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Immune complex stimulation of human monocytes

ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease and several distinct autoantibodies have been described in SSc patients, many correlating with specific clinical presentation. Numerous studies have documented the presence of immune complexes (IC) in sera, lungs and BAL of SSc patients, potentially implicating them in the pathogenesis. Monocyte/macrophage activation also have been observed in fibrotic SSc skin and lung tissue. While the upstream activators remain unknown, it is plausible that IC are amongst the key triggers in activating monocytes and sustaining the chronic inflammation and fibrosis in SSc tissue. To test this hypothesis and find the specific downstream genes regulated by IC, we compare the gene expressions of the monocytes stimulated by control medium, LPS and IC using RNA seq. OPN was one of these IC regulated genes. Our paper further suggested that circulating OPN levels serve as a systemic proxy for IC driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc-ILD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155687 | GEO | 2020/08/05

REPOSITORIES: GEO

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Project description:OBJECTIVE: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc-related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease. METHODS: Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc-related ILD and in 4 controls. High-resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2-3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein. RESULTS: Lung microarray data distinguished patients with SSc-related ILD from healthy controls. In the lungs of patients with SSc-related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor β (TGFβ)- and interferon (IFN)-regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < -0.1), including IFN and macrophage markers, chemokines, and heat-shock proteins. CONCLUSION: These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc-related ILD: macrophage emigration and activation, and up-regulated expression of TGFβ- and IFN-regulated genes

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Immune complex stimulation of human monocytes

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