Neural Immunoregulation of Post-Traumatic Autoimmunity

创伤后自身免疫的神经免疫调节

• 批准号: 9765423
• 负责人: DAVID J. CLARK
• 金额: $ 33.48万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765423
• 关键词: Adrenergic Agents; Affect; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Antinuclear Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Binding; Biopsy; Bone callus; Calcitonin-Gene Related Peptide Receptor; Cell Proliferation; Cells; Chronic; Clinical Trials; Complement Activation; Complex Regional Pain Syndromes; Consensus; Contralateral; Cutaneous; Dendritic Cells; Deposition; Dermal; Development; Distal; Edema; Etiology; Exhibits; Extravasation; FDA approved; Foundations; Fracture; Functional disorder; Future; Goals; Hindlimb; Immobilization; Immunity; Immunoglobulin M; Immunoglobulins; Inflammatory; Intravenous Immunoglobulins; Investigation; Label; Langerhans cell; Lead; Limb structure; Maintenance; Maps; Mediating; Microvascular Permeability; Modeling; Molecular; Molecular Target; Mus; Natural Immunity; Nerve; Neuroimmune; Neuropeptides; Nociception; Nuclear; Nuclear Antigens; Pain; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Play; Proliferating; Quality of life; Reporting; Role; Sensory; Serum; Signal Pathway; Signal Transduction; Skin; Skin Temperature; Spinal Cord; Spinal cord injury; Substance P; Symptoms; Syndrome; System; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Trauma; Work; adaptive immune response; adaptive immunity; allodynia; beta-2 Adrenergic Receptors; bone loss; chronic pain; cohort; cytokine; effective therapy; experimental study; fluorophore; genetic association; immunoregulation; improved; injured; keratinocyte; limb fracture; lymph nodes; mouse model; neoantigens; novel; pain reduction; recruit; relating to nervous system; rituximab; sciatic nerve; therapeutic target; tibia; trafficking; translational study

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.

项目总结 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尚无共识， 而翻译和CRPS组织研究显然需要确定治疗靶点和有效 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。更多的报告表明：1)朗格汉斯抗原呈现 CRPS患肢细胞增殖，2)部分CRPS患者存在抗核自身抗体， (3)在部分CRPS患者中可发现与特定的人类白细胞抗原基因座相关的基因。我们自己的 研究表明，骨折小鼠模型中CRPS样变化依赖于抗体的产生，并且 被动转移自身免疫在输注骨折小鼠或CRPS患者的血清后发生 转化为抗体缺陷的骨折小鼠。此外，在小鼠骨折后，P物质信号被夸大 刺激抗体在皮肤、神经和脊髓中积聚，支配受伤的后肢和 触发后爪皮肤中的朗格汉斯细胞增殖。此外，从日本血吸虫中获得的IgM血清抗体 骨折小鼠在骨折肢体皮肤与真皮细胞核抗原结合，但在健侧完好的后肢不结合 皮肤。这些观察结果可能是范式的转变。指导我们工作的中心假设是 肢体创伤导致神经激活固有的和适应性的免疫系统，与区域 新抗原的表达最终支持伤害性敏感化。 这项建议的主要目标是确定成功治疗的特定药物靶点。 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图 皮肤、淋巴结、坐骨神经的募集、成熟、运输和适应性免疫反应 脊髓，2)以确定当获得免疫球蛋白时是否发生被动转移自身免疫 来自骨折小鼠或CRPS患者的注射到其他小鼠，可能重新点燃CRPS样 小鼠骨折后CRPS症状缓解后的后遗症，并使用小鼠和CRPS患者 识别局部限制性自身抗原断裂小鼠皮肤、神经、脊髓和骨折骨痂的抗体， 和CRPS患者皮肤中，以及3)确定感觉神经肽或交感肾上腺素 信号对于创伤后自身免疫反应的发展是必需的。 这些实验将为探索创伤后的机制奠定坚实的基础。 自身免疫，极大地提高了我们对CRPS的认识，为未来的CRPS识别特定的分子靶点 试验，并可能提出支持其他神秘的慢性疼痛综合征的新机制。