The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis

Abstract

We have characterized the immune system involvement in the disease processes of idiopathic pulmonary fibrosis in novel ways. To do so, we analyzed lung tissue from 21 cases of idiopathic pulmonary fibrosis and 21 (non-fibrotic, non-cancerous) controls for immune cell and inflammation-related markers. The immunohistochemical analysis of the tissue was grouped by patterns of severity in disease pathology. There were significantly greater numbers of CD68+ and CD80+ cells, and significantly fewer CD3+, CD4+, and CD45RO+ cells in areas of relatively (histologically) normal lung in biopsies from idiopathic pulmonary fibrosis patients compared to controls. In zones of active disease, characterized by epithelial cell regeneration and fibrosis, there were significantly more cells expressing CD4, CD8, CD20, CD68, CD80, CCR6, S100, IL-17, tumor necrosis factor-α, and retinoic acid-related orphan receptors compared to histologically normal lung areas from idiopathic pulmonary fibrosis patients. Inflammation was implicated in these active regions by the cells that expressed retinoid orphan receptor-α, -β, and -γ, CCR6, and IL-17. The regenerating epithelial cells predominantly expressed these pro-inflammatory molecules, as evidenced by co-expression analyses with epithelial cytokeratins. Macrophages in pseudo-alveoli and CD3+ T cells in the fibrotic interstitium also expressed IL-17. Co-expression of IL-17 with retinoid orphan receptors, and epithelial cytoskeletal proteins, CD68, and CD3 in epithelial cells, macrophages, and T-cells, respectively, confirmed the production of IL-17 by these cell types. There was little staining for Foxp3, CD56, or CD34 in any idiopathic pulmonary fibrosis lung regions. The fibrotic regions had fewer immune cells overall. In summary, our study shows participation of innate and adaptive mononuclear cells in active-disease regions of idiopathic pulmonary fibrosis lung, where the regenerating epithelial cells appear to propagate inflammation. The regenerative mechanisms become skewed to ultimately result in lethal, fibrotic restriction of lung function.

C-X-C Motif Chemokine 13 (CXCL13) Is a Prognostic Biomarker of Idiopathic Pulmonary Fibrosis

“…These mediator expressions were localized to the intrapulmonary B-cell aggregates that are numerous in IPF lungs, and these in turn were typically proximate to fibroblastic foci ( Figure 1C), as also reported by other investigators (3). Additional studies showed that macrophage lineage cells (CD68 1 ) were the predominant source of the CXCL13 within the IPF B-cell aggregates (see Figure E2).…”

“…Assays here show that CD68 1 macrophage lineage cells within pulmonary B cell aggregates, which in turn are proximate to fibroproliferative lesions (3)(4)(5), are an origin of the CXCL13 among patients with IPF (Figures 1B and 1C; see Figure E2). In conjunction with demonstrations that the circulating B cells of patients with IPF are not uniquely ORIGINAL ARTICLE deficient in their expression of the chemotactic ligand CXCR5 (Figure 2), and numerous definitive reports in other populations (31)(32)(33)(34)(35)(36), it is thus highly likely the CXCL13-CXCR5 axis is involved in the focal accumulations of nonproliferating B cells that were found in IPF lungs here and in other studies (3)(4)(5) Figure 4).…”

“…IPF lungs show overexpressions of B-cell antibody genes (2), and focal aggregates of these lymphocytes in proximity to fibroproliferative lesions (3)(4)(5). B-cell aggregates in disease tissues are characteristic lesions of ongoing immune responses, and these lymphocytes have also been shown to directly exert numerous pathogenic effects (6)(7)(8)(9)(10).…”

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

“…25 And fibroblasts are regarded as the major cell type that mediates the onset and progression of lung fibrosis by secreting large amounts of ECM proteins. In addition, some insights of understanding the course of pulmonary fibrosis have come from greater number of CD8 þ cytotoxic T cells 5 and CD68 þ macrophages. 6 Moreover, alternatively activated macrophages appear to be key players in pathologic processes that are associated with fibrosis.…”

“…Some insights of understanding the course of pulmonary fibrosis have come from greater number of CD8 þ T cells 5 and CD68 þ macrophages. 6 Pro-inflammatory cytokine expression (especially tumor necrosis factor-alpha; TNF-a) participates in silica-induced lung fibrosis.…”