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Clinical and Vaccine Immunology, July 2008, p. 1060-1066, Vol. 15, No. 7
1071-412X/08/$08.00+0     doi:10.1128/CVI.00137-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Antibodies to Proteinase 3 Prime Human Oral, Lung, and Kidney Epithelial Cells To Secrete Proinflammatory Cytokines upon Stimulation with Agonists to Various Toll-Like Receptors, NOD1, and NOD2{triangledown}

Akiko Uehara,1* Yasuhiko Hirabayashi,2 and Haruhiko Takada1

Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan,1 Department of Hematology and Rheumatology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan2

Received 15 April 2008/ Returned for modification 5 May 2008/ Accepted 9 May 2008

Antineutrophil cytoplasmic antibodies (ANCA) are autoantibodies, the detection of which in serum can be used in the diagnosis of Wegener's granulomatosis (WG). Proteinase 3 (PR3) is a major target antigen of ANCA in WG patients, and the interaction of PR3 ANCA with leukocytes causes a debilitating autoimmune disease. The first signs and symptoms in WG patients are observed in the oral cavity, lungs, and kidneys. Human epithelial cells generally do not secrete proinflammatory cytokines upon stimulation with pathogen-associated molecular patterns (PAMPs). In this study, anti-PR3 antibodies (Abs) and PR3 ANCA-containing sera from WG patients endowed human oral, lung, and kidney epithelial cells with responsiveness to PAMPs in terms of the production of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein-1, and tumor necrosis factor alpha. Protease-activated receptor-2 (PAR-2) agonist peptides mimicked the priming effects of PR3 ANCA against PAMPs. Furthermore, the anti-PR3 Ab-mediated cell activation was significantly abolished by RNA interference targeting PAR-2 and NF-{kappa}B. This is the first report of priming effects of anti-PR3 Abs (PR3 ANCA) on epithelial cells. The results suggest that anti-PR3 Abs (PR3 ANCA) prime human epithelial cells to produce cytokines upon stimulation with various PAMPs, and these mechanisms may be involved in severe chronic inflammation in WG.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan. Phone: 81-22-717-8306. Fax: 81-22-717-8309. E-mail: kyoro{at}mail.tains.tohoku.ac.jp

{triangledown} Published ahead of print on 21 May 2008.

Clinical and Vaccine Immunology, July 2008, p. 1060-1066, Vol. 15, No. 7
1071-412X/08/$08.00+0     doi:10.1128/CVI.00137-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Harrison, N. K. (2009). Pulmonary infection in Wegener's granulomatosis and idiopathic pulmonary fibrosis. Thorax 64: 647-649 [Full Text]  


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