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.

项目总结 对于大多数神经病理性疼痛的患者来说，有效的治疗是难以捉摸的，这反映了 对潜在机制的不完全了解。我们的建议将推进对 外周神经病理性疼痛维持的B细胞分化和功能研究 周围神经损伤。我们的长期目标是利用神经免疫的疾病修正潜力。 治疗神经病理性疼痛的信号。作为实现这一目标的一步，此应用程序的总体目标 是为了发现外周神经损伤后B细胞是否以及如何引起神经病理性疼痛。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体，通过信号转导途径维持神经病理性疼痛 激活Fcγ受体(FcγR)亚型(I、III、IV)。我们认为，这是不够的 泡出(缺乏对凋亡细胞的非炎症性清除，导致相关危险的释放 神经损伤部位的分子模式(DAMPS)，触发自身免疫B细胞分化。这 这一假说是建立在浆细胞具有促伤害性的强有力证据的基础上的，因为我们证明了 分化B细胞的缺乏或药物耗尽保护雄性和雌性小鼠免受神经病变的影响 疼痛。我们的数据还表明，泡吞噬作用不足会导致B细胞分化，就像药理学上的 周围神经损伤时刺激胞吐减少免疫球蛋白G(Ig G)沉积 脊椎背角。检验我们假设的基本原理是，破译这一先前被忽视的适应性 周围神经损伤的免疫反应将为神经病提供新的、易处理的治疗靶点 疼痛。为了实现本应用程序的总体目标，我们将在小鼠模型中测试中心假设 跨以下特定目标的周围神经损伤：1)明确B细胞分化后的功能 周围神经损伤。验证研究将在周围损伤的仔猪模型上进行，并在生物学上进行 取自腰神经根病患者的样本；2)鉴定FcγR信号是否保持 神经病理性疼痛；以及，3)确定泡腾作用不足是否诱导B细胞分化导致 神经性疼痛。拟议的研究采取了多学科方法，包括药理学和遗传学。 操作，流式细胞术，原位杂交，过继转移，以及诱发和可操作的评估 疼痛行为。因为之前还没有涉及到胞吐和下游浆细胞分化 在创伤性神经性疼痛方面，我们的建议具有很高的创新性，并有望扩展我们的研究范式 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 通过揭示新的治疗干预部位来研究周围神经病理性疼痛。