Lymphoid follicles in (very) severe COPD: beneficial or harmful?

Inflammation is a main pathogenetic factor in the development and progression of chronic obstructive pulmonary disease (COPD). Recently, it has become clear that not only the innate, but also the specific immune response plays a role. A striking finding, in particular in lungs of patients with severe COPD, often with a predominant emphysema phenotype, is the presence of B-cell follicles. As seen in other tissues, these follicles are the result of lymphoid neogenesis. The finding of oligoclonality in B-cell follicles in COPD suggests that they play a role in local antigen specific immune responses. To date, it is not known which antigens may be involved; microbial antigens, cigarette smoke-derived antigens and antigens from extracellular matrix breakdown products have been suggested. Consequently, the pathogenetic role of this follicular B-cell response is not yet clear. It might be protective against microbial colonisation and infection of the lower respiratory tract and, therefore, beneficial, or it could be of a more harmful (autoimmune) nature, directed against lung tissue components. It is necessary to determine the specific antigen(s) and to explore the exact role of the COPD related B-cell response in order to include modulation of this response and develop therapeutic options.

Role of lymphotoxin-alpha in cigarette smoke-induced inflammation and lymphoid neogenesis.

In chronic obstructive pulmonary disease (COPD), chronic inflammation is accompanied by peribronchial lymphoid aggregates. Lymphotoxin (LT)-alpha, crucial in secondary lymphoid organogenesis, may be involved in lymphoid neogenesis. We examined cigarette smoke (CS)-induced pulmonary lymphoid neogenesis and inflammation in vivo in LTalpha knockout (LTalpha(-/-)) and wild-type (WT) mice and studied the expression of lymphoid chemokines by lung fibroblasts in vitro. T-cell numbers (in bronchoalveolar lavage fluid (BALF) and lungs) and lymphoid aggregate numbers were significantly higher in air-exposed LTalpha(-/-) mice than in WT animals, and increased upon chronic CS exposure in both genotypes. In contrast, local immunoglobulin A responses upon chronic CS exposure were attenuated in LTalpha(-/-) mice. CXC chemokine ligand (CXCL) 13 and CC chemokine ligand (CCL) 19 mRNA in total lung and CXCL13 protein level in BALF increased upon CS exposure in WT, but not in LTalpha(-/-) mice. In vitro lymphotoxin-beta receptor (LTbetaR) stimulation induced CXCL13 and CCL19 mRNA in WT lung fibroblasts. Furthermore, in vitro exposure to CS extract upregulated CXCL13 mRNA expression in WT, but not in LTbetaR(-/-), lung fibroblasts. In this murine model of COPD, CS induces pulmonary expression of lymphoid chemokines CXCL13 and CCL19 in a LTalphabeta-LTbetaR-dependent fashion. However, LTalpha is not required for CS-induced pulmonary lymphocyte accumulation and neogenesis of lymphoid aggregates.