Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States.
Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, United States.
Pain. 2023 Feb 1;164(2):421-434. doi: 10.1097/j.pain.0000000000002725. Epub 2022 Jul 7.
Previously, we observed that B cells and autoantibodies mediated chronic nociceptive sensitization in the mouse tibia fracture model of complex regional pain syndrome and that complex regional pain syndrome patient antibodies were pronociceptive in fracture mice lacking mature B cells and antibodies (muMT). The current study used a lumbar spinal disk puncture (DP) model of low back pain in wild-type (WT) and muMT mice to evaluate pronociceptive adaptive immune responses. Spinal disks and cords were collected 3 weeks after DP for polymerase chain reaction and immunohistochemistry analyses. Wild-type DP mice developed 24 weeks of hindpaw mechanical allodynia and hyperalgesia, grip weakness, and a conditioned place preference response indicative of spontaneous pain, but pain responses were attenuated or absent in muMT DP mice. Spinal cord expression of inflammatory cytokines, immune cell markers, and complement components were increased in WT DP mice and in muMT DP mice. Dorsal horn immunostaining in WT DP mice demonstrated glial activation and increased complement 5a receptor expressionin spinal neurons. Serum collected from WT DP mice and injected into muMT DP mice caused nociceptive sensitization, as did intrathecal injection of IgM collected from WT DP mice, and IgM immune complexes were observed in lumbar spinal disks and cord of WT DP mice. Serum from WT tibia fracture mice was not pronociceptive in muMT DP mice and vice versa, evidence that each type of tissue trauma chronically generates its own unique antibodies and targeted antigens. These data further support the pronociceptive autoimmunity hypothesis for the transition from tissue injury to chronic musculoskeletal pain state.
先前，我们观察到 B 细胞和自身抗体介导了复杂性区域疼痛综合征小鼠胫骨骨折模型中的慢性痛觉敏化，并且复杂性区域疼痛综合征患者的抗体在缺乏成熟 B 细胞和抗体（muMT）的骨折小鼠中具有致痛作用。本研究使用野生型（WT）和 muMT 小鼠的腰椎间盘穿刺（DP）模型来评估致痛适应性免疫反应。DP 后 3 周收集脊髓和脊髓进行聚合酶链反应和免疫组织化学分析。WT DP 小鼠发展出 24 周的后爪机械性痛觉过敏和痛觉过敏、握力减弱以及自发性疼痛的条件性位置偏好反应，但 muMT DP 小鼠的疼痛反应减弱或消失。WT DP 小鼠的脊髓炎症细胞因子、免疫细胞标志物和补体成分表达增加，muMT DP 小鼠也增加。WT DP 小鼠的背角免疫染色显示胶质细胞激活和脊髓神经元中补体 5a 受体表达增加。从 WT DP 小鼠收集的血清并注射到 muMT DP 小鼠中引起痛觉敏化，WT DP 小鼠的鞘内注射 IgM 也是如此，并且在 WT DP 小鼠的腰椎间盘和脊髓中观察到 IgM 免疫复合物。WT 胫骨骨折小鼠的血清在 muMT DP 小鼠中没有致痛作用，反之亦然，这表明每种类型的组织创伤都会慢性产生其自身独特的抗体和靶向抗原。这些数据进一步支持了从组织损伤到慢性肌肉骨骼疼痛状态的过渡的致痛自身免疫假说。
