Relevance of interferon-gamma in pathogenesis of life-threatening rapidly progressive interstitial lung disease in patients with dermatomyositis

Abstract

Background: Dermatomyositis (DM) with rapidly progressive interstitial lung disease (DM RP-ILD) is a life-threatening condition. Serum cytokine levels are potentially suitable biomarkers for DM RP-ILD. However, the relationships among cytokine levels, lung imaging findings, and lung pathology have not been investigated. The aim of the present retrospective study was to determine the association between hypercytokinemia and lung inflammation in patients with DM RP-ILD.

Methods: The study subjects were nine patients with life-threatening DM RP-ILD and severe hypoxemia (partial arterial oxygen pressure (PaO₂)/fraction of inspired oxygen (FiO₂) ratio ≤ 200) before receiving intensive care management, who were admitted to our hospital between 2006 and 2015. The controls included 10 patients with DM without RP-ILD and 19 healthy subjects. We assessed the association between serum cytokine levels and computed tomography (CT) scores of the lung (ground glass opacity-score, G-score; fibrosis-score, F-score). Lung, hilar lymph nodes, and spleen from two autopsies were examined by hematoxylin-eosin (H&E) staining and immunostaining.

Results: Serum interferon (IFN)-γ, interleukin (IL)-1β and IL-12 levels were significantly higher in patients with DM RP-ILD than in the other two groups, whereas serum IL-6 levels were elevated in the two patient groups but not in the healthy subjects. Serum levels of IL-2, IL-4, IL-8, IL-10, IFN-α, and TNF (tumor necrosis factor)-α were not characteristically elevated in the DM RP-ILD group. Serum IFN-γ levels correlated with G-scores in patients with DM RP-ILD, while IL-1β was negatively correlation with F-scores. Immunohistochemical staining showed infiltration of numerous IFN-γ-positive histiocytes in the lung and hilar lymph nodes; but not in the spleen. Serum IL-6 levels did not correlate with the CT scores. Numerous IL-6-positive plasma cells were found in hilar lymph nodes, but not in the lungs or spleen.

Conclusions: Our results suggest strong IFN-γ-related immune reaction in the lungs and hilar lymph nodes of patients with life-threatening DM RP-ILD, and potential IFN-γ involvement in the pathogenesis of DM, specifically in the pulmonary lesions of RP-ILD.

Keywords: Dermatomyositis; IFN-γ; Rapidly progressive interstitial lung disease.

Fig. 1

Assessment of rapidly progressive interstitial lung disease (RP-ILD) by computed tomography (CT) scores. A Assessment of RP-ILD by CT ground glass opacity (GGO) scores (G-scores): (a) thin-section CT scan shows small areas with GGO compared with normal parenchyma at the right lower lobe (mild GGO = 1); (b) CT scan shows extensive GGO that could be easily identified when compared with the normal parenchyma at the right lower lobe (moderate GGO = 2); (c) thin-section CT scan shows areas with diffuse GGO at the right lower lobe (severe GGO = 3). B Assessment of RP-ILD by CT fibrosis scores (F-scores): (a) thin-section CT scan shows areas with thickened interlobular septum or predominant peripheral fibrosis (mild fibrosis = 1). (b) CT scan shows extensive fibrosis that could be easily identified when compared with normal parenchyma at the right lower lobe (moderate fibrosis = 2), moderate fibrosis and bronchiolectasis. (c) thin-section CT scan shows areas with diffuse fibrosis at the right lower lobe (severe fibrosis = 3). Note honeycombing, bronchiectasis, peribronchovascular thickening, and subpleural cysts

Fig. 2

Serum levels of IL-1β, IL-2, IL-4 IL-6, IL-8, IL-10, IL-12, interferon (IFN)-α, IFN-γ and TNF-α in patients with dermatomyositis (DM), patients with DM complicated with rapidly progressive interstitial lung disease (DM RP-ILD) and healthy donors (HD). Symbols represent data of individual subjects. Statistical analysis is by Kruskal-Wallis followed by Dunn’s multiple comparison test

Fig. 3

Histopathological findings from two autopsies. a Case 1: (1, 2) lung; hematoxylin-eosin (H&E) staining; (3, 4) lung, immunostaining for interferon (IFN)-γ; (5, 6) hilar lymph nodes, H&E staining; (7, 8) hilar lymph nodes, immunostaining for IFN-γ; (9, 10) spleen, H&E staining; (11, 12) spleen immunostaining for IFN-γ; (13, 14) lung, immunostaining for interleukin (IL)-6; (15, 16) hilar lymph nodes, immunostaining for IL-6; (17, 18) spleen, immunostaining for IL-6. b Case 2: (1, 2) lung, H&E staining; (3, 4) lung, immunostaining for IFN-γ; (5, 6) hilar lymph nodes, H&E staining; (7, 8) hilar lymph nodes, immunostaining for IFN-γ; (9, 10) spleen, H&E staining; (11, 12) spleen, immunostaining for IFN-γ; (13, 14) lung, immunostaining for IL-6; (15, 16) hilar lymph nodes, immunostaining for IL-6; (17, 18) spleen, immunostaining for IL-6. Red arrows show histiocytes, blue arrows show plasma cells