Investigating a Model for PM-Induced Exacerbation of Autoimmunity

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Epidemiologic studies strongly support that exposure to airborne pollution increases the incidence and severity autoimmunity, a diagnosis that encompasses more than 80 different disease processes and affects more than 20 million Americans. Patients typically suffer chronic symptoms that leave them ill for the rest of their lives. Surprisingly, despite the fact that inhaled particulate matter (PM) is well accepted as a risk for autoimmunity, the specific exposures that cause disease and the mechanisms involved are not known. This is likely because of the complexity of pollution that is generated by numerous sources with variable chemical composition, and the diverse genetic background of populations that are exposed. This lack of understanding has made efforts at regulation, remediation, and avoidance unsuccessful. Veterans may be at particularly high risk, as military personnel are exposed to high levels of PM from diesel engines and other sources. In addition, some unique exposures that may be particularly pathologic are found at sites of deployment, including burn pit exposures. Our group has spent the last few years examining the ability of different samples of PM to enhance an effector response and increase immunity. We have recently found that in a mouse model of experimental autoimmune encephalomyelitis (EAE), two Standard Reference Materials (SRMs) from diesel exhaust particles (DEP) significantly increased severity of disease. Analysis of the organic fractions of these samples show aryl hydrocarbon receptor (AHR)-dependent ability for enhancement of effector Th17 cell differentiation by these samples. In addition, analysis of polycyclic aromatic hydrocarbon (PAH) mixtures from these samples suggest this fraction may be central to the increased effector response in T cells. These findings have led us to generate the hypothesis that exposure to military service or deployment-related PM can increase self- reactive T-cell responses in an AHR-dependent manner, resulting in more severe autoimmune disease. We will explore the following aims: Aim 1: Identify DEP-mediated effects on T cells that lead to an increase in EAE clinical severity. We will test the hypothesis that DEP exposure in the B6-EAE model enhances disease severity by increasing the pathogenic potential of anti-MOG T cells, either directly through T cells or indirectly through DCs. This aim focuses on effects on immune cells irrespective of a role for the AHR Aim 2: Determine the contribution of the AHR, metabolism, and the PAHs in PM-driven autoimmune exacerbation. We will test the hypothesis that both DEPs aggravate EAE via the AHR, and will explore the importance of metabolism and PAH content. Aim 3: Screen source samples of military service or deployment-related PM for immune-altering activity. We will expose mice undergoing EAE to four samples relevant to military exposures, testing the hypothesis that aggravation of autoimmunity is source dependent. Aim 4: Determine the capacity of dietary interventions to mitigate DEP-mediated aggravation of disease in the B6-EAE model. We will test the hypothesis that dietary ligands can specifically reduce the effects of inhaled pollution on autoimmunity. We anticipate that PM will aggravate EAE through a direct effect on the AHR in T cells. We further predict that exposures unique to the military will aggravate disease, and oral supplementation with dietary AHR ligands will mute the aggravation of disease seen after PM exposure. This grant directly addresses the priority research area of interest regarding military service or deployment-related occupational exposures. Results from this grant will provide a rational for understanding which military environmental exposures are most pathogenic and aid in remediation, avoidance, and treatment strategies.