The role of adaptive immunity in organophosphate induced CNS injury

毒死蜱(CPF)是一种有机磷(OP)杀虫剂，被世界卫生组织列为化学威胁物质。 因为如果释放到平民人口中，可能会导致神经毒性。 在这种情况下，CPF和类似的OP化学物质有可能导致长期的慢性多发性 症状疾病(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，包括 认知困难、头痛、肌肉无力和疲劳，这些都对他们的生活质量产生了负面影响。 这些症状是由接触有机磷杀虫剂的个人报告的，被认为是由 适应不良免疫反应7。因此，这项提案将调查中央公积金在适应不良中的作用。 免疫反应，以开发未来的方法，以减轻与CMI相关的长期发病率。 通常情况下，一种小的化学物质不是抗原性的，但当它与内源蛋白质形成加合物时，它可以 被免疫系统识别为外来威胁因子，并激发适应性免疫反应。我们的 这方面的前期工作表明，某些农药代谢物可以与蛋白质形成加合物，然后诱导 一种适应性免疫反应，激活T和B细胞，最终有助于产生 针对它们的抗体与脑部炎症相对应。年发生的急性CPF中毒病例报告 人类通过证明CPF或CPF-oxon(CPO)可以在几种氨基酸上形成加合物来支持这一观点 人体白蛋白中的残留物，被认为是OP暴露的生物标志物。然而，目前还不清楚 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蛋白加合物可激活T细胞和B细胞反应， 从而产生抗体。我们认为CPF蛋白特异性抗体可能与大脑发生交叉反应。 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 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给药是否刺激免疫细胞，以及这是否符合 CPF暴露后小胶质细胞和星形胶质细胞的激活及神经炎症。我们将确定是否 脑免疫激活与CPF/CPO-蛋白加合物的形成有关。我们将研究 识别CPF/CPO修饰蛋白的免疫细胞和针对它们的抗体的存在 确定血液抗体是否会与大脑蛋白质发生交叉反应。了解OP-2的作用机制 诱导的CMI将促进针对免疫系统的对策努力的发展，以便 最大限度地减少平民人群在使用大规模化学品后与此类疾病相关的长期发病率 用CPF或类似的化学物质攻击。

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.