Mucosal Immunity

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The epithelium lining of the conducting airways plays a pivotal role in protecting the lungs from environmental insults and shaping the innate and adaptive immunity in the lungs. Patients with chronic obstructive pulmonary disease (COPD) often exhibit structural changes in the airway epithelium (1), which can affect its innate immune function, including its secretion of IgA. On the basis of the role of secretory IgA (SIgA) in gut mucosal immunity, it is speculated that SIgA may play a similar role in the airways, which are constantly bombarded with airborne pathogens. The data regarding SIgA in COPD airway fluid is controversial, with one study showing reduction (2), a second demonstrating no difference between normal and COPD (3), and a third reporting higher concentrations of SIgA in smokers and patients with COPD with mild to moderate disease (4). However, there appears to be variability in the concentrations of SIgA within the same patient on the basis of the airway remodeling that can range from normal-appearing to goblet cell hyperplasia, basal cell metaplasia, incompletely differentiated areas, and squamous metaplasia (2). SIgA was more abundant in normal-appearing than in remodeled zones, indicating a localized loss of SIgA. Importantly, loss of SIgA in small airways correlated with severe airway obstruction in COPD (5). Furthermore, mice lacking SIgA developed spontaneous COPD-like lung disease and showed the presence of bacteria in the affected airways (6).SIgA concentrations in the airways depend on IgA expression by plasma cells in the lamina propria, polymeric Ig receptor (PIGR)-dependent transcytosis of IgA from basolateral to apical surface of the epithelium (7), and degradation of SIgA by a protease. IgA production by plasma cells in the lamina propria appears to be normal in COPD (8). In COPD airways, protease concentrations and their activity is increased because of infiltrating inflammatory cells and bacterial pathogens (9), which can potentially reduce the concentrations of SIgA in the airway lumen. Depending on the extent of airway remodeling, expression of PIGR varies, and epithelium with squamous metaplasia shows a total loss of PIGR (2). Normal airway epithelium has a variety of cell types, and it is not known which cell types express and transport SIgA. In this issue of the Journal, Blackburn and colleagues (pp. 334–345) report that secretory cells positive for SCGB1A, SCGB3A2, or both, are the primary source of PIGR in human small airways, whereas ciliated cells, which are more abundant, showed relatively lower expression (10). Interestingly, single-cell RNA sequencing analysis of peripheral lung revealed significantly higher concentrations of PIGR mRNA expression in both secretory and ciliated cells. But, by immunofluorescence, they observed localized loss of PIGR protein, which coincided with the loss of luminal SIgA. The authors note that most of the normal cohort in this study were light smokers, whereas all the COPD subjects were former smokers. Previous studies have demonstrated increased expression of PIGR in smokers (11). Therefore, it is unclear from these studies whether the observed increase in PIGR protein is because of smoking status or dysregulation of protein translation because of an altered state of differentiation in club cells in COPD (12). Another limitation of this paper is that the authors do not consider the contribution of goblet cells to PIGR expression or SIgA concentrations. Although goblet cells are absent in the small airways of normal subjects, they are abundant in COPD small airways. In fact, mucus secreted by these goblet cells is the major cause of small airway obstruction in COPD.Another hypothesis is that loss of SIgA may be because of increased proteolytic activity in COPD airways. Interestingly, the authors show that some airways, despite the expression of PIGR, show loss of SIgA (13). These airways were positive for eubacterial 16S RNA and contained infiltrated neutrophils, macrophages, and other inflammatory cells, all of which contribute to increased concentrations of proteases. In addition, they demonstrate the degradation of IgA by proteases elaborated by nontypeable Haemophilus influenzae, a major bacterial pathogen in COPD. If this hypothesis is true, treatment with antiproteinases or protease inhibitors should increase the concentrations of SIgA and improve the mucosal immunity in COPD. However, because of different classes of proteases in the COPD airways, this treatment strategy is not considered for patients with COPD unless the patients have alpha-1 antitrypsin deficiency.The authors