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.

项目摘要 有效治疗对于大多数神经性疼痛患者都是弹性的，这反映了 对基本机制的不完整知识。我们的建议将提高对机械的理解 通过研究B细胞的分化和功能，在 周围神经损伤。我们的长期目标是利用神经免疫的疾病改良潜力 信号处理神经性疼痛。作为实现这一目标的一步，该应用程序的总体目标 是要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 该周围神经损伤诱导B细胞分化为浆细胞。浆细胞秘密 与自身抗原形成复合物的自身抗体通过信号传导来维持神经性疼痛的复合物 沿疼痛神经毒素激活FC伽马受体（FcγR）亚型（I，III，IV）。我们提出了不够的 凋亡（凋亡细胞的非炎性清除率，导致危险释放） 在神经损伤部位的分子模式（潮湿））触发自身免疫性B细胞分化。这 假设基于有力的证据表明浆细胞是促症状的，因为我们表明的是本构成 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性疗法 疼痛。我们的数据还表明，由于药物的效率不足会导致B细胞分化 周围神经损伤时刺激肿瘤的刺激性细胞增生会减少免疫球蛋白G（IgG）沉积物中的沉积物 脊髓角。测试我们的假设的理由是解读此先前被忽视的适应性 对周围神经损伤的免疫反应将揭示神经疗法的新的且可进行的治疗靶标 疼痛。为了实现此应用程序的总体目标，我们将测试鼠标模型中的中心假设 在以下特定目的中的周围神经损伤的 周围神经损伤。验证研究将在外周损伤的小猪模型中进行，并在生物学中进行 从腰椎肿瘤病患者获得的样品； 2）确定FCγR信号是否保持 神经性疼痛； 3）确定效率不足是否诱导B细胞分化导致 神经性疼痛。拟议的研究采用多学科方法，包括药物和遗传学 操纵，流式细胞仪，原位杂交，自适应转移和诱发者和操作员的评估 疼痛行为。由于先前尚未实施，因此未实施递增细胞增多症和下游浆细胞分化 在创伤性神经性疼痛中，我们的建议具有很高的创新性，并有望扩大我们的范式 周围神经性疼痛的神经免疫调节。结果将对治疗产生重大影响 通过揭示用于治疗干预的新部位的周围神经性疼痛。