Myelin Autoantigens in Neuropathic Pain

我们认为，由无害的机械刺激引起的病理性疼痛，如轻微的触摸或轻微的空气 运动(定义为机械性痛觉异常)代表女性的一种自身免疫性疾病。这在概念上是 对这种顽固性慢性疼痛表型的新观点是我们更新应用的首要论题。近期 开创性工作涉及获得性免疫/T细胞和先天性免疫系统/小胶质细胞在 雌性和雄性啮齿动物的机械性痛觉异常。然而，这种性行为的机制 二态现象比较隐晦。我们的突破性数据表明，一种已知的自身抗原，髓鞘 碱性蛋白(MBP)是机械性异位痛性二形性的机制关键。我们建议 机械敏感型Aβ传入纤维上的任何髓鞘损伤，包括物理损伤，都会导致蛋白分解 释放隐蔽的MBP多肽，通常不受免疫监视。编码该基因的多肽 MBP的中央(84-104)区域(MBP84-104)对光接触(Aβ)产生直接、强大和持久的超敏反应 纤维介导)，而不是热(C纤维介导)刺激。保守的组氨酸(H)-89位点需要 MBP84-104的细胞内转运和镇痛活性。使用生化和分子工具，包括 质谱学、RNA测序、生物信息学、结构建模和免疫捕获野生型， 突变多肽和对照多肽，结合严格的药理学、神经病理学和行为学 分析，我们发现了一组MBP84-104相互作用因子和下游信号转导因子促进 女性(和/或保护男性免受)痛觉过敏症的发展。这些与MBP84-104相关的销售线索 在痛觉回路中已确定的角色，如X染色体印记基因白介素6，在这里与一种 脂质、免疫和雌激素受体信号通路的主要调节者，肝脏X受体，这是新的 痛苦的领域。凭借我们独特的、累积的工具集和严格的数据，在 PI、Veronica Shubayev(UCSD)、Tony Yaksh(UCSD)和Alex Strongin(SBP)的团队，我们的目标是 确定神经、背根神经节和脊髓中导致性行为的精确分子事件 神经病理性疼痛中的二形性。我们希望我们的创新发现将促进概念上的发展 用于顽固性慢性疼痛的新型止痛疗法。

We propose that pathological pain from innocuous mechanical stimulation such as light touch or slight air movement (defined as mechanical allodynia) represents an autoimmune disorder in females. This conceptually new view of this refractory chronic pain phenotype is the overarching thesis of our renewal application. Recent seminal work implicates adaptive immune/T cells and innate immune system/microglia in the development of mechanical allodynia in female and male rodents, respectively. However, the mechanisms of this sexual dimorphism phenomenon are obscure. Our groundbreaking data suggests that a known auto-antigen, myelin basic protein (MBP), holds the mechanistic key to sexual dimorphism in mechanical allodynia. We suggest that any, including physical, damage to myelin sheath on mechanosensitive Aβ-afferent fibers results in proteolytic liberation of cryptic MBP peptides normally sheltered from immunosurveillance. The peptide encoding the central (84-104) region of MBP (MBP84-104) produces direct, robust and lasting hypersensitivity to light touch (Aβ fiber-mediated) but not thermal (C fiber-mediated) stimulation. The conserved histidine (H)-89 site is required to intracellular transport and the algesic activity of MBP84-104. Using biochemical and molecular tools, including mass-spectrometry, RNA-sequencing, bioinformatics, structural modeling, and immunocapture of wildtype, mutant and control peptides, combined with rigorous pharmacological, neuropathological, and behavioral analyses, we identified a cluster of the MBP84-104 interactors and downstream signaling factors promoting in females (and/or protecting males from) the development of allodynia. These MBP84-104-related leads with the established roles in pain circuitry, such as the X-chromosome imprinted gene interleukin 6, are here linked to a master-regulator of lipid, immune and estrogen receptor signaling pathways, liver X receptor, which is new to the pain field. With our unique, accrued toolset and rigorous data obtained in a prolific collaboration among the teams of the PI, Veronica Shubayev (UCSD) with Tony Yaksh (UCSD) and Alex Strongin (SBP), we aim to identify the precise molecular events in nerve, dorsal root ganglia and spinal cord leading to the sexual dimorphism in neuropathic pain. We expect our innovative findings will foster the development of conceptually novel analgesic therapeutics useful in refractory types of chronic pain.