Type V Collagen Induced Tolerance Suppresses Collagen Deposition, TGF-β and Associated Transcripts in Pulmonary Fibrosis

Abstract

RationaleIdiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-col(V) immunity in IPF patients. The objective of our study was to determine the specificity of col(V) expression profile and anti-col(V) immunity relative to col(I) in clinical IPF and the efficacy of nebulized col(V) in pre-clinical IPF models.MethodsCol(V) and col(I) expression profile was analyzed in normal human and IPF tissues. C57-BL6 mice were intratracheally instilled with bleomycin (0.025 U) followed by col(V) nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses.ResultsCompared to normal lungs, IPF lungs had higher protein and transcript expression of the alpha 1 chain of col(V) and col(I). Systemic anti-col(V) antibody concentrations, but not of anti-col(I), were higher in IPF patients. Nebulized col(V), but not col(I), prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. Col(V) treatment suppressed systemic levels of anti-col(V) antibodies, IL-6 and TNF-α; and local Il-17a transcripts. Compared to controls, nebulized col(V)-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-α and IFN-γ. In a clinically relevant established fibrosis model, nebulized col(V) decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis (Tgf-β, Il-1β, Pdgfb), matrix (Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3) and members of the TGF-β superfamily (Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb).ConclusionsAnti-col(V) immunity is pathogenic in IPF, and col(V)-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- β-related signaling pathways.

Regulation of Collagen V Expression and Epithelial-Mesenchymal Transition by miR-185 and miR-186 during Idiopathic Pulmonary Fibrosis

“…During IPF, Col(V) is overexpressed in both mRNA and protein levels in the lungs. 6 The anti-Col(V) immunity has been shown to play critical roles in the pathogenesis of IPF. 6 A mechanistic understanding of Col(V) overexpression could be useful for the developments of biomarkers for early detection and treatment of IPF.…”

“…6 The anti-Col(V) immunity has been shown to play critical roles in the pathogenesis of IPF. 6 A mechanistic understanding of Col(V) overexpression could be useful for the developments of biomarkers for early detection and treatment of IPF. The possible mechanisms leading to Col(V) overexpression include pretranscriptional mechanisms, such as genetic mutations, single-nucleotide polymorphism, DNA methylation and histone modifications, and posttranscriptional mechanisms such as miRNA regulations.…”

“…Previous studies show that Col(V) is overexpressed in the lungs during IPF and that the Col(V)-related immune response plays a critical role in the pathogenesis of pulmonary fibrosis. 5,6 Overexpression of Col(V) is relatively characteristic of IPF and has been described in only one other disease, obliterative bronchiolitis, which is a fibrotic airway lesion due to chronic rejection of lung transplantation. 7e10 The mechanism that leads to Col(V) overexpression is unknown.…”

Oral immunotherapy with type V collagen in idiopathic pulmonary fibrosis

“…Autoreactive T-cells against lung antigens were also detected in the same studies, supporting the idea that an ongoing adaptive immune response against autoantigens may play an important role in the disease progression for some IPF patients. Previous studies have shown that 40-60% of IPF patients may display an autoimmune response against type V collagen (col(V)) [10,11].…”

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

“…The production of autoantibodies with specificities for varied autoantigens is a common feature of immunologic diseases (15). Several selfreactive antibodies have also been identified in IPF cohorts (12,14,(16)(17)(18)(19)(20)(21)(22)(23)(24). Moreover, some of these IPF autoantibodies have direct profibrotic, proinflammatory, or cytotoxic effects, and/or are highly associated with the clinical manifestations and outcomes of individual patients (14,(17)(18)(19)(20)(21).…”