Immunoglobulin-producing AT2-like cells secrete IgA into the extracellular matrix in pulmonary fibrosis

Abstract Pulmonary fibrosis is an interstitial lung disease that can be caused by various factors, such as exposure to workplace environmental factors, drugs or X-rays1–3. As one driving factor of pulmonary fibrosis, epithelial cells can proliferate and secrete many kinds of cytokines to affect fibroblasts, although the molecular mechanism is unclear4. IgA, traditionally thought to be secreted by B cells5, can activate fibroblasts6. Here, we first observed extensive IgA deposition in the extracellular matrix (ECM) of the lungs of mice with pulmonary fibrosis induced by silica inhalation. Consistent with this phenomenon, spatial transcriptomic sequencing of fresh mouse lung tissues from control mice and model mice showed that Igha transcripts were highly expressed in the lesion area. Single-cell RNA sequencing (scRNA-seq) of whole mouse lung tissue from the control group and model group and reconstruction of B cell receptor (BCR) sequences revealed a new cluster of cells with a shared BCR and high expression of genes related to immunoglobulin IgA production. Surprisingly, these clonal cells had more characteristics of AT2 (alveolar epithelial cell type 2) cells than B cells, such as Sftpc, Sftpa1, and Sftpb; thus, these cells were named AT2-like cells. Therefore, we propose that secretion of IgA into the ECM by AT2-like cells is an important process that occurs during lung fibrosis. In fact, IgA has been reported to promote lung fibrosis by acting on fibroblasts6. Our research suggests that IgA levels can be used as a diagnostic tool for this type of lung fibrosis with IgA deposition. Targeted blockade of lung epithelial cell secretion of IgA may be a potential approach for treating pulmonary fibrosis.