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Enhanced Expression of Programmed Death-1
(PD-1)/PD-L1 in Salivary Glands of Patients with Sjögren's Syndrome
MASAYA KOBAYASHI, SEIJI KAWANO, SAORI HATACHI, CHIYO KURIMOTO, TAKU OKAZAKI, YOSHIKO IWAI, TASUKU HONJO, YOSHIMASA TANAKA, NAGAHIRO MINATO, TAKAHIDE KOMORI, SAKAN MAEDA, and SHUNICHI KUMAGAI
ABSTRACT.
Objective. Programmed death-1 (PD-1) mediates a negative signal and introduces tolerance for lymphocytes. Dysfunction of the PD-1 pathway is thought to result in autoimmune diseases such as rheumatoid arthritis (RA). To investigate the role of the PD-1/PD-L system in the pathology of Sjögren's syndrome (SS), we examined the expression of PD-1 and its ligand PD-L1 in salivary lymphocytes and salivary glands from patients with SS. Methods. Flow cytometry analysis was used to determine expression of PD-1 in SS salivary lymphocytes. Intracellular staining of interleukin 10 (IL-10) was performed after stimulation with PMA and ionomycin. Indirect immunohistochemistry was used to investigate the expression of PD-1 and PD-L1. Results. The mean fluorescence intensity of PD-1 expression in SS salivary lymphocytes was significantly higher than that from healthy controls and patients with RA or systemic lupus erythematosus. PD-1-positive SS salivary lymphocytes expressed IL-10 intracellularly upon PMA/ionomycin stimulation. Immunohistochemical analysis showed that PD-1 was expressed on infiltrating lymphocytes in salivary gland from 52% of SS patients, and PD-L1 was expressed on ductal and acinar epithelial cells from 68% of SS patients. In vitro analysis using HSG cells revealed that PD-L1 was induced by interferon-g but not by tumor necrosis factor-a and IL-1ß. Conclusion. PD-1 is expressed on T lymphocytes and PD-L1 on epithelial cells from inflamed salivary glands of patients with SS, which suggests that dysfunction of the PD-1/PD-L1 pathway may be related to tolerance for lymphocytes, which causes SS. (J Rheumatol 2005;32:2156-63) Key Index Terms:
SJÖGREN'S SYNDROME
From the Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Kobe; Department of Medical Chemistry, Graduate School of Medicine, Kyoto University; Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto; Department of Oral and Maxillofacial Surgery, Kobe University; and Department of Biomedical Informatics, Division of Molecular Pathology, Kobe University, Kobe, Japan. Supported in part by a Grant-in-Aid for Scientific Research (14370164) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. M. Kobayashi, MS; S. Kawano, MD, PhD; S. Hatachi, MD, PhD; C. Kurimoto, MD; S. Kumagai, MD, PhD, Professor, Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine; T. Okazaki, MD, PhD; Y. Iwai, MD, PhD; T. Honjo, MD, PhD, Department of Medical Chemistry, Graduate School of Medicine, Kyoto University; Y. Tanaka, PhD; N. Minato, MD, PhD, Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University; T. Komori, DDS, PhD, Department of Oral and Maxillofacial Surgery, Kobe University; S. Maeda, MD, PhD, Department of Biomedical Informatics, Division of Molecular Pathology, Kobe University. Address reprint requests to Dr. S. Kumagai, Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: kumagais@kobe-u.ac.jp Accepted for publication June 21, 2005. |