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.

慢性下背痛（LBP）和骨关节炎（OA）关节痛是慢性的最常见原因禁用疼痛，尽管进行了广泛的研究，这些疾病的病理生理仍然不确定关于他们的临床管理存在很大的争议。显然，当前的假设是组织损伤导致疼痛残疾的进展并没有，没有从体内消除疼痛的关节，产生有效且安全的治疗方法。我们最近在小鼠胫骨骨折模型的研究区域疼痛综合征（CRP）表明，所有CRPS患者均表现出IGM自身抗体倾斜度内注射后的pronocativative被动转移效果进入受伤的后肢或鞘内注入缺乏B细胞和免疫球蛋白的Mumt骨折小鼠，这些引起感染CRPS IgM C5a补体信号传导和炎症细胞因子释放介导了效果。小鼠胫骨骨折引起C5a受体（C5AR）的增加，在骨折肢体和C5AR中表达巨噬细胞在相应的脊髓段中表达小胶质细胞，这些激活的免疫细胞释放响应C5A信号传导的肌肉炎症性细胞因子。而且，在小鼠骨折后，夸张的神经肽和交感神经肾上腺素能信号传导刺激了引起感染的IgM抗体在皮肤和脊髓中积聚。这些观察结果可能是范式转移。中央指导我们工作的假设是组织创伤引起先天和适应系统的神经激活免疫力，在受伤的组织和相应的脊髓中具有局部新抗原表达触发以形成生发B细胞为特征的淋巴器官生发中心反应，随后的proactactive免疫复合物沉积和补体激活支持局部慢性伤心敏化。该提案的主要目的是确定特定的药理学成功治疗LBP和OA的目标。具体目标是； 1）识别自身免疫性介导慢性LBP的腰椎穿刺（DP）小鼠模型中的伤害感受敏化的反应在碘乙酸酯单钠关节炎（MIA）慢性膝关节疼痛的模型中，以确定 LBP和OA患者的造影抗体的患病率，并确定适应性免疫反应 LBP患者脊髓椎间盘和OA患者关节，2）临时映射淋巴结生发的形成中心，其特征是诱导T卵泡辅助细胞（TFH），生发中心B细胞和在DP和MIA小鼠模型中产生摄影性抗体，以及3）是否确定是否是否感觉神经肽和交感神经肾上腺素能信号构成激活的统一机制并维持对组织损伤的免疫反应。这些实验可能会建立严格的基础，用于探索组织损伤的机制引起的自身免疫，推动我们的了解肌肉骨骼疼痛，并确定未来临床试验的特定靶标。

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）

Passive transfer autoimmunity in a mouse model of complex regional pain syndrome.

DOI：
10.1097/j.pain.0000000000001046
发表时间：
2017-12
期刊：
Pain
影响因子：
7.4
作者：
Guo TZ;Shi X;Li WW;Wei T;Clark JD;Kingery WS
通讯作者：
Kingery WS

Systematic Immunophenotyping Reveals Sex-Specific Responses After Painful Injury in Mice.

系统免疫表型分析揭示了小鼠遭受痛苦伤害后的性别特异性反应。

DOI：
10.3389/fimmu.2020.01652
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Tawfik,VivianneL;Huck,NolanA;Baca,QuentinJ;Ganio,EdwardA;Haight,ElenaS;Culos,Anthony;Ghaemi,Sajjad;Phongpreecha,Thanaphong;Angst,MartinS;Clark,JDavid;Aghaeepour,Nima;Gaudilliere,Brice
通讯作者：
Gaudilliere,Brice

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

DOI：
10.1113/jp278991
发表时间：
2020-01
期刊：
The Journal of physiology
影响因子：
0
作者：
Tawfik VL;Quarta M;Paine P;Forman TE;Pajarinen J;Takemura Y;Goodman SB;Rando TA;Clark JD
通讯作者：
Clark JD

IL-6 signaling mediates the germinal center response, IgM production and nociceptive sensitization in male mice after tibia fracture.

DOI：
10.1016/j.bbi.2021.02.015
发表时间：
2021-05
期刊：
Brain, behavior, and immunity
影响因子：
0
作者：
Li WW;Yang Y;Guo TZ;Sahbaie P;Shi XY;Guang Q;Kingery WS;Herzenberg LA;Clark JD
通讯作者：
Clark JD

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