Increased Neutrophil Elastase and Proteinase 3 and Augmented NETosis Are Closely Associated with β-cell Autoimmunity in Patients with Type 1 Diabetes
- Yudong Wang1,2,†,
- Yang Xiao3,†,
- Ling Zhong1,2,†,
- Dewei Ye1,2,4,
- Jialiang Zhang1,2,
- Yiting Tu3,
- Stefan R. Bornstein5,
- Zhiguang Zhou3⇑,
- Karen S.L. Lam1,2⇑ and
- Aimin Xu1,2,4⇑
- 1State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
- 2Department of Medicine, The University of Hong Kong, Hong Kong, China
- 3Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
- 4Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China
- 5Department of Medicine, University of Dresden, 01307 Dresden, Germany.
- Corresponding authors: Aimin Xu or Karen S.L. Lam, E-mail: ; or . Or Zhiguang Zhou, E-mail: .
Type 1 diabetes (T1D) is an autoimmune disease resulting from self-destruction of insulin-producing β cells. Reduced neutrophil counts have been observed in patients with T1D. However, the pathological roles of neutrophils in the development of T1D remain unknown. Here we show that circulating protein levels and enzymatic activities of neutrophil elastase (NE) and proteinase 3 (PR3), both of which are neutrophil serine proteases (NSPs) stored in neutrophil primary granules, were markedly elevated in patients with T1D, especially those with disease duration of less than one year. Furthermore, circulating NE and PR3 levels increased progressively with the increase of the positive numbers and titers of the autoantibodies against β-cell antigens. An obvious elevation of NE and PR3 was detected even in those autoantibody-negative patients. Increased NE and PR3 in T1D patients are closely associated with elevated formation of neutrophil extracellular traps. By contrast, the circulating levels of α1-antitrypsin (A1AT), an endogenous inhibitor of NSPs, are decreased in T1D patients. These findings support an early role of neutrophil activation and augmented NSPs activities in the pathogenesis of β-cell autoimmunity, and also suggest that circulating NE and PR3 may serve as sensitive biomarkers for diagnosis of T1D.
† These authors contributed equally to this work.
- Received March 24, 2014.
- Accepted July 28, 2014.
- © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.