Abstract
This review examines the current literature on the effects of atmospheric particulate matter (PM) on autoimmune disease and proposes a new role for the aryl hydrocarbon receptor (AHR) as a modulator of T cells in PM-mediated autoimmune disease. There is a significant body of literature regarding the strong epidemiologic correlations between PM exposures and worsened autoimmune diseases. Genetic predispositions account for 30% of all autoimmune disease leaving environmental factors as major contributors. Increases in incidence and prevalence of autoimmune disease have occurred concurrently with an increase in air pollution. Currently, atmospheric PM is considered to be the greatest environmental health risk worldwide. Atmospheric PM is a complex heterogeneous mixture composed of diverse adsorbed organic compounds such as polycyclic aromatic hydrocarbons (PAHs) and dioxins, among others. Exposure to atmospheric PM has been shown to aggravate several autoimmune diseases. Despite strong correlations between exposure to atmospheric PM and worsened autoimmune disease, the mechanisms underlying aggravated disease are largely unknown. The AHR is a ligand activated transcription factor that responds to endogenous and exogenous ligands including toxicants present in PM, such as PAHs and dioxins. A few studies have investigated the effects of atmospheric PM on AHR activation and immune function and demonstrated that atmospheric PM can activate the AHR, change cytokine expression, and alter T cell differentiation. Several studies have found that the AHR modulates the balance between regulatory and effector T cell functions and drives T cell differentiation in vitro and in vivo using murine models of autoimmune disease. However, there are very few studies on the role of AHR in PM-mediated autoimmune disease. The AHR plays a critical role in the balance of effector and regulatory T cells and in autoimmune disease. With increased incidence and prevalence of autoimmune disease occurring concurrently with increases in air pollution, potential mechanisms that drive inflammatory and exacerbated disease need to be elucidated. This review focuses on the AHR as a potential mechanistic target for modulating T cell responses associated with PM-mediated autoimmune disease providing the most up-to-date literature on the role of AHR in autoreactive T cell function and autoimmune disease.
Highlights
There are over 80 recognized autoimmune diseases [1]
Some AHR ligands have been shown to ameliorate autoimmune disease and others to exacerbate disease in vitro and in vivo (Table 1), but despite these differences it is clear that AHR ligands shift the balance between effector and regulatory T cells determining autoimmune disease outcomes
One question that has been raised is what gives certain ligands the ability to exacerbate disease vs. ameliorate disease? Previously it was thought that AHR regulated Th17 and Treg differentiation in vitro and in vivo in a ligand-specific manner [44, 46]
Summary
There are over 80 recognized autoimmune diseases [1]. In the United States alone, autoimmune diseases are among the most prevalent diseases effecting 24.5 million people or approximately 8% of the population [1, 2]. While genetic predispositions play a role in disease incidence [13], epidemiologic studies strongly support that high levels of air pollution, particulate matter (PM) in the atmosphere, increase the incidence and severity of autoimmune disease [1, 3]. It was discovered that TCDD exposure caused severe toxicity and life-threatening manifestations such as progressive liver failure, emphysema, renal failure, and myocardial degeneration, among other pathologies [43] In addition to these manifestations, rodent studies described immune phenotypes of TCDD exposure revealing a role of AHR in the immune system. We examine the data demonstrating the effects of organic constituents adhered to PM, AHR ligands, on T cells and suggest the AHR pathway as a target for modulating PM-mediated autoimmune disease. We propose a novel hypothesis that AHR ligands present in atmospheric PM activate the AHR shifting the T cell balance from regulatory to effector leading to PM-mediated autoimmune disease
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