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：该转化研究计划介绍了伤害感受传播的分子和病​​理生理过程，以及研究慢性疼痛，自身免疫性疾病，传染病及其相互作用的潜在汇合的新方法。慢性神经性疼痛会影响身体的任何部位，并且可能由于多种侮辱，感染和自身免疫性或代谢性疾病（例如糖尿病性周围神经病）而发生。我们正在检验以下假设：在某些患者中，慢性疼痛是通过与外周神经或schwann细胞中蛋白质或中枢神经系统中可能成分的蛋白质产生的自身抗体有关的免疫病理过程和/或维持的。在某些大型纤维副塑性外周神经病中，自身抗体是已知的罪魁祸首。在疼痛是成分的地方，我们假设存在自身抗体与由小直径疼痛感（伤害感受）C-或A-二尔特神经纤维引起的神经末端发现的蛋白质。为了测试疼痛神经性疾病具有自身免疫性成分的假设，我们建立了一种敏感，定量，液相发光测定法，该测定法使用重组蛋白抗原 - 葡萄酸酶融合剂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）人类慢性疼痛障碍的基于的（a）分子和细胞生物学机制，以及（b）使用这些知识来设计新的治疗方法和诊断疼痛和其他可以适应的疾病。 我们建立的方法是，荧光素酶免疫沉淀系统（LIPS）稳健地测定并敏感地检测血清，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疾病，包括有和没有神经系统受累和自身免疫性疾病的传染病，这些疾病在患者子集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。我们正在基于已发表的报告（尤其是β-肾上腺素能受体和钾通道）检查靶标的神经性疼痛障碍。 我们的目的是确定嘴唇测定是否可以检测适当患者的这些蛋白质自身抗体。我们完成了一项有关带状疱疹（疱疹带状疱疹）的研究和疱疹，其中带有疼痛的神经系统疾病，称为疗程后神经痛（PHN）。我们在亚群中检测到一些中和中和抗周围的自身抗体，有趣的是，所有这些都有PHN。这很重要，因为它表明某些PHN患者可能需要额外的干预措施来控制这种疾病，而不仅仅是镇痛药。在最近的出版物中，我们分别证明了验尸后人类三叉神经节和全血的HSV1转录本和HSV1抗体。 滴度和转录本之间的对应关系为100％。 我们使用RNA-seq的事实使我们能够对齐HSV1读取与HSV1基因组以及与HSV1潜伏期相关转录本（LAT）一致的所有转录本，这表明在死亡时，没有一个受试者在死亡时具有病毒重新激活。我们打算将这种方法用作更大的头痛和偏头痛研究中的组成部分。 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逐步分层和演变。随着我们增加测试抗原的数量，以及跨疾病和疾病的测定，我们会汇总对免疫和自身免疫反应的全面评估。这是通过确定（a）对直系同源蛋白和蛋白质片段的免疫反应的程度和特异性来实现的，（b）在抗原特征中重叠，指示了共同的分母或一般机制，以及（c）涉及与细胞间或细胞内通信的整个信号通路内的抗原性。例子是Sjogren综合征中的蛋白质家族，我们基于自身抗原的红斑红斑病患者的分类以及最近检查了HPV驱动的癌症中对癌基产品的抗体。新用途用于公共卫生监测的一个例子是，我们较早地展示了唾液中的自身抗体测量值，这突出了建立非侵入性测定的可行性，是脆弱的人群或儿科人群。最终，可以实施完整的多种抗原分析，以更深入地了解许多复杂人类疾病状态的免疫成分。