title: Increased neutrophil elastase and proteinase 3 and augmented NETosis are closely associated with β-cell autoimmunity in patients with type 1 diabetes.
abstract: Type 1 diabetes (T1D) is an autoimmune disease resulting from the 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 stored in neutrophil primary granules, were markedly elevated in patients with T1D, especially those with disease duration of less than 1 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, an endogenous inhibitor of neutrophil serine proteases, are decreased in T1D patients. These findings support an early role of neutrophil activation and augmented neutrophil serine proteases activities in the pathogenesis of β-cell autoimmunity and also suggest that circulating NE and PR3 may serve as sensitive biomarkers for the diagnosis of T1D.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Diabetes 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Diabetes 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.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Medicine, University of Dresden, Dresden, Germany.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: Diabetes 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 amxu@hku.hk ksllam@hku.hk zhouzg@hotmail.com.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China amxu@hku.hk ksllam@hku.hk zhouzg@hotmail.com.
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China Department of Medicine, The University of Hong Kong, Hong Kong, China Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China amxu@hku.hk ksllam@hku.hk zhouzg@hotmail.com.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
mesh_terms: D000293:Adolescent; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D016022:Case-Control Studies; D016923:Cell Death / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000276:immunology; D065206:Extracellular Traps / Q000276:immunology*; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology*; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D053146:Myeloblastin / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology*; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase; D053146:Myeloblastin