Autonomic Regulation of the Immunological Response to Limb Injury

最近疼痛研究领域的一个重大进展是对免疫系统的识别 管理失调是造成最严重的伤害不良后果的一个因素。两者都是自体炎症 涉及炎症介质和涉及自身抗体的自身免疫已在 肢体创伤后有慢性疼痛和残疾的患者。利用这些进步， 这项拟议研究的首要目标是确定控制免疫系统的新方法 肢体损伤后激活，从而在减少的同时提高恢复的速度和质量 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，该项目将侧重于 损伤后免疫系统的自主调节。拟议的实验涉及一种经过充分验证的 啮齿动物四肢损伤胫骨骨折模型及慢性肢体疼痛标本 在创伤性事件之后。我们的中心假设是，由同情心发起的 免疫级联将通过减少IL-6的产生来大大提高恢复的速度和质量， 自身抗体的形成和补体的级联激活。 该项目分为三个目标。在第一个目标中，我们将确定自主神经的调制 胫骨骨折后的外流降低了免疫活性，并改善了康复的关键方面。我们 假设创伤后交感神经系统的激活会使免疫学 运动途径包括IL-6表达、IgM自身抗体产生和补体激活 最终导致慢性疼痛、功能衰退、焦虑和认知衰退。激活 副交感神经系统可能会产生相反的作用。使用神经消融剂和药理学 方法，我们将使用一组旨在解决多个问题的结果度量来检验这一假设 复苏的维度。 在项目的第二个目标中，我们主要关注肢体损伤后IL-6信号作为中介的作用 支持IgM自身抗体的产生。我们假设阻止同情性增强的 肢体损伤后IL-6的产生将减少损伤肢体、区域淋巴中自身抗原的表达 结节肥大、B细胞分化和IgM自身抗体产生。我们还将使用基因工具 作为临床上可用的生物和小分子抗IL-6药物来确定该细胞因子在 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与损伤相关的自身抗体是否支持不良反应 通过外周和中枢补体系统激活的结果。我们假设免疫球蛋白M 肢体损伤小鼠产生的自身抗体，翻译过来，肢体损伤患者支持补体 级联激活导致促痛C5a的产生和神经元对C5b-9膜的损伤 攻击复合体。我们预测遗传补体成分缺失和药理学C5a 受体阻断将加速肢体骨折后的恢复。此外，我们预测局部注射 损伤的小鼠和人的IgM会导致受累肢体的疼痛敏感化和功能丧失。 生化和免疫组织化学研究将确定局部补体激活和纤维丢失。 创伤和手术后的慢性疼痛综合征，包括CRPS，有实质性的疼痛，功能性的， 神经精神和经济后果。现有的治疗方法效果不佳。在……结束时 这些实验将使我们能够设计临床方案，评估交感神经溶解的影响， 应用临床可用的工具进行免疫调节和抗补体治疗对创伤后康复的影响 还有一些目前处于后期开发阶段。

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.