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: 10417954
• 负责人: Peter M Grace
• 金额: $ 62.15万
• 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/10417954
• 关键词: Adoptive Transfer; Ally; Antibodies; Antigen-Antibody Complex; Antigen-Presenting Cells; Apoptosis; Apoptotic; Attenuated; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Process; B cell differentiation; B-Lymphocytes; Biochemical; Biochemistry; Biological; Biological Assay; Cells; Cerebrospinal Fluid; Complex; Data; Deposition; Disease; Docking; Female; Flow Cytometry; Functional disorder; Genetic; Goals; Human; IgG Receptors; Immunoglobulin G; Immunologist; In Situ Hybridization; Injury; Knock-out; Knowledge; Link; Maintenance; Measures; Microscopy; Mission; Molecular; Monitor; Mus; National Institute of Neurological Disorders and Stroke; Necrosis; Nervous system structure; Neuraxis; Neuroimmune; Neutrophil Infiltration; Nociception; Pain; Patients; Pattern; Peripheral; Peripheral nerve injury; Pharmacology; Plasma Cells; Public Health; Radiculopathy; Receptor Signaling; Reflex action; Regulation; Research; Role; Sampling; Signal Pathway; Signal Transduction; Site; Solid; Spinal; Sum; T-Lymphocyte; Tail; Techniques; Testing; Therapeutic Intervention; Time; adaptive immune response; base; cell injury; dorsal horn; effective therapy; genetic manipulation; innovation; interdisciplinary approach; male; mouse model; nerve injury; pain behavior; pain signal; painful neuropathy; 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