Fig. 7

Summary of DEP mediated autoimmune disease. Two DEPs, SRM1650b from a 4-cylinder diesel engine, and SRM2975 from a 2-cylinder diesel engine, were tested for the effects on T cell differentiation and autoimmune disease. SRM1650b enters the T cell, binds AHR, which then translocate to the nucleus and binds DNA, driving transcription of CYP enzymes (top). SRM1650b enhances Th17 differentiation in an AHR-dependent manner and worsens autoimmune disease (top). Based on the in vivo EAE data, SRM1650b requires the particle to aggravate autoimmune disease because of bioavailability of the PAHs and their ability to activate the AHR. Similarly, SRM1975 enters the T cell, binds AHR, moves to the nucleus, binds DNA, and drives transcription of CYP enzymes (bottom). SRM2975 enhances Th1 differentiation in an AHR-dependent manner and worsens autoimmune disease (bottom). Based on the in vivo EAE data demonstrating SRM2975 worsens autoimmune disease in PM and OF forms and the in vitro data showing a role of CYP enzymes in T cell differentiation, metabolism of SRM2975 plays a role in its ability to worsen autoimmune disease in that CYP metabolism of PAHs may lead to more potent intermediate that drives the response in vivo. Additionally, in the presence of PAHs and AHR activation, enhanced effector differentiation by both samples results in increase in Th17 or Th1 cells and a reduction in Treg cells. However, when PAHs are diluted at low doses, enhanced effector differentiation is no longer observed, and the balance is switched to enhanced Treg differentiation. Abbreviations: SRM, standard reference materials; DEPs, diesel exhaust particles; AHR, aryl hydrocarbon receptor; CYP, cytochrome P450; PAH, polycyclic aromatic hydrocarbons