Excessive production of IFN-γ in patients with systemic lupus erythematosus and its contribution to induction of B lymphocyte stimulator/B cell-activating factor/TNF ligand superfamily-13B
Excessive production of IFN-γ in patients with systemic lupus erythematosus and its contribution to induction of B lymphocyte stimulator/B cell-activating factor/TNF ligand superfamily-13B
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DOI：
10.4049/jimmunol.181.3.2211
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发表时间：
2008-08-01
影响因子：
4.4
通讯作者：
Miyasaka, Nobuyuki
中科院分区：
文献类型：
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作者：
Harigai, Masayoshi;Kawamoto, Manabu;Miyasaka, Nobuyuki
IFN-γ是小鼠狼疮中的关键细胞因子，其在人类系统性红斑狼疮（SLE）中的表达及其免疫学意义尚未明确。在本研究中，我们研究了IFN-γ在SLE患者外周血T细胞中的表达及其在可溶性B淋巴细胞刺激因子（sBLyS）产生中的作用。ELISA、流式细胞术和定量RT-PCR三种分析方法显示，SLE患者外周血T细胞在抗CD 3单抗和抗CD 28单抗刺激下，IFN-γ的表达量显著高于正常对照组。SLE患者CD 3（+）CD 4（+）和CD 3（+）CD 8（+）细胞中IFN-γ产生性T细胞与效应记忆性T细胞的比例明显高于正常对照组。SLE患者T细胞表达的T-box（T-bet）mRNA/GATA结合蛋白-3（加塔-3）mRNA比值显著高于正常对照组。SLE患者的T细胞培养上清液中sBLyS诱导活性显著高于正常对照组，这几乎完全被抗人IFN-γ mAb抑制。SLE患者外周血单核细胞BLyS阳性率明显高于正常对照组。SLE患者的单核细胞对IFN-γ的反应产生的sBLyS显著高于正常对照组。综上所述，这些数据有力地表明，IFN-γ在外周血T细胞中的过表达通过单核细胞/巨噬细胞诱导sBLyS而有助于SLE的免疫发病机制，这将促进B细胞活化和成熟。
Expression and immunological significance of IFN-gamma, 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-gamma 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-gamma 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-gamma-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-gamma 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-gamma than those from normal controls. Taken together, these data strongly indicate that the overexpression of IFN-gamma 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.