The role of adaptive immunity in organophosphate induced CNS injury

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.

Grant Number: 5R21NS131162-02
NIH Institute/Center: NIH
Principal Investigator: Laila Abdullah