The role of adaptive immunity in organophosphate induced CNS injury

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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.