Neural immunoregulation of post-traumatic autoimmunity

慢性下腰痛(LBP)和骨关节炎(OA)关节痛是慢性腰痛的最常见原因 致残疼痛，尽管进行了广泛的研究，但这些情况的病理生理学仍未确定 关于它们的临床管理也有相当大的争议。显然，当前的假设是关于 组织损伤到疼痛残疾的进展，除了从身体上移除疼痛的关节外， 产生了有效和安全的治疗方法。我们最新研究的复合型小鼠胫骨骨折模型 区域疼痛综合征(CRPS)显示所有CRPS患者均表达IgM自身抗体 损伤后肢或鞘内足底注射的伤害性被动转移效应 注射入缺乏B细胞和免疫球蛋白的木乃伊骨折小鼠，以及这些促伤害性CRPS IgM C5a补体信号和炎性细胞因子的释放介导了上述作用。小鼠胫骨骨折模型的建立 导致骨折肢体真皮和C5aR中表达C5aR的巨噬细胞增加 在相应的脊髓节段表达小胶质细胞，这些激活的免疫细胞释放 促伤害性炎症细胞因子对C5a信号的反应。此外，在小鼠骨折后， 夸大神经肽和交感肾上腺素能信号刺激伤害性前体液免疫球蛋白M抗体 积聚在皮肤和脊髓中。这些观察结果可能是范式的转变。中环 指导我们工作的假设是，组织创伤导致固有和适应性系统的神经激活 新抗原在损伤组织和相应的脊髓中的定位表达 触发淋巴器官生发中心反应，其特征是形成生发B细胞， 随后的伤害性免疫复合体沉积和补体激活支持局部性 慢性伤害敏感化。这项建议的主要目标是确定特定的药理作用 成功治疗LBP和OA的目标。具体的目标是：1)识别自身免疫 慢性LBP腰椎间盘穿刺术(DP)小鼠模型的伤害性敏化反应 并在碘乙酸单钠关节炎(MIA)小鼠的慢性膝骨关节炎模型上，测定 LBP和OA患者中伤害性原抗体的流行率，并确定获得性免疫反应在 LBP患者的腰椎间盘和OA患者的关节，2)时间标测淋巴生发的形成 中心，其特征是诱导T滤泡辅助细胞(TFH)、生发中心B细胞和 在DP和MIA小鼠模型中产生伤害感受性抗体，以及3)确定 感觉神经肽和交感肾上腺素能信号构成激活的统一机制 以及维持对组织损伤的免疫反应。这些实验可能会建立一个 为探索组织损伤诱导自身免疫的机制奠定坚实的基础，促进我们的 了解肌肉骨骼疼痛，并确定未来临床试验的特定靶点。

Chronic low back pain (LBP) and osteoarthritic (OA) joint pain are the most common causes of chronic disabling pain and despite extensive investigation the pathophysiology of these conditions remains undefined and there is considerable controversy regarding their clinical management. Clearly current hypotheses for the progression of tissue injury to painful disability have not, short of removing the painful joint from the body, generated effective and safe treatments. Our recent studies in the mouse tibia fracture model of complex regional pain syndrome (CRPS) demonstrated that all CRPS patients expressed IgM autoantibodies with pronociceptive passive transfer effects after intraplantar injection into the injured hindlimb or intrathecal injection into muMT fracture mice lacking B cells and immunoglobulin, and these pronociceptive CRPS IgM effects were mediated by C5a complement signaling and inflammatory cytokine release. Tibia fracture in mice caused an increase of C5a receptor (C5aR) expressing macrophages in the fracture limb dermis and C5aR expressing microglia in the corresponding spinal cord segments, and these activated immune cells release pronociceptive inflammatory cytokines in response to C5a signaling. Moreover, after fracture in mice, exaggerated neuropeptide and sympathetic adrenergic signaling stimulated pronociceptive IgM antibody accumulation in the skin and spinal cord. These observations are potentially paradigm shifting. The central hypothesis guiding our work is that tissue trauma causes neural activation of the innate and adaptive systems of immunity, with localized neoantigen expression in the injured tissue and corresponding spinal cord triggering lymph organ germinal center reactions characterized by the formation germinal B cells, with subsequent pronociceptive immune complex deposition and complement activation supporting localized chronic nociceptive sensitization. The primary objective of this proposal is to identify specific pharmacologic targets for the successful treatment of LBP and OA. The specific aims are; 1) to identify the autoimmune responses mediating nociceptive sensitization in the lumbar disc puncture (DP) mouse model of chronic LBP and in the monosodium iodoacetate arthritis (MIA) mouse model of chronic OA knee pain, to determine the prevalence of pronociceptive antibodies in LBP and OA patients, and to identify adaptive immune responses in LBP patient spinal discs and OA patient joints, 2) to temporally map the formation of lymph node germinal centers, characterized by the induction of T follicular helper cells (Tfh), germinal center B cells, and the production of pronociceptive antibodies in the DP and MIA mouse models, and 3) to determine whether sensory neuropeptide and sympathetic adrenergic signaling constitute a unifying mechanism for the activation and maintenance of the immune response to tissue injury. These experiments potentially will establish a rigorous foundation for exploring mechanisms of tissue injury induced autoimmunity, advance our understanding of musculoskeletal pain, and identify specific targets for future clinical trials.