Bacteria-driven peribronchial lymphoid neogenesis in bronchiectasis and cystic fibrosis

Abstract

We aimed to characterise lymphoid neogenesis in bronchiectasis and cystic fibrosis (CF) lungs and to examine the role of bacterial infection.Lymphoid aggregates were examined using immunohistochemical staining and morphometric analysis in surgical lung sections obtained from nonsmokers and patients with bronchiectasis or CF. Sterile, - or-coated agarose beads were instilled intratracheally in mice. Kinetics of lymphoid neogenesis and chemokine expression were examined over 14 days.Lymphoid aggregates were scarce in human lungs of nonsmokers, but numerous peribronchial lymphoid aggregates containing B-lymphocytes, T-lymphocytes, germinal centres and high endothelial venules were found in bronchiectasis and CF. Mouse lungs contained no lymphoid aggregate at baseline. During persistent or airway infection peribronchial lymphoid neogenesis occurred. At day 14 after instillation, lymphoid aggregates expressed markers of tertiary lymphoid organs and the chemokines CXCL12 and CXCL13. The airway epithelium was an important site of CXCL12, CXCL13 and interleukin-17A expression, which began at day 1 after instillation.Peribronchial tertiary lymphoid organs are present in bronchiectasis and in CF, and persistent bacterial infection triggered peribronchial lymphoid neogenesis in mice. Peribronchial localisation of tertiary lymphoid organs and epithelial expression of chemokines suggest roles for airway epithelium in lymphoid neogenesis.

Peribronchial tertiary lymphoid structures persist after rituximab therapy in patients with cystic fibrosis

“…Tertiary lymphoid structures (TLS) are usually absent in normal lungs, but peribronchial TLS are found in the lungs of patients with bronchiectasis or cystic fibrosis (CF) 1. Recently, our group reported studies in mice showing that persistent bacterial infection induced peribronchial TLS, suggesting that chronic infection is a major trigger of lymphoid neogenesis in CF airways 1.…”

Lung lymphoid neogenesis in cystic fibrosis: a model of adaptive responses to bacteria?

“…This was reproduced by FLEIGE et al [20] upon repeated instillations of P. aeruginosa in mice, which induced BALT following IL-17-driven CXCL12, despite the absence of follicular dendritic cells, in contrast to BALT induced by the modified vaccinia virus Ankara. The results of the study reported by FRIJA-MASSON et al [9] rather suggest that the recruitment/differentiation of these dendritic cells, observed in lymphoid follicles induced by both P. aeruginosa and S. aureus, depends on the persistence of the bacterial trigger rather than the nature of the pathogen. The chronicity is thus a key issue, very relevant to cystic fibrosis lung disease, which is usually characterised even at early stages, by the chronic or repeated presence of opportunistic pathogens in the lung.…”

“…This dichotomic view of infection-versus autoimmunity-related neolymphogenesis is however challenged by recent observations in cystic fibrosis. Although bacterial infection was for long suspected to induce BALT in the cystic fibrosis lung, as nicely confirmed herein using appropriate tools [9], autoantibodies to bactericidal permeability-increasing protein (BPI) as well as to carbamylated proteins are frequently found in patients with cystic fibrosis (up to 80% of cases) and correlated with worse prognosis in terms of mortality, lung function, exacerbations and pan-resistant P. aeruginosa [25]. Interestingly, a recent study unravelled that P. aeruginosa-mediated formation of neutrophil extracellular traps results in BPI cleavage by P. aeruginosa elastase [26], suggesting a novel mechanism of autoimmunity and indicating that complex relationships link infection, (neutrophilic) inflammation and autoimmunity in the cystic fibrosis lung ( figure 1).…”

“…FRIJA-MASSON et al [9] reveal, in this issue of the European Respiratory Journal, the presence of lymphoid follicles in peribronchial areas of the lungs from patients with cystic fibrosis or with localised bronchiectasis, following careful examination of their structures including B-and T-cells, germinal centres and high-endothelial veinules. In addition, by using an elegant murine model of instillation of microbeads coated with Staphylococcus aureus or Pseudomonas aeruginosa, they were able to recapitulate in these mice the formation of lung lymphoid follicles upon persistent infection.…”

“…Besides sterile pathogenic mechanisms operating in cystic fibrosis [27], addressing these issues may pave the way for current and future studies of the complex interactions between bacteria and airway host tissues in the chronic diseased lung, which probably underlie disease severity, and for which FRIJA-MASSON et al [9] have laid an important foundation stone.…”