Crosstalk Between Environmental Tobacco Smoke and Gut Microbiota Shapes Autoimmune Disease by Modulating the Th17 Response of Lung-gut-axis

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PROJECT SUMMARY Rheumatoid arthritis (RA) is an autoimmune disorder that classically involves joints. Pulmonary complications are common and major contributors to RA mortality. The etiopathogenesis of RA remain unclear. The low concordance rate of RA in monozygotic twins ( 15%) suggests the importance of environmental factors in RA. Secondhand smoke, or environmental tobacco smoke (ETS) is an important environmental hazard to both children and adults, but children are especially susceptible. Gut microbiota is another potential environmental trigger for disease. We have reported that segmented filamentous bacteria (SFB), a type of gut commensal, drives autoimmune arthritis by inducing Th17-mediated B cell differentiation. Excitingly, our most recent data show that a human commensal Escherichia coli isolate 2A (termed E.coli 2A) from spondyloarthritis patients also cause autoimmune augmentation. Immune cells activated at the environmental frontline, the mucosa, share similar homing receptors and thus lymphocytes activated from one mucosal site can home to other mucosal tissues. Based on this “common mucosal immune system” principle, we hypothesize that ETS and gut microbiota crosstalk at the mucosal interface of the lung-gut axis to prime the Th17-mediated autoantibody (auto-Ab) response in the lung, triggering the RA-related lung disease that sets off systemic joint disease. We will test our hypothesis in both juvenile and adult K/BxN mice by determining: 1) the age-based window and mechanism for the ETS-mediated lung-gut axis of Th17 response with and without SFB or E.coli 2A; and 2) the role of the ETS- and SFB- (or E.coli 2A-) mediated Th17 of lung-gut axis in causing auto-Abs and disease. Remarkably, our new data support our hypothesis by showing that a robust SFB-induced Th17 response is accompanied by much higher auto-Ab level in the lung than spleen, the organ traditionally considered as the primary auto-Ab producing site in K/BxN mice. Next, we will determine the mechanism underlying ETS- and microbiota-mediated Th17 response by regulating survival, proliferation, differentiation, and/or recruitment of Th17 cells; or by affecting regulatory T cells, altering Th17 response. Because Th17 can exist as long-lived memory cells and the detrimental effect from childhood-exposure to ETS can last a lifetime, we will also examine the Th17 response after ETS cessation. As Th17 cells help B cell differentiation in K/BxN mice, we hypothesize that ETS- and microbiota-mediated lung Th17 cells can cause lung disease by inducing auto-Abs. We will perform a temporal comparison, and expect that ETS and microbiota will induce an earlier Th17 response, accompanied by B cell differentiation in the lung prior to the spleen. We will use Th17 ablation and molecular signatures of pathogenic and non-pathogenic Th17 cells to study the role of Th17 cells in ETS/microbiota-induced autoimmunity. Mucosal immunoregulation remains poorly understood but is of profound importance, as the mucosa harbors the frontline immune response to environmental stimuli, and their interactions can subsequently shape both mucosal and systemic diseases.