Cigarette smoke exposure sets up a pro-inflammatory circuit in the lung that induces the hyper-activation of myelin-specific T helper cells

Inhalation of cigarette smoke (CS) is a risk factor for multiple sclerosis (MS) and it is estimated to account for 20% of disease cases. However, the mechanism of how CS exposure promotes autoimmunity in MS is not understood. To investigate the potential mechanisms driving this immune phenotype, we investigated the effect of CS exposure on the development of myelin-specific autoimmunity in experimental autoimmune encephalomyelitis (EAE) models of MS. We observed that CS exposure enhanced myelin-specific Th1 responses in peripheral lymphoid compartment, but puzzlingly delayed the onset of EAE. Further studies done using a Th17 passive EAE model revealed that EAE was delayed with CS because myelin-specific T cells were retained in the lungs where they became hyperactivated and produced greater levels of Th1/Th17 cytokines and GM-CSF. Neutralizing IL-12p40 reduced these effects of CS on T cells. This work identifies a potential mechanism for how CS exposure enhances MS and identifies a potential target for treatment.