Regulation of Peripheral Neuropathic Pain by B Cells

B 细胞对周围神经病理性疼痛的调节

• 批准号: 10588250
• 负责人: Peter M Grace
• 金额: $ 62.66万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588250
• 关键词: Adoptive Transfer; Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Apoptosis; Apoptotic; Attenuated; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Process; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biochemical; Biochemistry; Biological; Biological Assay; Cell secretion; Cells; Central Nervous System; Cerebrospinal Fluid; Complex; Cytoprotection; Data; Deposition; Disease; Docking; Female; Flow Cytometry; Functional disorder; Genetic; Goals; Human; IgG Receptors; Immunoglobulin G; Immunologist; In Situ Hybridization; Induction of Apoptosis; Injury; Knock-out; Knowledge; Link; Maintenance; Measures; Microscopy; Mission; Molecular; Monitor; Mus; National Institute of Neurological Disorders and Stroke; Necrosis; Nervous System; Neuroimmune; Neutrophil Infiltration; Nociception; Pain; Patients; Pattern; Peripheral; Peripheral nerve injury; Plasma Cells; Public Health; Radiculopathy; Receptor Signaling; Reflex action; Regulation; Research; Role; Sampling; Signal Pathway; Signal Transduction; Site; Solid; Spinal; T-Cell Activation; Tail; Techniques; Testing; Therapeutic Intervention; Time; Vertebral column; adaptive immune response; cell injury; dorsal horn; effective therapy; genetic manipulation; humoral immunity deficiency; innovation; interdisciplinary approach; male; mouse model; nerve injury; pain behavior; pain signal; painful neuropathy; pharmacologic; plasma cell differentiation; porcine model; receptor; response; therapeutic target; transcriptome; validation studies

PROJECT SUMMARY Effective treatments are elusive for the majority of patients with neuropathic pain, which is reflective of the incomplete knowledge of the underlying mechanisms. Our proposal will advance mechanistic understanding of peripheral neuropathic pain maintenance by investigating the differentiation and function of B cells after peripheral nerve injury. Our long-term goal is to harness the disease-modifying potential of neuroimmune signaling to treat neuropathic pain. As a step toward achieving this goal, the overall objective of this application is to discover if and how B cells cause neuropathic pain after peripheral nerve injury. Our central hypothesis is that peripheral nerve injury induces differentiation of B cells into plasma cells. The plasma cells secrete autoantibodies that form complexes with autoantigens which maintain neuropathic pain by signaling through the activating Fc gamma receptor (FcγR) subtypes (I, III, IV) along the pain neuraxis. We propose that insufficient efferocytosis (deficient non-inflammatory clearance of apoptotic cells, leading to release of Danger Associated Molecular Patterns (DAMPs)) at the site of nerve injury, triggers autoimmune B cell differentiation. This hypothesis is based on strong evidence that plasma cells are pro-nociceptive, as we show that either constitutive deficiency or pharmacological depletion of differentiating B cells protects male and female mice from neuropathic pain. Our data also reveal that insufficient efferocytosis leads to B cell differentiation, as pharmacological stimulation of efferocytosis at the time of peripheral nerve injury reduces immunoglobulin G (IgG) deposits in the spinal dorsal horn. The rationale for testing our hypothesis is that deciphering this previously overlooked adaptive immune response to peripheral nerve injury will reveal new and tractable therapeutic targets for neuropathic pain. To accomplish the overall objective of this application, we will test the central hypothesis in a mouse model of peripheral nerve injury across the following specific aims: 1) Define the function of B cell differentiation after peripheral nerve injury. Validation studies will be performed in a piglet model of peripheral injury, and in biological samples obtained from patients with lumbar radiculopathy; 2) Identify whether FcγR signaling maintains neuropathic pain; and, 3) Determine whether insufficient efferocytosis induces B cell differentiation leading to neuropathic pain. The proposed studies take a multidisciplinary approach, including pharmacologic and genetic manipulations, flow cytometry, in situ hybridization, adoptive transfer, and assessment of evoked and operant pain behaviors. As efferocytosis and downstream plasma cell differentiation have not been previously implicated in traumatic neuropathic pain, our proposal is highly innovative and is expected to expand our paradigm for neuroimmune regulation of peripheral neuropathic pain. The results will have significant impact on the treatment of peripheral neuropathic pain by revealing new sites for therapeutic intervention.

项目概要 对于大多数神经性疼痛患者来说，有效的治疗是难以捉摸的，这反映了 对底层机制的了解不完整。我们的建议将促进对机制的理解 通过研究 B 细胞的分化和功能来维持周围神经性疼痛 周围神经损伤。我们的长期目标是利用神经免疫的疾病缓解潜力 治疗神经性疼痛的信号。作为实现这一目标的一步，该应用程序的总体目标 目的是发现周围神经损伤后 B 细胞是否以及如何引起神经性疼痛。我们的中心假设是 周围神经损伤诱导 B 细胞分化为浆细胞。浆细胞分泌 自身抗体与自身抗原形成复合物，通过信号传导维持神经性疼痛 沿疼痛神经轴激活 Fc γ 受体 (FcγR) 亚型（I、III、IV）。我们建议，不足 胞吞作用（凋亡细胞的非炎症清除不足，导致危险相关物质的释放） 神经损伤部位的分子模式 (DAMP) 可触发自身免疫 B 细胞分化。这 假设是基于浆细胞具有促伤害感受性的有力证据，正如我们表明的那样 分化 B 细胞的缺乏或药理耗竭可保护雄性和雌性小鼠免受神经病的侵害 疼痛。我们的数据还表明，胞吞作用不足会导致 B 细胞分化，如药理学作用 周围神经损伤时刺激胞吞作用可减少免疫球蛋白 G (IgG) 沉积 脊髓背角。检验我们假设的基本原理是破译这种以前被忽视的适应性 对周围神经损伤的免疫反应将为神经病揭示新的、易于处理的治疗靶点 疼痛。为了实现此应用程序的总体目标，我们将在小鼠模型中测试中心假设 围绕以下具体目标对周围神经损伤进行研究： 1) 定义 B 细胞分化后的功能 周围神经损伤。验证研究将在仔猪外周损伤模型和生物学研究中进行 取自腰椎神经根病患者的样本； 2) 鉴定FcγR信号是否维持 神经性疼痛； 3) 确定胞吞作用不足是否会诱导 B 细胞分化，从而导致 神经性疼痛。拟议的研究采用多学科方法，包括药理学和遗传学 操作、流式细胞术、原位杂交、过继转移以及诱发和操作评估 疼痛行为。由于之前并未涉及胞吞作用和下游浆细胞分化 在创伤性神经病理性疼痛方面，我们的建议具有高度创新性，有望扩展我们的范例 周围神经病理性疼痛的神经免疫调节。结果将对治疗产生重大影响 通过揭示治疗干预的新位点来治疗周围神经性疼痛。