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. 2020 Nov 2;15(11):e0241719.
doi: 10.1371/journal.pone.0241719. eCollection 2020.

CXCL9, CXCL10, and CXCL11; biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases-associated interstitial lung disease and interstitial pneumonia with autoimmune features

Masami Kameda  1 , Mitsuo Otsuka  2 , Hirofumi Chiba  1 , Koji Kuronuma  1 , Takehiro Hasegawa  3 , Hiroki Takahashi  4 , Hiroki Takahashi  1
Affiliations

CXCL9, CXCL10, and CXCL11; biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases-associated interstitial lung disease and interstitial pneumonia with autoimmune features

Masami Kameda et al. PLoS One. .

Abstract

Introduction: Interstitial lung disease (ILD) is a heterogeneous group of diseases characterized by varying degrees of lung inflammation and/or fibrosis. We investigated biomarkers to infer whether patients with collagen vascular diseases associated ILD (CVD-ILD) and interstitial pneumonia with autoimmune features (IPAF) benefit from immunosuppressive therapy.

Materials and methods: We retrospectively investigated patients with CVD-ILD, IPAF, and idiopathic pulmonary fibrosis (IPF) between June 2013 and May 2017 at our department. First, we assessed differences in serum and bronchoalveolar lavage fluid (BALF) levels of cytokines between groups. Second, we assessed the associations of patient's clinical variables with serum and BALF levels of those cytokines that were different between groups. Finally, we assessed the associations of diagnosis and response to immunosuppressive therapy with serum levels of those cytokines that were different between groups.

Results: We included 102 patients (51 with IPF, 35 with IPAF, and 16 with CVD-ILD). Serum and BALF levels of CXCL9, CXCL10, and CXCL11 were significantly elevated in patients with IPAF or CVD-ILD compared with those in patients with IPF. BALF levels of CXCL9 and CXCL10 were correlated with the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9 and CXCL10 were correlated with BALF levels. Serum levels of CXCL9, CXCL10, and CXCL11 were correlated C-reactive protein, percent predicted forced vital capacity, alveolar-arterial oxygen difference, and the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9, CXCL10, and CXCL11 showed moderate accuracy to distinguish patients with CVD-ILD from those with IPAF and IPF. Pre-treatment serum levels of CXCL9 and CXCL11 showed strong positive correlations with the annual forced vital capacity changes in patients with IPAF and CVD-ILD treated with immunosuppressive drugs.

Conclusions: Serum CXCL9, CXCL10, and CXCL11 are potential biomarkers for autoimmune inflammation and predictors of the immunosuppressive therapy responses in ILD with background autoimmunity.

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Conflict of interest statement

Masami Kameda, Mitsuo Otsuka, and Takehiro Hasegawa have a pending patent application belonging to Sysmex Corporation and Sapporo Medical University. This does not alter our adherence to PLOS ONE policies on materials.

Figures

Fig 1
Fig 1. Patient selection flowchart.
Fig 2
Fig 2. Associations between serum cytokines and treatment responsiveness in the CVD–ILD and IPAF groups.
Associations between pretreatment serum CXCL9, CXCL10, and CXCL11 levels and annual FVC changes in the CVD–ILD and IPAF groups. a) CXCL9, b) CXCL10, and c) CXC11. The p-values were estimated using Spearman’s rank correlation coefficient. CXCL: C-X-C motif chemokine; FVC: forced vital capacity; ×: CVD–ILD; ●: IPAF.
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Grants and funding

MK, MO, and HT received funding from Sysmex Corp. TH is an employee of Sysmex Corp. T.H. contributed to the measurement of cytokines. The funder provided support in the form of salaries for TH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.