(1) The role of the immune response in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains controversial. We hypothesized that peripheral blood immune phenotypes will be different in IPF patients and may relate to the disease severity and progression. (2) Whole blood flow cytometry staining was performed at diagnosis in 32 IPF patients, and in 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. (3) The main results showed that: (1) compared to matched controls, at diagnosis, patients with IPF showed more neutrophils, CD8⁺HLA-DR⁺ and CD8⁺CD28⁻ T cells, and fewer B lymphocytes and naïve T cells; (2) in IPF, circulating neutrophils, eosinophils and naïve T cells were associated with lung function abnormalities; (3) patients whose disease progressed during the 12 months of follow-up showed evidence of cytotoxic dysregulation, with increased CD8⁺CD28⁻ T cells, decreased naïve T cells and an inverted CD4/CD8 ratio at baseline; and (4) blood cell alterations were stable over time in survivors. (4) IPF is associated with abnormalities in circulating immune cells, particularly in the cytotoxic cell domain. Patients with progressive IPF, despite antifibrotic therapy, present an over-activated and exhausted immunophenotype at diagnosis, which is maintained over time.

Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs.

Introduction: Bronchiectasis (BE) is characterized by alterations in the local pulmonary immune response. We aimed to explore if there are also alterations in the systemic immune cell profile and their relationship with disease severity. Methods: Clinically stable patients with BE were recruited in the Clinic Barcelona Hospital (Spain). The presence of BE was determined by computed tomography and its severity by the Bronchiectasis Severity Index (BSI) score. The immune profile in whole blood was assessed using flow cytometry analysis. Results: 59 patients with clinically stable bronchiectasis were studied: mean age was 63±9 years, 62.7% were female and 28% had chronic infection with P. aeruginosa (PA). According to their BSI score, 51.7% of the cases were mild, 32.8% moderate and 15.5% severe. The latter group presented a lower percentage of CD56brightCD16-NK cells (p=0.027), and a higher percentage of monocytes (p=0.002), T CD8+CD28- (p=0.044) and Tregs (p=0.02) in blood, compared to patients with mild or moderate BE. Patients with chronic PA infection showed a similar profile, with also activated (HLA-DR+) Th17 and effector CD4+(p=0.033 and p=0.028) T cells. Conclusions: Patients with severe BE and/or chronic PA infection showed a decrease in NK cells and an increase of monocytes, T lymphocytes with an "exhausted/activated” phenotype and an inverted Th17/Tregs ratio in peripheral blood, indicating an altered systemic immune response in these patients. Funding: Instituto de Salud Carlos III (PI21/00419), SEPAR and Serra Hunter Program.