Mi-Hyun Ahn1,2, Jae Ho Han1,2, Young-Jun Chwae1,2, Ju-Yang Jung1,2, Chang-Hee Suh1,2, Ji Eun Kwon1,2, Hyoun-Ah Kim3,4. 1. From the departments of Rheumatology, Pathology, and Microbiology, Ajou University School of Medicine, Suwon, Korea. 2. M.H. Ahn, PhD, Department of Rheumatology, Ajou University School of Medicine; J.H. Han, MD, PhD, Department of Pathology, Ajou University School of Medicine; Y.J. Chwae, MD, PhD, Department of Microbiology, Ajou University School of Medicine; J.Y. Jung, MD, PhD, Department of Rheumatology, Ajou University School of Medicine; C.H. Suh, MD, PhD, Department of Rheumatology, Ajou University School of Medicine; J.E. Kwon, MD, PhD, Department of Pathology, Ajou University School of Medicine; H.A. Kim, MD, PhD, Department of Rheumatology, Ajou University School of Medicine. M.H. Ahn and J.H. Han contributed equally to this work. 3. From the departments of Rheumatology, Pathology, and Microbiology, Ajou University School of Medicine, Suwon, Korea. nakhada@naver.com. 4. M.H. Ahn, PhD, Department of Rheumatology, Ajou University School of Medicine; J.H. Han, MD, PhD, Department of Pathology, Ajou University School of Medicine; Y.J. Chwae, MD, PhD, Department of Microbiology, Ajou University School of Medicine; J.Y. Jung, MD, PhD, Department of Rheumatology, Ajou University School of Medicine; C.H. Suh, MD, PhD, Department of Rheumatology, Ajou University School of Medicine; J.E. Kwon, MD, PhD, Department of Pathology, Ajou University School of Medicine; H.A. Kim, MD, PhD, Department of Rheumatology, Ajou University School of Medicine. M.H. Ahn and J.H. Han contributed equally to this work. nakhada@naver.com.
Abstract
OBJECTIVE: Release of neutrophil extracellular traps (NET) has been described as an effector mechanism of polymorphonuclear neutrophils in several inflammatory diseases. Thus, this study was performed to evaluate the role of NET in the pathogenesis of adult-onset Still disease (AOSD). METHODS: We determined the serum levels of NET molecules and investigated their associations with clinical disease activities in patients with AOSD. Further, we analyzed the differences in the NETosis response in AOSD patients compared to healthy controls (HC). To explore the in vivo involvement of NET in AOSD, we performed immunohistochemical analysis of skin and lymph node (LN) biopsies for proteins related to NET in patients with active AOSD. RESULTS: Serum levels of cell-free DNA, myeloperoxidase (MPO)-DNA complex, and α-defensin were significantly increased in patients with AOSD compared to HC. Serum levels of the NET molecules, cell-free DNA, MPO-DNA, and α-defensin were correlated with several disease activity markers for AOSD. In followup of patients with AOSD after treatment with corticosteroid, the levels of cell-free DNA and α-defensin decreased significantly. On immunohistochemistry, neutrophil elastase-positive and MPO-positive inflammatory cells were detected in skin and LN of patients with AOSD, and were expressed in fiber form in the lesions. The serum from patients with active AOSD induced NETosis in neutrophils from HC. NET molecules induced interleukin 1β production in monocytes, representing a novel mechanism in the pathogenesis of AOSD. CONCLUSION: The findings presented here suggest that NET may contribute to the inflammatory response and pathogenesis in AOSD.
OBJECTIVE: Release of neutrophil extracellular traps (NET) has been described as an effector mechanism of polymorphonuclear neutrophils in several inflammatory diseases. Thus, this study was performed to evaluate the role of NET in the pathogenesis of adult-onset Still disease (AOSD). METHODS: We determined the serum levels of NET molecules and investigated their associations with clinical disease activities in patients with AOSD. Further, we analyzed the differences in the NETosis response in AOSD patients compared to healthy controls (HC). To explore the in vivo involvement of NET in AOSD, we performed immunohistochemical analysis of skin and lymph node (LN) biopsies for proteins related to NET in patients with active AOSD. RESULTS: Serum levels of cell-free DNA, myeloperoxidase (MPO)-DNA complex, and α-defensin were significantly increased in patients with AOSD compared to HC. Serum levels of the NET molecules, cell-free DNA, MPO-DNA, and α-defensin were correlated with several disease activity markers for AOSD. In followup of patients with AOSD after treatment with corticosteroid, the levels of cell-free DNA and α-defensin decreased significantly. On immunohistochemistry, neutrophil elastase-positive and MPO-positive inflammatory cells were detected in skin and LN of patients with AOSD, and were expressed in fiber form in the lesions. The serum from patients with active AOSD induced NETosis in neutrophils from HC. NET molecules induced interleukin 1β production in monocytes, representing a novel mechanism in the pathogenesis of AOSD. CONCLUSION: The findings presented here suggest that NET may contribute to the inflammatory response and pathogenesis in AOSD.