Persistence of pulmonary tertiary lymphoid tissues and anti-nuclear antibodies following cessation of cigarette smoke exposure

Abstract

Formation of pulmonary tertiary immune structures is a characteristic feature of advanced COPD. In the current study, we investigated the mechanisms of tertiary lymphoid tissue (TLT) formation in the lungs of cigarette smoke-exposed mice. We found that cigarette smoke exposure led to TLT formation that persisted following smoking cessation. TLTs consisted predominantly of IgM positive B cells, while plasma cells in close proximity to TLTs expressed IgM, IgG, and IgA. The presence of TLT formation was associated with anti-nuclear autoantibody (ANA) production that also persisted following smoking cessation. ANAs were observed in the lungs, but not the circulation of cigarette smoke-exposed mice. Similarly, we observed ANA in the sputum of COPD patients where levels correlated with disease severity and were refractory to steroid treatment. Both ANA production and TLT formation were dependent on interleukin-1 receptor 1 (IL-1R1) expression. Contrary to TLT and ANA, lung neutrophilia resolved following smoking cessation. These data suggest a differential regulation of innate and B cell-related immune inflammatory processes associated with cigarette smoke exposure. Moreover, our study further emphasizes the importance of interleukin-1 (IL-1) signaling pathways in cigarette smoke-related pulmonary pathogenesis.

Role of BAFF in pulmonary autoantibody responses induced by chronic cigarette smoke exposure in mice

“…2004; Morissette et al. 2014). To assess the role of BAFF in the formation of TLTs and production of ANA, we exposed BALB/c mice to cigarette smoke or room air for 24 weeks and blocked BAFF using BAFFR‐Fc during the last 12 weeks of exposure (Fig.…”

“…2004; Morissette et al. 2014). Therefore, we investigated whether BAFF blockade, and its associated reduction in TLTs and ANAs, impacted inflammatory processes in the lungs.…”

“…We previously reported elevated levels of autoantibodies following 24 weeks of smoke exposure that persisted following smoking cessation, and coincided with the formation of TLT in the lungs (Morissette et al. 2014). We utilized BAFFR‐Fc to block BAFF, using several different experimental protocols, to investigate the function of BAFF in the context of cigarette smoke exposure as well as following smoking cessation.…”

“…2010; Morissette et al. 2014). Briefly, mice were exposed twice daily to twelve 3R4F reference cigarettes (Center for Tobacco Reference Products, University of Kentucky, KY), with filters removed, for 5 days per week (Monday–Friday).…”

“…2010; Morissette et al. 2014). We recently reported the presence of broad‐spectrum autoantibodies recognizing antinuclear antigens in the lungs of mice exposed to cigarette smoke; a phenomenon linked with the presence of tertiary lymphoid tissues (TLTs) (Morissette et al.…”