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.

Chlorpyrifos（CPF）是一种有机磷酸盐（OP）农药，被归类为化学威胁剂 国土安全部是因为如果释放到平民人口中，可能会引起神经毒性。 在这种情况下，CPF和类似的OP化学物质有可能引起长期慢性多种 症状疾病（CMI），例如肌力性脑脊髓炎/慢性疲劳综合征（ME/CFS）。迄今为止， 东京地铁沙林气体攻击的许多受害者仍在遇到慢性健康问题，包括 认知困难，头痛，肌肉弱点和疲劳，对他们的生活质量产生负面影响。 暴露于Op农药的人报告了此类症状，被认为是由 适应性免疫反应7。因此，该提案将调查CPF在适应不良中的作用 对开发未来方法的免疫反应，以减轻与CMI相关的长期发病率。 通常，一种小化学物质不是抗原性的，但是当它与内源性蛋白形成加合物时，可以是 被免疫系统认可为外国威胁代理，并引起适应性免疫反应。我们的 该领域的先前工作表明，某些农药代谢物可以用蛋白质形成加合物，然后引起 自适应免疫反应，激活T型和B细胞，最终有助于产生 针对它们的抗体，与大脑炎症相对应。急性CPF中毒的帐户 人类通过表明CPF或CPF-OXON（CPO）可以在几种氨基酸上形成加合物来支持这一概念 人白蛋白中的残留物被认为是OP暴露的生物标志物。但是，未知是否 这些CPF/CPO蛋白加合物在激活免疫系统中起作用。因此，我们假设 CPF/CPO蛋白加合物在CPF暴露后在体内形成的加合物可以激活T细胞和B细胞反应，即 导致抗体产生。我们建议CPF蛋白特异性抗体可能与脑反应 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 农药介导的不良适应性免疫反应的现有科学前提。这些研究会 表征急性CPF给药是否刺激免疫细胞，以及是否与 CPF暴露后，小胶质细胞和星形胶质细胞的激活以及神经炎症。我们将确定是否 脑免疫激活与CPF/CPO蛋白质加合物的形成有关。我们将检查 存在识别CPF/CPO修饰蛋白的免疫细胞和针对它们的抗体 确定血液抗体是否可以与脑蛋白交叉反应。了解操作的机制 诱导的CMI将促进针对免疫系统的对策努力的发展 最小化与这种疾病相关的长期发病率在大众化学后的平民种群中 用CPF或类似化学物质攻击。