Rheumatoid arthritis (RA) is an autoimmune arthropathy mainly mediated by Th17 cells. The development of AR is the result of the interaction between genetic and environmental factors such as exposure to chemicals present in industrial products, pollutants and cigarette smoke. Recently, it was demonstrated that a intracellular sensor of these pollutants, the aryl hydrocarbon receptor (AHR), is highly expressed in Th17 cells. AHR activation enhances expansion and effector function of these cells, on the other hand, AHR absence or blockage protects the development of experimental arthritis and encephalomyelytis. Thus, the AHR has been considered a link between environmental factors and the triggering of autoimmune diseases. Recent observations suggest that its activation may alter both apoptotic as anti-proliferative pathways and thereby support the survival and expansion of activated cell. In this context, it has been shown correlation between AHR expression and c-Kit receptor, Notch and IL-7R. Notch and IL-7R were previously correlated with expansion of Th17 cells. Additionally, in silico studies suggest that AHR can induce the expression of IL-23 receptor (IL-23R) and IL-1beta (IL-1R1), both related to expansion of Th17 cells. Given this evidence, the objective of the project is to identify the molecular mechanisms involved in enhancement of Th17 response mediated by AHR, focusing on c-Kit receptor, Notch, IL-7R, molecules involved in anti-apoptotic pathways, cell proliferation and Th17 differentiation (IL-23R, IL-1R). For this purpose, we will (1) describe the relationship between AHR and its potential target during in vitro differentiation of Th17 cells, (2) evaluate this relationship during the development of experimental arthritis and finally (3) to correlate the findings with AHR activity, clinical and immune response pattern in biological samples of patients with RA. Such mechanisms may be further used for the development of new therapeutic targets for the treatment of autoimmune diseases such as RA.
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