A Hairline Crack in the Levee: Focal Secretory IgA Deficiency as a First Step toward Emphysema.

Among the many ways smoking annually kills more than 5 million humans (1), arguably none is as cruel as the slow, relentless suffocation inflicted by emphysema. Attaining comprehensive molecular understanding of emphysema pathogenesis has also been agonizingly slow. Emphysema was recognized at autopsy in the early 1800s by Laennec (2), who advanced a now-refuted theory of its origin, but the first conceptual breakthrough came from identification of emphysema subtypes, notably centrilobular emphysema (CLE) (3). With these subtypes now quantifiable in living subjects by radiographic imaging (4), there is hope that research progress will accelerate. Emphysema might be arrested at many downstream steps, but it would be most efficient to block its initiation. Two major hypotheses on the origin of emphysema have emerged. One could be termed the Canadian hypothesis, as it germinated in Montreal and flowered there and in Vancouver among the groups of Profs. Cosio and Hogg, respectively. It emphasized inflammation in small (,2 mm diameter) airways, leading to their disappearance before CLE develops (5). A second hypothesis, from investigators originally and now largely again in Denver, focused on vascular endothelial apoptosis (6). It was heavily influenced by experimental models (7) and less specifically linked to emphysema subtype. Importantly, neither group claimed that their mechanisms exclusively explain emphysema pathogenesis. Both might pertain in different disease stages, or perhaps specific emphysema subtypes result from the balance between epithelial damage, vascular injury, or other factors. The goal of this simplified formulation is not to slight the very significant contributions of other investigators worldwide but to contextualize another compelling advance, coincidently supporting the Canadian hypothesis. In this issue of the Journal, Polosukhin and colleagues (pp. 1010–1021) demonstrate a molecular mechanism that explains why airway injury develops in small airways precisely where Hogg and colleagues showed it begins (8). This exciting new study builds on decades of work on the key role of secretory immunoglobulin A (SIgA) in respiratory epithelial defense (9). Hence, appreciating three points about SIgA physiology is essential (Figure 1). First, relative to serum IgA, the SIgA complex is specialized for export into mucosal lumens and subsequent sustained activity (Figure 1A). Second, IgA does not activate complement, permitting “immune exclusion” without inflammation. Third, because epithelial tight junctions, like the levees protecting cities along major rivers from devastating flooding, block bidirectional macromolecule transit, IgA cannot simply diffuse into the airway lumen. Instead, dimeric IgA (and pentameric IgM) must be transcytosed by the polymeric Ig receptor (pIgR) expressed on basolateral epithelial cell membranes (Figure 1B). At the luminal surface, cleavage of pIgR liberates SIgA, still bound to a portion of pIgR called the secretory component. Reduced secretory component (and hence SIgA) was shown in bronchoalveolar lavage fluid of smokers (10) and in small airways of patients with chronic obstructive pulmonary disease (COPD) (11), and then the Vanderbilt group and collaborators linked reduced pIgR expression and localized SIgA deficiency in small airways to cross-sectional COPD severity (12, 13). The next and crucial step in the logical chain of emphysema pathogenesis comes in this issue of the Journal, which meticulously used fluorescence microscopy (for SIgA) and in situ hybridization (for intracellular bacteria) to analyze human lung samples (total n = 89, including lifelong nonsmokers, ex-smokers without COPD, and all Global Initiative for Chronic Obstructive Lung Disease stages) (8). Results convincingly show that pathological changes, regardless of subject group, were limited almost exclusively to small airways classified as SIgA deficient. Changes included all those characterizing early COPD, including distorted epithelial morphology, inflammatory cell infiltration, and fibrotic remodeling. Most tellingly, only SIgA-deficient small airway epithelia were invaded by bacteria and showed nuclear factor-kB activation (Figure 1C). Together with complementary results from this group’s studies using transgenic mice lacking PIgR (14), these data strongly implicate a specific localized defect in innate immunity in the earliest stages of smoking-induced damage to terminal bronchi. This significant advance is congruent with findings in the skin and gut, where failure to contain bacteria leads to escalating adaptive immune countermeasures, culminating in frank autoimmunity. As at those other interfaces, subtle innate immune defects, perhaps acquired as in this study (8), but likely also genetic, could explain why only certain ever-smokers transition into greater epithelial damage plus a more aggressive lung microbiome exploiting that damage (15) and why, once initiated, pathology may be sustained despite smoking cessation. Supported by Clinical Science Research and Development Service, Department of Veterans Affairs Merit Review Award I01 CX000911; National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Public Health Service grants R01 AI120526 and R21 AI 117371; and a grant from MedImmune Corporation, Ltd. The opinions in this editorial are exclusively those of the author and do not reflect the official positions of the Department of Veterans Affairs or the U.S. Public Health Service.