Neural Immunoregulation of Post-Traumatic Autoimmunity

项目摘要 肢体创伤可导致复杂区域疼痛综合征（CRPS）的发展，这是一种潜在的 使人衰弱的慢性状态目前对CRPS的发病机制或治疗方法还没有达成共识， 明确需要翻译和CRPS组织研究来确定治疗靶点和有效的 治疗。 最近的观察表明，一些CRPS患者表达自身抗体，并对 静脉注射免疫球蛋白治疗。其他报告表明：1）Langerhans抗原提呈 细胞在CRPS受累肢体中增殖，2）抗核自身抗体存在于一些CRPS患者中， 和3）在某些CRPS患者中可以鉴定出与特定HLA基因座的遗传关联。我们自己 研究表明，骨折小鼠模型中的CRPS样变化依赖于抗体的产生， 用骨折小鼠或CRPS患者血清治疗后， 移植到缺乏抗体的骨折小鼠体内。此外，在小鼠骨折后， 刺激抗体在皮肤、神经和支配受伤后肢的脊髓中积聚， 触发后爪皮肤中的朗格汉斯细胞增殖。此外，从以下来源获得的IgM血清抗体 骨折小鼠与骨折肢皮肤中的真皮细胞核抗原结合，但在对侧完整后肢中不结合 皮肤这些观察结果可能会改变范式。指导我们工作的核心假设是， 肢体创伤引起先天性和适应性免疫系统的神经激活， 新抗原的表达最终支持伤害性敏化。 该提案的主要目的是确定成功治疗的特定药理学靶点。 CRPS的治疗具体目标是：1）绘制骨折后树突状细胞抗原的变化 皮肤、淋巴结、坐骨神经中的募集、成熟、运输和适应性免疫应答，以及 脊髓，2）以确定是否被动转移自身免疫发生时，免疫球蛋白获得 将来自骨折小鼠或CRPS患者的药物注射到其他小鼠体内，可能会重新点燃CRPS样 在骨折后小鼠中的后遗症，并解决CRPS症状，此外，使用小鼠和CRPS患者 用于鉴定区域限制性自身抗原的抗体骨折小鼠皮肤、神经、脊髓和骨折骨痂， 和CRPS患者皮肤中，以及3）确定是否感觉神经肽或交感肾上腺素能 信号传导是创伤后自身免疫反应发展所必需的。 这些实验将为探索创伤后应激反应的机制奠定坚实的基础 自身免疫，大大提高我们对CRPS的认识，确定未来CRPS的特异性分子靶点 试验，并可能提出新的机制，支持其他神秘的慢性疼痛综合征。

PROJECT SUMMARY Limb trauma can lead to the development of complex regional pain syndrome (CRPS), a potentially debilitating chronic state. Currently there is no consensus on either the pathogenesis or treatment for CRPS, and translational and CRPS tissue studies are clearly needed to identify therapeutic targets and effective treatments. Recent observations suggest that some CRPS patients express autoantibodies and respond profoundly to intravenous immunoglobulin treatment. Additional reports suggest that: 1) Langerhans antigen presenting cells proliferate in CRPS affected limbs, 2) that antinuclear autoantibodies are present in some CRPS patients, and 3) that genetic associations with specific HLA loci can be identified in some CRPS patients. Our own studies indicate that CRPS-like changes in the fracture mouse model are reliant upon antibody production, and that passive transfer autoimmunity occurs after transfusing serum from either fracture mice or CRPS patients into antibody deficient fracture mice. Moreover, after fracture in mice, exaggerated substance P signaling stimulates antibody accumulating in the skin, nerves, and spinal cord innervating the injured hindlimb and triggers Langerhans cell proliferation in the hindpaw skin. Furthermore, IgM serum antibodies obtained from fracture mice bind to dermal cell nuclear antigens in fracture limb skin, but not in contralateral intact hindlimb skin. These observations are potentially paradigm shifting. The central hypothesis guiding our work is that limb trauma causes the neural activation of the innate and adaptive systems of immunity, with the regional expression of neo-antigens ultimately supporting nociceptive sensitization. The primary objective of this proposal is to identify specific pharmacologic targets for the successful treatment of CRPS. The specific aims are: 1) to map post-fracture changes in dendritic cell antigen recruitment, maturation, trafficking and adaptive immune responses in skin, lymph nodes, sciatic nerve, and spinal cord, 2) to determine whether passive-transfer autoimmunity occurs when immunoglobulin obtained from the fracture mice or from CRPS patients is injected into other mice, potentially rekindling CRPS-like sequelae in post-fracture mice with resolving CRPS symptoms, and in addition, to use mouse and CRPS patient antibodies to identify regionally restricted autoantigens fracture mouse skin, nerve, cord, and fracture callus, and in CRPS patient skin, and 3) to determine whether sensory neuropeptide or sympathetic adrenergic signaling is required for the development of post-traumatic autoimmune responses. These experiments will establish a rigorous foundation for exploring the mechanisms of post-traumatic autoimmunity, greatly improve our understanding of CRPS, identify specific molecular targets for future CRPS trials, and potentially suggest novel mechanisms supporting other enigmatic chronic pain syndromes.