BACKGROUND: Interstitial lung disease (ILD) is a common but serious extra-articular manifestation of rheumatoid arthritis (RA). RA-associated ILD (RA-ILD), which often presents with the usual interstitial pneumonia (UIP) pattern, can resemble idiopathic pulmonary fibrosis (IPF), though the treatment and progression of these two conditions differ. However, the immunologic and molecular mechanisms associated with RA-ILD and IPF development have not been well elucidated at the single-cell level. METHODS: To investigate the underlying mechanisms associated with RA-ILD and IPF development, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from five RA-ILD patients and five patients with IPF with a matched age and sex distribution. RESULTS: A high-quality scRNA-seq dataset comprising 31,416 peripheral immune cells was generated. Overall immune composition was similar between groups; however, a significant elevation of NK cells was seen among the RA-ILD PBMCs, with increased expression of cytotoxic and inflammation-related genes (GZMB, GZMH, PRF1) as well as interferon‑related genes (STAT1, STAT3, IRF9, IFNG). Myeloid subsets displayed distinct transcriptional programs in IPF and RA-ILD: IPF CD16⁺ monocytes were enriched for TGF‑β-driven fibrotic signaling, whereas RA-ILD monocytes exhibited type I/II interferon pathway activation. Fibrosis‑related genes (TGFB1, SMAD3, SMAD7, TGIF1) were specifically upregulated in IPF. Conclusions: RA‑ILD and IPF share similar peripheral immune cell compositions, but exhibit distinct transcriptional activation patterns. RA‑ILD is characterized by increased NK‑cell-driven cytotoxic and interferon‑related responses, along with interferon‑activated monocytes. In contrast, IPF shows a TGF‑β-dominant fibrotic program, with transcriptional activation of CD16⁺ monocytes and upregulation of fibrosis‑related genes.
Kim et al. (Tue,) studied this question.