Mechanisms of Pain and Immune Processes

疼痛和免疫过程的机制

• 批准号: 9555580
• 负责人: Andrew Mannes
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9555580
• 关键词: Acute; Acute Pain; Adaptive Immune System; Address; Affect; Analgesics; Animal Model; Animals; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Autopsy; Biological; Biological Assay; Biological Factors; Biological Markers; Body part; C Fiber; Caliber; Cell membrane; Cells; Cerebrospinal Fluid; Cessation of life; Chemotherapy-induced peripheral neuropathy; Chickenpox; Childhood; Chronic; Classification; Clinical Research; Communicable Diseases; Communication; Complex; Data; Data Set; Diabetes Mellitus; Diagnostic; Diagnostic tests; Disease; Disease susceptibility; Evaluation; Evolution; Fiber; Ganglia; Generations; Genes; Genome; Goals; Headache; Herpes zoster disease; Herpesviridae; Herpesvirus 1; Human; Human Papillomavirus; Immune; Immune response; Immunology; Immunoprecipitation; Infection; Inflammation; Injury; Intervention; Investigation; Ion Channel; Knowledge; Life; Liquid substance; Luciferases; Lupus; Maintenance; Malignant Neoplasms; Mammalian Cell; Measurement; Measures; Metabolic Diseases; Methodology; Migraine; Modeling; Molecular; Monitor; Nature; Nerve; Nerve Endings; Nerve Fibers; Nervous system structure; Neuraxis; Neurobiology; Neurons; Neuropathy; Nociception; Oncoproteins; Operative Surgical Procedures; Pain; Pain Disorder; Paraneoplastic Polyneuropathy; Pathogenicity; Pathologic; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Plasma; Play; Population; Postherpetic neuralgia; Potassium Channel; Predictive Value; Process; Production; Protein Family; Protein Fragment; Proteins; Public Health; Publications; Publishing; Recombinant Proteins; Recording of previous events; Reporting; Research; Role; Saliva; Sampling; Schwann Cells; Serum; Severities; Signal Pathway; Sjogren' s Syndrome; Specificity; Spinal Cord; Spinal cord damage; Structure of trigeminal ganglion; System; TRIM Family; Technology; Testing; Time; Tissues; Tracer; Transcript; Traumatic CNS injury; Traumatic injury; Viral; Vulnerable Populations; Whole Blood; base; beta-adrenergic receptor; chemotherapeutic agent; chronic neuropathic pain; chronic pain; cytokine; diabetic; disorder control; drug development; human disease; insight; latency associated transcript; luminescence; nerve injury; nervous system disorder; neutralizing antibody; painful neuropathy; patient subsets; receptor; relating to nervous system; tool; transcriptome; transcriptome sequencing; translational research program; transmission process; virology

Overview: This translational research program addresses molecular and pathophysiological processes of nociceptive transmission and new ways to investigate the potential confluence of chronic pain, autoimmune conditions, infectious diseases and their intersections in human patients. Chronic neuropathic pain can affect any part of the body and can occur due to a variety of insults, infections, and autoimmune or metabolic disorders (e.g., diabetic peripheral neuropathy). We are testing the hypothesis that, in some patients, chronic pain is initiated and/or maintained by immunopathological processes related to autoantibodies generated against proteins in peripheral nerve or Schwann cells or possibly components of the central nervous system. Autoantibodies are known culprits in certain large fiber paraneoplastic peripheral neuropathies. Where pain is a component, we hypothesize the presence of autoantibodies to proteins found in nerve endings arising from small diameter pain-sensing (nociceptive) C- or A-delta nerve fibers. To test the hypothesis that painful neuropathic conditions have an autoimmune component we established a sensitive, quantitative, liquid phase luminescence assay that uses recombinant protein antigen-luciferase fusions as tracers with expression in mammalian cells. The goals of this research are to understand (a) molecular and cell biological mechanisms underlying human chronic pain disorders, and (b) to use this knowledge to devise new treatments and diagnostics for pain and other disorders to which it can be adapted. The methodology we established, luciferase immunoprecipitation systems (LIPS) assay robustly and sensitively detects antibodies in serum, plasma, cerebrospinal fluid or saliva. Our early investigations evaluated a range of diseases and disorders that antibodies play a role in, including infectious diseases with and without nervous system involvement and autoimmune disorders, which have nervous system symptomology in subsets of patients. In many neural autoimmune disorders, the major autoantigens are frequently plasma membrane receptors or ion channels. We are in the process of examining neuropathic pain disorders for targets based on published reports, notably the beta-adrenergic receptor and a potassium channel. Our aim is to determine if the LIPS assay can detect auto-antibodies to these proteins in appropriate patients. We completed a study on shingles (herpes zoster) and patients in which shingles evolved into a painful neurological disorder called post-herpetic neuralgia (PHN). We detected some neutralizing anti-cytokine autoantibodies in a subpopulation and, interestingly, all of these had PHN. This is important because it suggests that some patients with PHN may require additional intervention to control the disorder other than just analgesic medications. In a recent publication we demonstrated both HSV1 transcripts and HSV1 antibodies in post-mortem human trigeminal ganglion and whole blood, respectively. The correspondence between titer and transcript was 100%. The fact that we used RNA-seq allowed us to align the HSV1 reads to the HSV1 genome and all of the transcripts aligned with the HSV1 latency associated transcript (LAT), indicating that none of the subjects had viral re-activation at the time of death. We intend to use this approach as a component in a larger study of headache and migraine. One of the most compelling aspects of this project is its broad applicability and the progressive layering and evolution of the datasets. As we increase the number of test antigens, and assay across conditions and diseases, we assemble comprehensive evaluations of immune and autoimmune responses. This is accomplished by determination of (a) the extent and specificity of immune response to orthologous proteins and protein fragments, (b) overlap in antigen profiles indicative of common denominators or general mechanisms, and (c) antigenicity within an entire signaling pathway involved in inter- or intracellular communication. Examples are the TRIM family of proteins in Sjogren's Syndrome, our autoantigen-based classification of patients with Lupus Erythematosis, and a recent examination of antibodies to oncogene products in HPV driven cancers. An example of a new use for public health monitoring is our earlier demonstration of autoantibody measurements in saliva, which highlights the feasibility of establishing non-invasive assays vulnerable populations or the pediatric population. Eventually, full multiple antigen profiling can be implemented to obtain a deeper level of understanding of the immune component of many complex human disease states.

