Airborne pollution is well documented as a risk factor for multiple airway diseases, and is implicated in aggravating autoimmunity, both in the lung and systemically. In this grant we investigate the importance of inhaled particulate matter (PM), and specifically polycyclic aromatic hydrocarbons (PAHs) in PM, to enhance Th17 differentiation systemically and aggravate autoimmunity in a murine model of experimental autoimmune encephalomyelitis (EAE). We will present preliminary data that inhaled PM increases Th17 differentiation in remote lymph nodes and worsens EAE. Based on these findings and previous data, we have developed the hypothesis that patients at risk for development of autoimmunity experience a dysregulation of their Treg/Th17 balance when confronted with prolonged or acute airborne exposures that can aggravate existing disease or stimulate new onset disease. The recent finding that the aryl hydrocarbon receptor (AHR) plays a central role in the regulatory T cell (Treg)/Th17 balance, where some ligands of the AHR can enhance Treg differentiation and other ligands can enhance Th17 differentiation led us to predict that PAHs (which are known AHR ligands) in PM are responsible for pollution induced Th17 deviation. Our model is that PAHs in pollution, encountered through inhalation, bind to the AHR on immune cells, leading to increased Th17 differentiation, decreased Treg generation, and enhanced autoimmunity. If this model is correct, we postulate that a number of environmentally induced autoimmune diseases may be influenced by a similar mechanism. We will explore the following aims:
Aim 1 : Determine the lower limits of PM capacity to exacerbate EAE and examine the associated changes in the T cell responses to MOGp35-55.
Aim 2 : Determine the component(s) of PM responsible for aggravation of EAE after inhalation.
Aim 3 : Determine the requirements for AHR expression in PM- mediated EAE aggravation. The unique features of this grant and future studies are the ability we have based on our expertise to examine specific components of PM and their interaction with the AHR, the numerous recombinant mouse models at our disposal, and our ability to compare standard reference materials to real world samples to develop and test the components of PM that enhance autoimmunity. The connections of this project to public health are supported by the high incidence of autoimmunity, the known connection of these morbid diseases to environmental exposures, and the lack of understanding of mechanisms of disease or adequate treatments for those suffering from them. We predict that our findings will allow development of avoidance strategies, more focused remediation, and identify the cell types, receptor, and cytokines to target with immunomodulators.
It is well accepted that environmental exposures, including pollution, aggravate autoimmunity. The mechanism and the specific exposures remain unclear. In this proposal we extend our own experience with inhaled particulate matter (PM) and its effects on the immune system, particularly its ability to activate the aryl hydrocarbon receptor (AHR) and aggravate Th17 differentiation. We will apply this to a model of Experimental Autoimmune Encephalomyelitis (EAE) in mice. Based on our previous experiments and preliminary data in this model, we predict that inhaled PM, and specifically the polycyclic aromatic hydrocarbons in PM, aggravate EAE through the AHR. By documenting the mechanism and components of inhaled pollution that aggravate autoimmunity, we will be able to propose avoidance strategies and novel targets for future pharmaceutical treatments of patients suffering from these illnesses.
| O'Driscoll, Chelsea A; Gallo, Madeline E; Hoffmann, Erica J et al. (2018) Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro. PLoS One 13:e0209690 |
| O'Driscoll, Chelsea A; Owens, Leah A; Gallo, Madeline E et al. (2018) Differential effects of diesel exhaust particles on T cell differentiation and autoimmune disease. Part Fibre Toxicol 15:35 |
| Julliard, Walker; De Wolfe, Travis J; Fechner, John H et al. (2017) Amelioration of Clostridium difficile Infection in Mice by Dietary Supplementation With Indole-3-carbinol. Ann Surg 265:1183-1191 |
| Julliard, W; Owens, L A; O'Driscoll, C A et al. (2016) Environmental Exposures-The Missing Link in Immune Responses After Transplantation. Am J Transplant 16:1358-64 |
