-07. Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain. https://doi.org/10.1101/2024.05.04.592533

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