Neural immunoregulation of post-traumatic autoimmunity

创伤后自身免疫的神经免疫调节

基本信息

批准号：
10698029
负责人：
DAVID J. CLARK
金额：
$ 54.21万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
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/10698029
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 Innate Immune Response Interleukin-6 Intrathecal Injections Investigation Iodoacetates Joints Knee Osteoarthritis Knee joint Low Back Pain Macrophage Maintenance Maps Mediating Mediator Microglia Modeling Molecular Mus Musculoskeletal Diseases Musculoskeletal Pain Natural Immunity Neuroimmune Neurons Neuropeptides Nociception Orthopedics Pain Pain Free Patients Pharmaceutical Preparations Pharmacological Treatment 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 Vertebral column Wild Type Mouse Work adaptive immune response adaptive immunity chronic pain cytokine disability economic impact effective therapy experience experimental study immunoregulation improved injured innovation knee pain limb fracture lymph nodes lymphoid organ mouse model neoantigens neural neural initiation novel osteoarthritis pain pain chronification pain patient pain reduction pharmacologic receptor response rituximab spinal disk injury tibia tissue injury tissue trauma

项目摘要

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) 关节痛是慢性腰痛的最常见原因致残性疼痛，尽管进行了广泛的研究，但这些病症的病理生理学仍未明确关于其临床管理存在相当大的争议。显然当前的假设组织损伤进展为痛苦的残疾，除非将疼痛的关节从身体上移除，产生有效且安全的治疗方法。我们最近对复杂小鼠胫骨骨折模型的研究局部疼痛综合征 (CRPS) 表明，所有 CRPS 患者均表达 IgM 自身抗体受伤后肢或鞘内注射后的伤害感受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，这些刺激性 CRPS IgM 作用是由 C5a 补体信号传导和炎症细胞因子释放介导的。小鼠胫骨骨折导致骨折肢体真皮和 C5aR 中表达 C5a 受体 (C5aR) 的巨噬细胞增加在相应的脊髓节段表达小胶质细胞，这些激活的免疫细胞释放刺激性炎症细胞因子响应 C5a 信号传导。此外，在小鼠骨折后，夸大的神经肽和交感肾上腺素信号刺激的促伤害性 IgM 抗体在皮肤和脊髓中蓄积。这些观察结果可能会带来范式转变。中央指导我们工作的假设是组织创伤导致先天和适应性系统的神经激活免疫，在受损组织和相应的脊髓中出现局部新抗原表达触发淋巴器官生发中心反应，其特征是形成生发 B 细胞，随后的促伤害性免疫复合物沉积和补体激活支持局部慢性伤害性过敏。该提案的主要目标是确定特定的药理学成功治疗 LBP 和 OA 的目标。具体目标是； 1）识别自身免疫性疾病慢性 LBP 腰椎间盘穿刺 (DP) 小鼠模型中介导伤害性敏化的反应并在慢性 OA 膝关节疼痛的碘乙酸单钠关节炎 (MIA) 小鼠模型中，确定 LBP 和 OA 患者中促伤害性抗体的流行情况，并鉴定适应性免疫反应 LBP 患者椎间盘和 OA 患者关节，2) 临时绘制淋巴结生发形成图中心，其特征是诱导滤泡辅助 T 细胞 (Tfh)、生发中心 B 细胞和在 DP 和 MIA 小鼠模型中产生伤害性抗体，以及 3) 确定是否感觉神经肽和交感肾上腺素信号传导构成了激活的统一机制以及维持对组织损伤的免疫反应。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，推进了我们的研究了解肌肉骨骼疼痛，并确定未来临床试验的具体目标。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exercise Reverses Nociceptive Sensitization, Upregulated Neuropeptide Signaling, Inflammatory Changes, Anxiety, and Memory Impairment in a Mouse Tibia Fracture Model.

运动可逆转小鼠胫骨骨折模型中的伤害性敏感性、上调神经肽信号、炎症变化、焦虑和记忆损伤。

DOI：
发表时间：
2018
期刊：
影响因子：
8.8
作者：
Shi, Xiaoyou;Guo, Tian;Li, Wenwu;Sahbaie, Peyman;Rice, Kenner C;Sulima, Agnieszka;Clark, J David;Kingery, Wade S
通讯作者：
Kingery, Wade S

Sex differences in the temporal development of pronociceptive immune responses in the tibia fracture mouse model.

胫骨骨折小鼠模型中伤害性免疫反应时间发展的性别差异。

DOI：
10.1097/j.pain.0000000000001592
发表时间：
2019-09-01
期刊：
Pain
影响因子：
7.4
作者：
T. Guo;Xiaoyou Shi;Wen;Tzuping Wei;J. Clark;W. Kingery
通讯作者：
W. Kingery

C5a complement and cytokine signaling mediate the pronociceptive effects of complex regional pain syndrome patient IgM in fracture mice.

C5a 补体和细胞因子信号传导介导骨折小鼠中复杂区域疼痛综合征患者 IgM 的促伤害作用。

DOI：
发表时间：
2021-05-01
期刊：
影响因子：
7.4
作者：
Shi, Xiaoyou;Guo, Tian;Li, Wen;Birklein, Frank;Escolano, Fabiola L;Herrnberger, Myriam;Clark, J David;Kingery, Wade S
通讯作者：
Kingery, Wade S

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome.

复杂区域疼痛综合征胫骨骨折模型中适应性免疫的神经肽调节。

DOI：
发表时间：
2018-04-11
期刊：
影响因子：
0
作者：
Li, Wen;Guo, Tian;Shi, Xiaoyou;Birklein, Frank;Schlereth, Tanja;Kingery, Wade S;Clark, J David
通讯作者：
Clark, J David

Angiotensin receptor blockade mimics the effect of exercise on recovery after orthopaedic trauma by decreasing pain and improving muscle regeneration.

血管紧张素受体阻断通过减轻疼痛和改善肌肉再生来模拟运动对骨科创伤后恢复的影响。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Tawfik, Vivianne L;Quarta, Marco;Paine, Patrick;Forman, Thomas E;Pajarinen, Jukka;Takemura, Yoshinori;Goodman, Stuart B;Rando, Thomas A;Clark, J David
通讯作者：
Clark, J David