Neural Immunoregulation of Post-Traumatic Autoimmunity

创伤后自身免疫的神经免疫调节

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要肢体创伤可以导致复杂区域疼痛综合征（CRP）的发展，这是一种潜在的使人衰弱的慢性状态。当前，关于CRP的发病机理或治疗均未达成共识显然需要转化和CRPS组织研究来鉴定治疗靶标和有效治疗。最近的观察结果表明，一些CRPS患者表达自身抗体并深刻反应静脉免疫球蛋白治疗。其他报告表明：1）Langerhans抗原呈现细胞在受影响的CRP中增殖，2）一些CRPS患者存在抗核自身抗体， 3）可以在一些CRPS患者中鉴定与特定HLA基因座的遗传关联。我们自己的研究表明，断裂小鼠模型中CRP的变化依赖于抗体的产生，并且这种被动转移自身免疫发生在从骨折小鼠或CRPS患者的血清输血后发生进入抗体缺陷骨折小鼠。此外，在小鼠骨折后，夸张的物质P信号传导刺激在皮肤，神经和脊髓中积聚的抗体，从而支配受伤的后肢和触发后爪皮中的Langerhans细胞增殖。此外，从中获得的IgM血清抗体骨折小鼠与骨折肢体皮肤中的皮肤细胞核抗原结合，但在对侧完整的后肢中没有皮肤。这些观察结果可能是范式转移。指导我们工作的中心假设是肢体创伤导致免疫的先天和自适应系统的神经激活，区域性新抗原的表达最终支持伤害性敏化。该提案的主要目的是确定成功的特定药理目标 CRP的处理。具体目的是：1）在树突细胞抗原中绘制裂缝后变化皮肤，淋巴结，坐骨神经和脊髓，2）确定当获得免疫球蛋白时是否发生被动转移自身免疫性从骨折小鼠或CRPS患者中注射到其他小鼠中，可能会重新燃起CRPS样骨折后小鼠的后遗症具有解决CRPS症状，此外，使用小鼠和CRP患者识别区域限制自身抗原骨折的抗体，神经，绳索和骨折愈伤组织，在CRPS患者皮肤中，以及3）确定感觉神经肽或交感神经肾上腺素是否创伤后自身免疫反应需要信号传导。这些实验将为探索创伤后的机制建立严格的基础自身免疫性大大提高了我们对CRP的理解，确定了未来CRP的特定分子靶标试验，并有可能提出支持其他神秘慢性疼痛综合征的新型机制。