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Excessive Production of IFN- in Patients with Systemic Lupus Erythematosus and Its Contribution to Induction of B Lymphocyte Stimulator/B Cell-Activating Factor/TNF Ligand Superfamily-13B¹

Masayoshi Harigai^2,*,,, Manabu Kawamoto^¶, Masako Hara^¶, Tetsuo Kubota^,, Naoyuki Kamatani^¶ and Nobuyuki Miyasaka

^* Department of Pharmacovigilance and Department of Medicine and Rheumatology, Tokyo Medical and Dental University Graduate School of Medicine, Clinical Research Center, Tokyo Medical and Dental University, and Department of Microbiology and Immunology, Tokyo Medical and Dental University Graduate School of Health Sciences, Tokyo, Japan; and ^¶ Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan

Expression and immunological significance of IFN-, a pivotal cytokine in murine lupus, have not been clearly demonstrated in human systemic lupus erythematosus (SLE). In the present study we investigated the expression of IFN- in peripheral blood T cells from patients with SLE and its role in the production of the soluble B lymphocyte stimulator (sBLyS). Peripheral blood T cells from patients with SLE expressed significantly larger amounts of IFN- in response to stimulation with anti-CD3 mAb plus anti-CD28 mAb than those from normal controls as shown by three analytical methods, including ELISA, flow cytometry, and quantitative RT-PCR. The ratio of IFN--producing T cells to effector memory T cells in CD3⁺CD4⁺ and CD3⁺CD8⁺ populations in patients with SLE was significantly higher than that of normal controls. The T-box expressed in T cells (T-bet) mRNA/GATA-binding protein-3 (GATA-3) mRNA ratio was significantly higher in patients with SLE than in normal controls. T cell culture supernatants from patients with SLE contained significantly higher sBLyS-inducing activity than normal controls; this was almost completely inhibited by the addition of anti-human IFN- mAb. Percentages of BLyS-expressing peripheral blood monocytes in patients with SLE were significantly higher than those of normal controls. Monocytes from patients with SLE produced significantly larger amounts of sBLyS in response to IFN- than those from normal controls. Taken together, these data strongly indicate that the overexpression of IFN- in peripheral blood T cells contributes to the immunopathogenesis of SLE via the induction of sBLyS by monocytes/macrophages, which would promote B cell activation and maturation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grant-in-aid from the Japanese Ministry of Health, Labor, and Welfare.

² Address correspondence and reprint requests to Dr. Masayoshi Harigai, Department of Pharmacovigilance, Tokyo Medical and Dental University Graduate School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: mharigai.mpha{at}tmd.ac.jp

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; BAFF, B cell-activating factor; BLyS, B lymphocyte stimulator; GATA-3, GATA-binding protein-3; PC7, PE-cyanine 7; pSS, positive Sjögren’s syndrome; sBLyS, soluble BLyS; SLEDAI, SLE disease activity index; T-bet, T-box expressed in T cells; T_CM, central memory T cell; T_EM, effector memory T cell; T_EMRA, CD3⁺CD8⁺CD45RA⁺CCR7^– effector memory T cell.