概述：该转化研究项目致力于研究伤害性传播的分子和病​​理生理学过程，以及研究人类患者中慢性疼痛、自身免疫性疾病、传染病及其交叉点的潜在融合的新方法。慢性神经性疼痛可以影响身体的任何部位，并且可能由于各种损伤、感染以及自身免疫或代谢紊乱（例如糖尿病周围神经病变）而发生。我们正在测试这样的假设：在一些患者中，慢性疼痛是由与针对周围神经或雪旺细胞或可能的中枢神经系统成分中的蛋白质产生的自身抗体相关的免疫病理学过程引发和/或维持的。已知自身抗体是某些大纤维副肿瘤性周围神经病的罪魁祸首。如果疼痛是其中的一个组成部分，我们假设存在针对小直径疼痛感知（伤害性）C-或A-δ神经纤维的神经末梢中发现的蛋白质的自身抗体。为了检验疼痛性神经病具有自身免疫成分的假设，我们建立了一种灵敏、定量、液相发光测定法，该测定法使用重组蛋白抗原-荧光素酶融合物作为在哺乳动物细胞中表达的示踪剂。这项研究的目标是了解（a）人类慢性疼痛疾病的分子和细胞生物学机制，以及（b）利用这些知识来设计针对疼痛和其他可适应的疾病的新治疗和诊断方法。 我们建立的方法，荧光素酶免疫沉淀系统 (LIPS) 测定法可以稳健、灵敏地检测血清、血浆、脑脊液或唾液中的抗体。我们的早期研究评估了抗体在其中发挥作用的一系列疾病和病症，包括有或没有神经系统受累的传染病和自身免疫性疾病，这些疾病在部分患者中具有神经系统症状。在许多神经自身免疫性疾病中，主要的自身抗原通常是质膜受体或离子通道。我们正在根据已发表的报告，特别是β-肾上腺素能受体和钾通道，检查神经性疼痛疾病的目标。 我们的目的是确定 LIPS 检测是否可以在适当的患者中检测到这些蛋白质的自身抗体。我们完成了一项关于带状疱疹（带状疱疹）和带状疱疹患者的研究，在这些患者中带状疱疹演变成一种称为带状疱疹后神经痛（PHN）的痛苦神经系统疾病。我们在一个亚群中检测到一些中和性抗细胞因子自身抗体，有趣的是，所有这些人都患有 PHN。这很重要，因为它表明一些 PHN 患者可能需要额外的干预来控制疾病，而不仅仅是镇痛药物。在最近的一篇出版物中，我们分别在死后的人类三叉神经节和全血中证明了 HSV1 转录本和 HSV1 抗体。 滴度与转录本的对应率为100%。 事实上，我们使用 RNA-seq 使我们能够将 HSV1 读数与 HSV1 基因组对齐，并将所有转录本与 HSV1 潜伏相关转录本 (LAT) 对齐，这表明没有受试者在死亡。我们打算使用这种方法作为更大规模的头痛和偏头痛研究的一部分。 该项目最引人注目的方面之一是其广泛的适用性以及数据集的渐进分层和演变。随着我们增加测试抗原的数量以及跨条件和疾病的检测，我们对免疫和自身免疫反应进行了综合评估。这是通过确定（a）对直系同源蛋白质和蛋白质片段的免疫反应的程度和特异性，（b）指示共同点或一般机制的抗原谱的重叠，以及（c）参与的整个信号传导途径内的抗原性来实现的。细胞间或细胞内通讯。例如干燥综合征中的 TRIM 蛋白家族、我们基于自身抗原的红斑狼疮患者分类，以及最近对 HPV 驱动的癌症中癌基因产物抗体的检查。公共卫生监测新用途的一个例子是我们之前对唾液中自身抗体测量的演示，这凸显了对弱势群体或儿科群体建立非侵入性检测的可行性。最终，可以实施完整的多抗原分析，以更深入地了解许多复杂的人类疾病状态的免疫成分。