Autonomic Regulation of the Immunological Response to Limb Injury

疼痛研究领域最近的一个主要进展是对免疫系统的认识 失调是导致损伤最严重不良后果的因素。自身炎症 涉及炎症介质和涉及自身抗体的自身免疫， 肢体创伤后慢性疼痛和残疾的患者。利用这些进步， 这项研究的首要目标是确定控制免疫系统的新方法。 肢体受伤后的激活，从而提高速度，提高恢复的质量，同时减少 慢性疼痛、功能丧失和神经精神后果，如焦虑和认知能力下降。 基于免疫学、疼痛和康复领域的证据，该项目将重点关注 损伤后免疫系统的自主调节。拟议的实验涉及一个经过充分验证的 啮齿类动物肢体损伤的胫骨骨折模型以及从患有慢性肢体疼痛的患者获得的样品 在创伤事件之后。我们的中心假设是， 免疫级联通过减少IL-6的产生将大大提高恢复的速度和质量， 自身抗体的形成和补体级联的激活。 该项目分为三个目标。在第一个目标，我们将确定是否调制自主神经 胫骨骨折后的流出减少了免疫激活并改善了恢复的关键方面。我们 假设创伤后交感神经系统激活会引起免疫反应， 包括IL-6表达、IgM自身抗体产生和补体激活的运动途径 最终导致慢性疼痛、功能衰退、焦虑和认知能力下降。激活 副交感神经系统可能有相反的效果。使用神经消融和药物 方法，我们将使用一组旨在解决多个问题的结果指标来检验这一假设。 复苏的维度。 在该项目的第二个目标中，我们强烈关注肢体损伤后IL-6信号转导作为介导者的作用 支持IgM自身抗体产生。我们假设阻断交感神经增强的 肢体损伤后IL-6的产生将减少损伤肢体、区域淋巴结和淋巴结中自身抗原的表达， 淋巴结肥大、B细胞分化和IgM自身抗体产生。我们也会使用基因工具 作为临床上可用的生物和小分子抗IL-6剂，以确定这种细胞因子在 支持肢体损伤的长期不良后果。 最后，该项目的第三个目标是确定损伤相关的自身抗体是否支持不良反应。 结果通过外周和中枢补体系统激活。我们假设IgM 肢体受伤的小鼠和肢体受伤的患者产生的自身抗体支持补体 级联激活导致产生促痛C5 a和神经元损伤C5 b-9膜 攻击复合体我们预测，遗传补体成分缺失和药理学C5 a 受体阻滞剂将加速肢体骨折后的恢复。此外，我们预测， 损伤的小鼠和人IgM的释放会引起疼痛敏感化和相关肢体的功能丧失。 生物化学和免疫组织化学研究将确定局部补体激活和纤维丢失。 包括CRPS在内的损伤和手术后的慢性疼痛综合征具有显著的疼痛，功能性， 神经精神和经济后果。现有的治疗方法效果不佳。结束时 这些实验我们将能够设计评价交感神经溶解作用的临床方案， 使用临床可用工具的免疫调节和抗补体治疗对损伤恢复的影响 以及目前处于发展后期的一些。

A major recent advancement for the field of pain research is the recognition of immune system dysregulation as a contributor to the most serious adverse outcomes from injury. Both autoinflammation involving mediators of inflammation and autoimmunity involving autoantibodies have been identified in patients with chronic pain and disability after limb trauma. Taking advantage of these advancements, the overarching goal of the proposed research is to identify novel approaches to controlling immune system activation after limb injury thereby increasing the rate and improving the quality of recovery while reducing chronic pain, functional loss and neuropsychiatric consequences such as anxiety and cognitive decline. Building on evidence from the fields of immunology, pain and rehabilitation, this project will focus on the autonomic regulation of the immune system after injury. The proposed experiments involve a well-validated rodent tibial fracture model of limb injury as well as samples obtained from patients with chronic limb pain after traumatic events. Our central hypothesis is that interruption of a sympathetically-initiated immunological cascade will greatly enhance the rate and quality of recovery by reducing IL-6 production, autoantibody formation and activation of the complement cascade. The project is divided into three aims. In the first aim we will determine whether modulation of autonomic outflow after tibial fracture reduces immune activation and improves key dimensions of recovery. We hypothesize that post-traumatic activation of the sympathetic nervous system sets an immunological pathway in motion including IL-6 expression, IgM autoantibody production and complement activation ultimately leading to chronic pain, functional decline, anxiety and cognitive decline. Activation of the parasympathetic nervous system may have opposite effects. Using neuroablative and pharmacological approaches, we will test this hypothesis using a panel of outcome measures designed to address multiple dimensions of recovery. In the project’s second aim we focus strongly on the roles of IL-6 signaling after limb injury as a mediator supporting IgM autoantibody production. We hypothesize that blocking the sympathetically-enhanced production of IL-6 after limb injury will reduce autoantigen expression in the injured limbs, regional lymph node hypertrophy, B-cell differentiation and IgM autoantibody production. We will use genetic tools as well as clinically available biologic and small molecule anti-IL-6 agents to define the role of this cytokine in supporting the long-term adverse outcomes of limb injury. Finally, the project’s third aim is to determine whether injury-related autoantibodies support adverse outcomes via peripheral and central complement system activation. We hypothesize that IgM autoantibodies produced by limb injured mice and, translationally, limb injured patients support complement cascade activation leading to the generation of pain-promoting C5a and neuron injuring C5b-9 membrane attack complexes. We predict that genetic complement component deletion and pharmacological C5a receptor blockade will accelerate recovery after limb fracture. In addition, we predict that the local injection of injured mouse and human IgM will cause pain sensitization and functional loss in the involved limbs. Biochemical and immunohistochemical studies will identify local complement activation and fiber loss. Chronic pain syndromes after injuries and surgery including CRPS have substantial pain, functional, neuropsychiatric and financial consequences. Available treatments are poorly effective. At the conclusion of these experiments we will be in position to design clinical protocols evaluating the impact of sympatholysis, immunomodulation and anti-complement therapeutics on recovery from injury using clinically available tools and ones currently in late stages of development.