Abstract
Emerging evidence suggests that autoimmune processes are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). In this study, we assessed the expression of B‐cell activating factor (BAFF) in smokers, and investigated the functional importance of BAFF in the induction and maintenance of cigarette smoke‐induced pulmonary antinuclear antibodies (ANA) and tertiary lymphoid tissues (TLTs) using a preclinical mouse model. We observed that BAFF levels were elevated in smokers and mice exposed to cigarette smoke. In mice, BAFF expression was rapidly induced in the lungs following 4 days of cigarette smoke exposure and remained elevated following 8 and 24 weeks of exposure. Alveolar macrophages were the major source of BAFF. Blockade of BAFF using a BAFF receptor‐Fc (BAFFR‐Fc) construct prevented pulmonary ANA and TLT formation when delivered concurrent with cigarette smoke exposure. Under these conditions, no impact on lung inflammation was observed. However, administration of BAFFR‐Fc following smoking cessation markedly reduced the number of TLTs and ANA levels and, of note, reduced pulmonary neutrophilia. Altogether, this study shows for the first time a central role of BAFF in the induction and maintenance of cigarette smoke‐induced pulmonary ANA and suggests that BAFF blockade following smoking cessation could have beneficial effects on persistent inflammatory processes.In this study, we assessed the expression of B‐cell activating factor (BAFF) in smokers, and investigated the functional importance of BAFF in the induction and maintenance of cigarette smoke‐induced pulmonary antinuclear antibodies (ANA) and tertiary lymphoid tissues (TLTs) using a preclinical mouse model. Data presented show that BAFF plays a central role in the induction and maintenance of cigarette smoke‐induced pulmonary ANA and suggest a therapeutic potential for BAFF blockade in limiting autoimmune processes associated with smoking.
Highlights
Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD), a degenerative lung disease with significant impact on pulmonary and cardiovascular health resulting in low quality of life and mortality (Mannino 2002; Hogg 2004; Reardon et al 2006; Curtis et al 2007)
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 2014)
Given that BAFF blockade prevented the formation of TLT and antinuclear antibodies (ANA) induced by chronic cigarette smoke exposure, we investigated whether BAFF blockade was able to resolve established TLTs and attenuate ANA levels in the lungs following smoking cessation
Summary
Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD), a degenerative lung disease with significant impact on pulmonary and cardiovascular health resulting in low quality of life and mortality (Mannino 2002; Hogg 2004; Reardon et al 2006; Curtis et al 2007). It is widely accepted that chronic inflammation contributes to the pathogenesis of COPD. There is emerging interest in the role of the adaptive immune system in the pathogenesis of COPD. Autoimmune features, such as the presence of systemic autoantibodies, as well as clonal expansion of lung CD4 and CD8 T cells, have been observed in COPD patients and preclinical models of cigarette smoke-induced inflammation (Lee et al 2007; Motz et al 2008; Brandsma et al 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 2014)
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