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
Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, USA.
Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, USA.
Nat Commun. 2025 Aug 7;16(1):7311. doi: 10.1038/s41467-025-62380-y.
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.
副肿瘤性神经系统综合征源于对周围癌症的适应性免疫反应失调而引发的针对神经系统抗原的自身免疫反应。小细胞肺癌或恶性胸腺瘤患者可产生针对CV2/塌陷反应介质蛋白5（CRMP5）抗原的自身免疫反应，其中约80%的患者会出现疼痛性神经病变。在此，我们研究了抗CV2/CRMP5自身抗体（CV2/CRMP5-Abs）相关疼痛的潜在机制，发现源自患者的CV2/CRMP5-Abs与大鼠背根神经节（DRG）和脊髓浅表层的靶点结合，从而诱导DRG神经元兴奋性增高和机械性超敏反应。在用CRMP5 DNA疫苗免疫的大鼠中再现了源自患者抗体的这些效应，其中用抗CD20清除B细胞进行治疗可改善自身免疫和神经病变。因此，我们的数据揭示了副肿瘤性神经系统综合征患者神经性疼痛的一种机制，并表明CV2/CRMP5-Abs是治疗副肿瘤性神经系统综合征的一个潜在靶点。
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