The role of adaptive immunity in organophosphate induced CNS injury

适应性免疫在有机磷诱导的中枢神经系统损伤中的作用

• 批准号: 10629511
• 负责人: Laila Abdullah
• 金额: $ 24.43万
• 依托单位: ROSKAMP INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629511
• 关键词: Accidents; Acids; Acute; Adverse effects; Affect; Albumins; Amino Acids; Antibodies; Antibody Formation; Antidotes; Antigens; Area; Astrocytes; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Biological Markers; Blood; Brain; Cells; Central Nervous System; Chemical Warfare; Chemicals; Chlorpyrifos; Chronic; Chronic Fatigue Syndrome; Classification; Cognitive; Cross Reactions; Data; Development; Disease; Encephalitis; Environmental Exposure; Exposure to; Future; Gases; Headache; Health; Health system; Human; Immune; Immune System Diseases; Immune Targeting; Immune response; Immune system; Immunologic Stimulation; Individual; Intoxication; Iran; Iraq; Mass Spectrum Analysis; Mediating; Methods; Microglia; Morbidity - disease rate; Mus; Muscle Fatigue; Muscle Weakness; Neurons; Oral; Organophosphates; Peripheral; Peripheral Nervous System; Persian Gulf Syndrome; Pesticides; Plasma; Poison; Poisoning; Population; Proteins; Quality of life; Reporting; Role; Sarin; Security; Subway; Sydenham Chorea; Symptoms; Syria; T memory cell; T-Cell Activation; Testing; Tokyo; Toxic effect; Tyrosine; Veterans; Woman; Work; adaptive immune response; adaptive immunity; adduct; central nervous system injury; chemical threat; experience; immune activation; improved; in vivo; innovation; medical countermeasure; mouse model; nerve agent; nerve gas; neuroinflammation; neurotoxicity; novel; organophosphate poisoning; pesticide poisoning; programs; pyrethroid; response; standard of care; therapy development; toxic organophosphate insecticide exposure

Chlorpyrifos (CPF) is an organophosphate (OP) pesticide, classified as a chemical threat agent by the Department of Homeland Security because it can cause neurotoxicity if released into the civilian populations. Under these circumstances, CPF and similar OP chemicals have a potential to cause long-term chronic multi symptom illnesses (CMI), such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To date, many victims of the Tokyo subway sarin gas attack are still experiencing chronic health problems consisting of cognitive difficulties, headaches, muscle weaknesses and fatigue, which negatively impact their quality of life. Such symptoms are reported by individuals exposed to OP pesticides and are thought to be caused by maladaptive immune responses7. As such, this proposal will investigate the role of CPF in maladaptive immune responses to develop future approaches that mitigate long-term morbidity associated with CMI. Ordinarily, a small chemical is not antigenic, but when it forms adducts with endogenous proteins, it can be recognized by the immune system as a foreign threat agent and provoke an adaptive immune response. Our prior work in this area shows that certain pesticide metabolites can form adducts with proteins and then elicit an adaptive immune response, activating T- and B-cells that ultimately contribute to the production of antibodies against them and corresponding with brain inflammation. Accounts of acute CPF poisoning in humans support this notion by showing that CPF or CPF-oxon (CPO) can form adducts on several amino acid residues in human albumin, which are considered biomarkers of OP exposure. However, it is unknown whether these CPF/CPO-protein adducts have a role in activating the immune system. We therefore hypothesize that CPF/CPO-protein adducts formed in vivo after CPF exposure can activate T-cell and B-cell responses, resulting in antibody production. We propose that CPF-protein specific antibodies may cross-react with brain proteins and contribute to the development of chronic autoimmune disorders. The proposed work builds upon an existing scientific premise of pesticide-mediated maladaptive immune responses. These studies will characterize whether acute CPF administration stimulates immune cells and whether this corresponds with activation of the microglia and astroglia and neuroinflammation after CPF exposure. We will determine whether brain immune activation is associated with formation of CPF/CPO-protein adducts. We will examine the presence of immune cells that recognize CPF/CPO-modified proteins and antibodies against them to determine if blood antibodies can cross-react with brain proteins. Understanding the mechanisms of OP- induced CMI will facilitate the development of countermeasure efforts that target the immune system in order to minimize long-term morbidity associated with such illnesses in civilian populations following a mass chemical attack with CPF or similar chemicals.

毒死蜱（CPF）是一种有机磷农药，被列为化学威胁剂。 国土安全部，因为它可以导致神经毒性，如果释放到平民人口。 在这种情况下，CPF和类似的OP化学品有可能导致长期慢性多 症状性疾病（CMI），如肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）。到目前为止， 东京地铁沙林毒气袭击的许多受害者仍在经历慢性健康问题， 认知困难、头痛、肌肉无力和疲劳，这对他们的生活质量产生了负面影响。 这些症状是由暴露于有机磷农药的个人报告的，被认为是由以下原因引起的： 适应不良的免疫反应7.因此，本建议将调查CPF在适应不良中的作用， 免疫反应，以开发未来的方法，减轻长期发病率与CMI。 通常，小分子化学物质不是抗原性的，但当它与内源性蛋白质形成加合物时，它可以是抗原性的。 被免疫系统识别为外来威胁因子并引起适应性免疫应答。我们 这一领域的先前工作表明，某些农药代谢物可以与蛋白质形成加合物， 适应性免疫反应，激活T细胞和B细胞，最终有助于产生 它们的抗体和相应的脑部炎症。2001年急性CPF中毒病例报告 人类通过显示CPF或CPF-oxon（CPO）可以在几种氨基酸上形成加合物来支持这一观点 人白蛋白中的残基，被认为是OP暴露的生物标志物。然而，不知道是否 这些CPF/CPO-蛋白加合物具有激活免疫系统的作用。因此我们假设 CPF暴露后体内形成的CPF/CPO-蛋白加合物可以激活T细胞和B细胞应答， 导致抗体产生。我们认为，CPF蛋白特异性抗体可能与脑 蛋白质，并有助于慢性自身免疫性疾病的发展。拟议的工作建立在 这是一个关于杀虫剂介导的适应不良免疫反应的现有科学前提。这些研究将 表征急性CPF施用是否刺激免疫细胞，以及这是否对应于 CPF暴露后小胶质细胞和星形胶质细胞的活化和神经炎症。我们将决定 脑免疫激活与CPF/CPO-蛋白加合物的形成有关。我们会研究 存在识别CPF/CPO修饰的蛋白质和针对它们的抗体的免疫细胞， 确定血液抗体是否能与大脑蛋白质发生交叉反应。了解OP的机制- 诱导的CMI将促进针对免疫系统的对抗措施的发展， 最大限度地减少平民群体在大规模化学品爆炸后患上此类疾病的长期发病率 使用CPF或类似化学品进行攻击。