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. 2023 Sep 7;24(18):13832.
doi: 10.3390/ijms241813832.

Blood Immunophenotypes of Idiopathic Pulmonary Fibrosis: Relationship with Disease Severity and Progression

Nuria Mendoza  1   2   3 , Sandra Casas-Recasens  1   2 , Núria Olvera  1   2   4 , Fernanda Hernandez-Gonzalez  1   3   5 , Tamara Cruz  1   2 , Núria Albacar  1   2   5 , Xavier Alsina-Restoy  5 , Alejandro Frino-Garcia  5 , Gemma López-Saiz  5 , Lucas Robres  2 , Mauricio Rojas  6 , Alvar Agustí  1   2   3   5 , Jacobo Sellarés  1   2   5 , Rosa Faner  1   2   3
Affiliations

Blood Immunophenotypes of Idiopathic Pulmonary Fibrosis: Relationship with Disease Severity and Progression

Nuria Mendoza et al. Int J Mol Sci. .

Abstract

(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.

Keywords: antifibrotic therapy; immunity and inflammation; interstitial lung diseases.

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Conflict of interest statement

N. Mendoza reports support for the present manuscript from a PFIS predoctoral scholarship. N. Olvera reports support for the present manuscript from a PhD Fellowship FI-AGAUR. J. Sellares reports support for the present manuscript from SEPAR; grants or contracts from Boehringer, outside the submitted work; payment or honoraria from Boehringer Roche, Chiesi, Astra and Gebro, outside the submitted work; and support for attending meetings and/or travel from Boehringer and Roche, outside the submitted work. R. Faner reports support for the present manuscript from Instituto de Salud Carlos III, Menarini and European Research Council; grants or contracts from GlaxoSmithKline, AstraZeneca, outside the submitted work; consulting fees from GSK, outside the submitted work; and payment or honoraria from Chiesi, outside the submitted work. The remaining authors have nothing to disclose.

Figures

Figure 1
Figure 1
Characterization of the innate and adaptive compartment in IPF patients (orange box) and controls (blue box) (median [IQR]) (a) Comparison of % neutrophils and B lymphocytes. (b) Comparison of % CD8+CD28−, HLADR+, and naive CD8+ T cells from CD8+ pool. (c) Comparison of % Th1 and Th17 from CD4+ pool. (d) Comparison of Th1/Th17, Th17/Tregs, Neutrophil-to-lymphocyte (NRL), and Monocyte-to-lymphocyte (MLR) ratios. * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001.
Figure 2
Figure 2
Representative flow cytometry gatings of controls and IPF patients of the peripheral immune populations that were statistically significant between the study groups: comparison of neutrophils and B lymphocytes, CD8+CD28−, CD8+HLADR+ and naive CD8+ T cells from CD8+ pool, and Th1 and Th17 from CD4+ pool.
Figure 3
Figure 3
(a) Significant Spearman correlations between blood immune populations/ratios and lung function at recruitment in IPF patients. * p < 0.05, ** p < 0.01 and **** p < 0.0001. (b) Differential distribution of the baseline immune population in IPF progressors (pink box) and stable (green box); (median [IQR]): Comparison of % NKT-like cells; CD8+CD28− from CD8+ pool, different CD8+ and CD4+ T memory cells and CD4/CD8 ratio; Receiving Operating Characteristics (ROC) curve of the Elastic Net multivariate analysis identifying the immune cell populations associated with disease progression.
Figure 4
Figure 4
Paired analysis comparing the stability of the immune cell populations included in the Elastic Net, at baseline and second follow-up (18–60 months) in (a) progressors and (b) stable patients.
See this image and copyright information in PMC

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