confirmed their findings that secretory cells are the major cell type that transports SIgA. They generated mice lacking PIGR specifically in either ciliated cells or SCGB1A1-positive secretory (club) cells. Club cell-specific PIGR knockout (K/O) mice showed significantly lower concentrations of SIgA than the ciliated cell-specific PIGR K/O mice or wild-type mice. Previously, these authors have demonstrated that the global PIGR K/O mice, which display no SIgA in mucosal secretions (14), spontaneously develop age-dependent COPD-like lung disease such as emphysema and increased airway wall thickness and show microbial invasion in the airways (6). In addition, these PIGR K/O mice were more prone to develop emphysema and airway remodeling when exposed to cigarette smoke. Because both ciliated and club cells express PIGR, and ciliated cells are more abundant in the small airways, authors tested whether PIGR expressed by club cells is sufficient to prevent the age-dependent development of COPD-like disease. They show that mice lacking PIGR in ciliated cells do not develop age-dependent lung disease, confirming that SIgA transported by club cells is sufficient to protect the lungs. The relevance of these studies should be confirmed in mice that display COPD-like lung disease, including airway epithelial remodeling. Nevertheless, these studies provide important insight into the cell types that express PIGR and the protective role of SIgA in the lungs.ReferencesSection:ChooseTop of pageReferences <<1. Lapperre TS, Sont JK, van Schadewijk A, Gosman MM, Postma DS, Bajema IM, et al.; GLUCOLD Study Group. Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study. Respir Res 2007;8:85. Crossref, Medline, Google Scholar2. Polosukhin VV, Cates JM, Lawson WE, Zaynagetdinov R, Milstone AP, Massion PP, et al. Bronchial secretory immunoglobulin a deficiency correlates with airway inflammation and progression of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011;184:317–327. Abstract, Medline, Google Scholar3. Atiş S, Tutluoğlu B, Salepçi B, Ocal Z. Serum IgA and secretory IgA levels in bronchial lavages from patients with a variety of respiratory diseases. J Investig Allergol Clin Immunol 2001;11:112–117. Medline, Google Scholar4. Ohlmeier S, Mazur W, Linja-Aho A, Louhelainen N, Rönty M, Toljamo T, et al. Sputum proteomics identifies elevated PIGR levels in smokers and mild-to-moderate COPD. J Proteome Res 2012;11:599–608. Crossref, Medline, Google Scholar5. Pilette C, Godding V, Kiss R, Delos M, Verbeken E, Decaestecker C, et al. Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:185–194. Abstract, Medline, Google Scholar6. Richmond BW, Brucker RM, Han W, Du RH, Zhang Y, Cheng DS, et al. Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency. Nat Commun 2016;7:11240. Crossref, Medline, Google Scholar7. Johansen FE, Kaetzel CS. Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity. Mucosal Immunol 2011;4:598–602. Crossref, Medline, Google Scholar8. Li Y, Jin L, Chen T. The effects of secretory IgA in the mucosal immune system. BioMed Res Int 2020;2020:2032057. Medline, Google Scholar9. Dey T, Kalita J, Weldon S, Taggart CC. Proteases and their inhibitors in chronic obstructive pulmonary disease. J Clin Med 2018;7:244. Crossref, Medline, Google Scholar10. Blackburn JB, Schaff JA, Gutor S, Du R-H, Nichols D, Sherrill T, et al. Secretory cells are the primary source of pIgR in small airways. Am J Respir Cell Mol Biol 2022;67:334–345. Abstract, Google Scholar11. Gohy ST, Detry BR, Lecocq M, Bouzin C, Weynand BA, Amatngalim GD, et al. Polymeric immunoglobulin receptor down-regulation in chronic obstructive pulmonary disease. Persistence in the cultured epithelium and role of transforming growth factor-β. Am J Respir Crit Care Med 2014;190:509–521. Abstract, Medline, Google Scholar12. Rostami MR, LeBlanc MG, Strulovici-Barel Y, Zuo W, Mezey JG, O’Beirne SL, et al. Smoking shifts human small airway epithelium club cells toward a lesser differentiated population. NPJ Genom Med 2021;6:73. Crossref, Medline, Google Scholar13. Owen CA. Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2008;3:253–268. Crossref, Medline, Google Scholar14. Shimada S, Kawaguchi-Miyashita M, Kushiro A, Sato T, Nanno M, Sako T, et al. Generation of polymeric immunoglobulin receptor-deficient mouse with marked reduction of secretory IgA. J Immunol 1999;163:5367–5373. Medline, Google Scholar Supported by National Institutes of Health grant HL15725801 (U.S.). Originally Published in Press as DOI: 10.1165/rcmb.2022-0210ED on June 15, 2022 Author disclosures are available with the text of this article at www.atsjournals.org.

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