Integrative approach to address the heterogeneity and progression of Idiopathic Pulmonary Fibrosis: role of the immune response
[eng] BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unknown aetiology. It is believed that abnormally activated and/or damaged lung epithelial cells secrete a panel of profibrotic mediators that leads to extracellular matrix deposition, destruction of the lung ar...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/215372 |
| Acceso en línea: | https://hdl.handle.net/2445/215372 http://hdl.handle.net/10803/692236 |
| Access Level: | acceso abierto |
| Palabra clave: | Fibrosi pulmonar Immunologia Cèl·lules immunocompetents Pulmonary fibrosis Immunology Immunocompetent cells |
| Sumario: | [eng] BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unknown aetiology. It is believed that abnormally activated and/or damaged lung epithelial cells secrete a panel of profibrotic mediators that leads to extracellular matrix deposition, destruction of the lung architecture and recruitment of inflammatory cells. However, in this setting, the role of the immune response in the pathogenesis and progression of IPF remains controversial. HYPOTHESIS AND OBJECTIVES: The investigation of peripheral blood and lung immune cell populations in relation to different phenotypes (and endotypes) may provide new insights into IPF pathobiology and progression. The two specific aims are: 1) to characterize the peripheral immune cell profile and its association with IPF progression, and 2) to explore the level of immune infiltrate in lung tissue and its association with IPF heterogeneity. Methods: Whole blood immunological cell profile was determined by flow cytometry at diagnosis in 32 IPF patients, and 32 age- and smoking-matched healthy controls. Thirty-one IPF patients were followed up for one year and categorized as stable or progressors based on lung function deterioration and/or death. At 18–60 months, immunophenotypes were characterized again. Regarding aim two, immune signatures were assessed with Gene Set Variation Analysis (GSVA) and applied to the lung transcriptome of 109 IPF patients from the Lung Tissue Research Consortium (LTRC), followed by unbiased cluster analysis of GSVA immune-enrichment scores. Results were experimentally validated using flow cytometry analysis in the lung tissue of 26 IPF patients from the University of Pittsburgh. Finally, differential gene expression and hypergeometric test were used to explore non-immune differences between clusters. RESULTS: IPF patients showed alterations in the peripheral immune cell profile at diagnosis, compared to healthy controls, that were associated with lung function abnormalities. Patients with progressive IPF, despite antifibrotic therapy, presented an over-activated and exhausted immunophenotype at diagnosis, which was maintained over time. For the second aim, two clusters (C#1 and C#2) of IPF patients were identified: C#1 (n=58) presented an enrichment in GSVA immune signatures (mainly cytotoxic and memory T cells signatures), compared to C#2 (n=51). Those results were validated by flow cytometry with similar unbiased clustering generation. Differential gene expression between clusters identified differences in cilium, epithelial and secretory cell genes, showing an inverse correlation with the immune response signatures. Interestingly, both clusters showed similar clinical features. CONCLUSIONS: Patients with IPF showed significant alterations in the peripheral blood immunological profile at diagnosis, especially those with IPF progression who presented a dysregulated T CD8+ cells compartment, and an inverted CD4/CD8 ratio suggesting an over-activated, aged, and “exhausted” immune status potentially related to intracellular antigens. Moreover, two clusters of patients with very different levels of immune signatures and gene expression were identified in end-stage IPF lung tissue, despite showing similar clinical characteristics. However, whether these immune clusters can differentiate diverse disease trajectories remains unexplored. |
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