The transcriptome of CD14 + CD163 - HLA-DR low monocytes predicts mortality in Idiopathic Pulmonary Fibrosis

  1. Theodoros Karampitsakos
  2. Bochra Tourki
  3. Minxue Jia
  4. Carole Y. Perrot
  5. Bogdan Visinescu
  6. Amy Zhao
  7. Avraham Unterman
  8. Argyris Tzouvelekis
  9. Debabrata Bandyopadhyay
  10. Brenda M. Juan-Guardela
  11. Antje Prasse
  12. Imre Noth
  13. Stephen Liggett
  14. Naftali Kaminski
  15. Panayiotis V. Benos
  16. Jose D. Herazo-Maya
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Abstract

Rationale

The association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown.

Objectives

To determine immune-cell-specific transcriptomic profiles associated with IPF mortality.

Methods

We profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 immune-cell-specific transcriptomic profiles. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was used to calculate Up-scores based on these 16 gene profiles. Their association with outcomes was investigated in peripheral blood, Bronchoalveolar Lavage (BAL) and lung tissue of N=416 IPF patients from six cohorts. Findings were validated in an independent IPF, PBMC scRNA-seq dataset (N=38).

Measurements and main results

Cox-regression models demonstrated that 230 genes from CD14 + CD163 - HLA-DR low circulating monocytes predicted IPF mortality [Pittsburgh (p=0.02), Chicago (p=0.003)]. PBMC proportions of CD14 + CD163 - HLA-DR low monocytes were higher in progressive versus stable IPF (Yale, 0.13±0.05 versus 0.09±0.05, p=0.034). Receiving operating characteristic identified a 230 gene, Up-score >41.84 (Pittsburgh) predictive of mortality in Chicago (HR: 6.58, 95%CI: 2.15-20.13, p=0.001) and in pooled analysis of BAL cohorts (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003). High-risk patients had decreased expression of the T-cell co-stimulatory genes CD28 , ICOS , ITK and LCK (Pittsburgh and Chicago, p<0.01). 230 gene-up-scores negatively correlated with Forced Vital Capacity (FVC) in IPF lung tissues (LGRC, rho=-0.2, p=0.02). Results were replicated using a subset of 13 genes from the 230-gene signature (pooled PBMC cohorts - HR: 5.34, 95%CI: 2.83-10.06, p<0.0001).

Conclusions

The transcriptome of CD14 + CD163 - HLA-DR low monocytes is associated with increased IPF mortality.

Article activity feed

  1. Version published to 10.1101/2024.08.07.24311386 on medRxiv