Neural Immunoregulation of Post-Traumatic Autoimmunity

创伤后自身免疫的神经免疫调节

• 批准号: 9172811
• 负责人: DAVID J. CLARK
• 金额: $ 35.23万
• 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/9172811
• 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; Neuropeptides; Nociception; Nuclear; Nuclear Antigens; Pain; Pathogenesis; Patients; Pharmaceutical Preparations; 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 immunity; allodynia; beta-2 Adrenergic Receptors; bone loss; chronic pain; cohort; cytokine; effective therapy; fluorophore; genetic association; immunoregulation; improved; injured; keratinocyte; limb fracture; lymph nodes; mouse model; new therapeutic target; novel; relating to nervous system; research study; 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.

项目概要 肢体创伤可导致复杂区域疼痛综合征 (CRPS)，这是一种潜在的疾病 使人衰弱的慢性状态。目前对于 CRPS 的发病机制或治疗尚无共识， 显然需要转化和 CRPS 组织研究来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。其他报告表明：1) 朗格汉斯抗原呈递 细胞在 CRPS 受影响的肢体中增殖，2) 一些 CRPS 患者体内存在抗核自身抗体， 3) 在一些 CRPS 患者中可以鉴定出与特定 HLA 基因座的遗传关联。我们自己的 研究表明，骨折小鼠模型中类似 CRPS 的变化依赖于抗体的产生，并且 被动转移自身免疫发生在输入骨折小鼠或 CRPS 患者的血清后 注入抗体缺陷型骨折小鼠中。此外，小鼠骨折后，P 物质信号传导增强 刺激抗体在支配受伤后肢的皮肤、神经和脊髓中积聚， 触发后爪皮肤中的朗格汉斯细胞增殖。此外，IgM 血清抗体获得自 骨折小鼠与骨折肢体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带来范式转变。指导我们工作的中心假设是 肢体创伤导致先天性和适应性免疫系统的神经激活，区域性 新抗原的表达最终支持伤害性敏化。 该提案的主要目标是确定成功的特定药理学靶点 CRPS 的治疗。具体目标是：1）绘制树突状细胞抗原的骨折后变化图 皮肤、淋巴结、坐骨神经等部位的募集、成熟、运输和适应性免疫反应 脊髓，2) 确定获得免疫球蛋白时是否发生被动转移自身免疫 将来自骨折小鼠或 CRPS 患者的成分注射到其他小鼠体内，可能会重新点燃 CRPS 样物质 骨折后小鼠的后遗症可缓解 CRPS 症状，此外，还可以使用小鼠和 CRPS 患者 抗体识别区域限制性自身抗原骨折小鼠皮肤、神经、脊髓和骨折愈伤组织， 以及 CRPS 患者皮肤，3) 确定感觉神经肽或交感肾上腺素能 创伤后自身免疫反应的发展需要信号传导。 这些实验将为探索创伤后的机制奠定严格的基础 自身免疫，大大提高我们对CRPS的理解，确定未来CRPS的特定分子靶点 试验，并可能提出支持其他神秘慢性疼痛综合征的新机制。