Neural immunoregulation of post-traumatic autoimmunity

创伤后自身免疫的神经免疫调节

• 批准号: 10522859
• 负责人: DAVID J. CLARK
• 金额: $ 52.82万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522859
• 关键词: Adrenergic Agents; Antibodies; Antigen-Antibody Complex; Antigens; Arthralgia; Arthritis; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Binding; C5a anaphylatoxin receptor; Calcitonin-Gene Related Peptide Receptor; Cartilage; Cells; Chemicals; Chronic; Chronic disabling pain; Chronic low back pain; Clinical Management; Clinical Trials; Complement; Complement 5a; Complement Activation; Complex Regional Pain Syndromes; Cytokine Signaling; Degenerative polyarthritis; Deposition; Dermis; Development; FDA approved; Foundations; Fracture; Functional disorder; Future; Goals; Helper-Inducer T-Lymphocyte; Hindlimb; Immune; Immune response; Immunity; Immunoglobulin Isotypes; Immunoglobulin M; Immunoglobulins; Inflammatory; Injections; Injury; Interleukin-6; Intrathecal Injections; Investigation; Iodoacetates; Joints; Knee Osteoarthritis; Knee joint; Low Back Pain; Maintenance; Maps; Mediating; Mediator of activation protein; Microglia; Modeling; Molecular; Mus; Musculoskeletal Diseases; Musculoskeletal Pain; Natural Immunity; Neuroimmune; Neurons; Neuropeptides; Nociception; Orthopedics; Pain; Pain-Free; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Plasma; Play; Positioning Attribute; Prevalence; Production; Puncture procedure; Quality of life; Reaction; Rodent; Role; Sensory; Serum; Signal Pathway; Signal Transduction; Skin; Spinal; Spinal Cord; Structure of germinal center of lymph node; Substance P; System; Testing; Time; Tissue Sample; Tissues; Trauma; Wild Type Mouse; Work; adaptive immune response; adaptive immunity; base; chronic pain; cytokine; disability; economic impact; effective therapy; experience; experimental study; immunoregulation; improved; injured; innovation; knee pain; limb fracture; lymph nodes; lymphoid organ; macrophage; mouse model; neoantigens; novel; osteoarthritis pain; pain chronification; pain patient; pain reduction; receptor; relating to nervous system; response; rituximab; spinal disk injury; tibia; tissue injury; tissue trauma

Chronic low back pain (LBP) and osteoarthritic (OA) joint pain are the most common causes of chronic disabling pain and despite extensive investigation the pathophysiology of these conditions remains undefined and there is considerable controversy regarding their clinical management. Clearly current hypotheses for the progression of tissue injury to painful disability have not, short of removing the painful joint from the body, generated effective and safe treatments. Our recent studies in the mouse tibia fracture model of complex regional pain syndrome (CRPS) demonstrated that all CRPS patients expressed IgM autoantibodies with pronociceptive passive transfer effects after intraplantar injection into the injured hindlimb or intrathecal injection into muMT fracture mice lacking B cells and immunoglobulin, and these pronociceptive CRPS IgM effects were mediated by C5a complement signaling and inflammatory cytokine release. Tibia fracture in mice caused an increase of C5a receptor (C5aR) expressing macrophages in the fracture limb dermis and C5aR expressing microglia in the corresponding spinal cord segments, and these activated immune cells release pronociceptive inflammatory cytokines in response to C5a signaling. Moreover, after fracture in mice, exaggerated neuropeptide and sympathetic adrenergic signaling stimulated pronociceptive IgM antibody accumulation in the skin and spinal cord. These observations are potentially paradigm shifting. The central hypothesis guiding our work is that tissue trauma causes neural activation of the innate and adaptive systems of immunity, with localized neoantigen expression in the injured tissue and corresponding spinal cord triggering lymph organ germinal center reactions characterized by the formation germinal B cells, with subsequent pronociceptive immune complex deposition and complement activation supporting localized chronic nociceptive sensitization. The primary objective of this proposal is to identify specific pharmacologic targets for the successful treatment of LBP and OA. The specific aims are; 1) to identify the autoimmune responses mediating nociceptive sensitization in the lumbar disc puncture (DP) mouse model of chronic LBP and in the monosodium iodoacetate arthritis (MIA) mouse model of chronic OA knee pain, to determine the prevalence of pronociceptive antibodies in LBP and OA patients, and to identify adaptive immune responses in LBP patient spinal discs and OA patient joints, 2) to temporally map the formation of lymph node germinal centers, characterized by the induction of T follicular helper cells (Tfh), germinal center B cells, and the production of pronociceptive antibodies in the DP and MIA mouse models, and 3) to determine whether sensory neuropeptide and sympathetic adrenergic signaling constitute a unifying mechanism for the activation and maintenance of the immune response to tissue injury. These experiments potentially will establish a rigorous foundation for exploring mechanisms of tissue injury induced autoimmunity, advance our understanding of musculoskeletal pain, and identify specific targets for future clinical trials.

慢性腰痛（LBP）和骨关节炎（OA）关节疼痛是慢性腰痛（LBP）的最常见原因。 致残性疼痛，尽管进行了广泛的研究，但这些疾病的病理生理学仍不明确 并且关于它们的临床管理存在相当大的争议。显然，目前的假设， 组织损伤到疼痛性残疾的进展，除了从身体上移除疼痛的关节， 产生了有效和安全的治疗方法。我们最近在小鼠胫骨复杂骨折模型的研究 局部疼痛综合征（CRPS）显示，所有CRPS患者均表达IgM自身抗体， 足底或鞘内注射致痛性被动传递效应 注射到缺乏B细胞和免疫球蛋白的muMT骨折小鼠中， 作用由C5a补体信号传导和炎性细胞因子释放介导。小鼠胫骨骨折 引起骨折肢真皮中表达C5a受体（C5aR）的巨噬细胞增加， 在相应的脊髓节段中表达小胶质细胞，这些激活的免疫细胞释放 对C5a信号传导作出响应的致伤害性炎性细胞因子。此外，小鼠骨折后， 增强的神经肽和交感肾上腺素能信号刺激的原伤害感受IgM抗体 在皮肤和脊髓中积累。这些观察结果可能会改变范式。中央 指导我们工作的假设是，组织创伤引起先天和适应性系统的神经激活 在损伤组织和相应的脊髓中有局部新抗原表达 引发淋巴器官生殖中心反应，其特征在于形成生殖B细胞， 随后的原伤害性免疫复合物沉积和补体激活支持局部 慢性伤害性致敏该提案的主要目的是确定特定的药理学 成功治疗LBP和OA的靶点。具体目的是：1）识别自身免疫性 慢性LBP腰椎间盘穿刺（DP）小鼠模型中介导伤害性敏化的反应 以及在慢性OA膝关节疼痛的碘乙酸盐关节炎（MIA）小鼠模型中， 在LBP和OA患者中的原伤害感受抗体的患病率，并确定LBP和OA患者中的适应性免疫应答。 LBP患者的椎间盘和OA患者的关节，2）时间映射淋巴结转移的形成 中心，其特征在于诱导T滤泡辅助细胞（Tfh）、生发中心B细胞和 在DP和MIA小鼠模型中产生原伤害感受抗体，和3）确定是否 感觉神经肽和交感肾上腺素能信号传导构成了统一的激活机制 和维持对组织损伤的免疫应答。这些实验可能会建立一个 为探索组织损伤诱导自身免疫的机制奠定了坚实的基础， 了解肌肉骨骼疼痛，并确定未来临床试验的具体目标。