Mice lacking the IFN-γ receptor or fyn develop severe experimental autoimmune uveoretinitis characterized by different immune responses
Mice lacking the IFN-γ receptor or fyn develop severe experimental autoimmune uveoretinitis characterized by different immune responses
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DOI：
10.1007/s00251-005-0805-3
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发表时间：
2005-06-01
期刊：
影响因子：
3.2
通讯作者：
Ueno, H
中科院分区：
文献类型：
--
作者：
Fukushima, A;Yamaguchi, T;Ueno, H
内源性干扰素(IFN)- γ负调控实验性自身免疫性葡萄膜视网膜炎（EAU），一种th1介导的疾病。虽然众所周知，ifn - γ通过与ifn - γ受体（ifn - γ R）结合发挥作用，但ifn - γ R在EAU发展中的作用尚未被研究。据报道，Fyn可抑制Th2分化。我们的目的是研究影响Th1/ Th2分化的内源性ifn - γ R和fyn如何参与EAU的发展。比较性别匹配的6 ~ 10周龄C57BL/6野生型（WT）、ifn - γ R敲除（GRKO）和fyn敲除（fyn KO）小鼠。将人光感受器间类视黄醇结合蛋白肽1 - 20乳化于弗氏完全佐剂中皮下免疫小鼠，同时腹腔注射百日咳杆菌毒素。3周后处死小鼠，分别取眼和脾进行组织病理学分析和细胞免疫应答检测。通过测定脾细胞的增殖反应和细胞因子[白细胞介素(IL)-4、IL-5、IL-6、IL-13、ifn - γ和肿瘤坏死因子(TNF)- α]的产生来评估细胞免疫应答。WT小鼠的EAU发生率为40.0%，GRKO小鼠为59.3%，fyn KO小鼠为78.6%。WT小鼠的平均EAU评分为0.294，GRKO小鼠为0.917，fyn KO小鼠为1.063。在EAU诱导下，与WT小鼠相比，GRKO和fyn KO小鼠的眼睛中观察到明显的嗜酸性粒细胞浸润。GRKO小鼠的脾细胞对抗原和有丝分裂原的增殖比WT和fyn KO小鼠更强烈。与WT和fyn KO小鼠相比，用抗原刺激GRKO小鼠的脾细胞诱导更高的IL-4、IL-6、IL-13和ifn - γ的产生。相比之下，与WT和GRKO小鼠相比，fyn KO小鼠的脾细胞产生的IL-5和tnf - α最为丰富。GRKO和fyn KO小鼠的EAU发生率和平均严重程度显著高于WT小鼠，提示内源性ifn - γ R和fyn负性调节EAU的发生。GRKO和fyn小鼠的细胞因子产生模式不同，表明ifn - γ R和fyn介导的负调控机制可能不同。
Endogenous interferon (IFN)-gamma negatively regulates experimental autoimmune uveoretinitis (EAU), a Th1-mediated disease. Although it is well known that IFN-gamma exerts its effects by binding to the IFN-gamma receptor (IFN-gamma R), the role that IFN-gamma R plays in the development of EAU has not been investigated. Fyn has been reported to inhibit Th2 differentiation. We aimed to investigate how endogenous IFN-gamma R and fyn, which influence Th1/ Th2 differentiation, participate in the development of EAU. Sex-matched 6- to 10-week-old C57BL/6 wild-type (WT), IFN-gamma R knockout (GRKO) and fyn knockout (fyn KO) mice were compared. Mice were immunized subcutaneously with human interphotoreceptor retinoid-binding protein peptide 1 - 20 emulsified in Freund's complete adjuvant together with an intraperitoneal injection of Bordetella pertussis toxin. Three weeks later, mice were sacrificed, and their eyes and spleens were harvested for histopathologic analyses and examination of cellular immune responses, respectively. Cellular immune responses were evaluated by measuring the proliferative responses and cytokine production [ interleukin (IL)-4, IL-5, IL-6, IL-13, IFN-gamma and tumor necrosis factor (TNF)-alpha] of splenocytes. The incidence of EAU was 40.0% in WT mice, 59.3% in GRKO mice and 78.6% in fyn KO mice. The average EAU score was 0.294 in WT mice, 0.917 in GRKO mice and 1.063 in fyn KO mice. Upon EAU induction, significant infiltration of eosinophils into the eyes was observed in GRKO and fyn KO mice compared to WT mice. Splenocytes from GRKO mice proliferated against the antigen and a mitogen more vigorously than those from WT and fyn KO mice. Stimulation of splenocytes with the antigen induced a higher production of IL-4, IL-6, IL-13 and IFN-gamma in GRKO mice compared to WT and fyn KO mice. In contrast, IL-5 and TNF-alpha were most abundantly produced by splenocytes from fyn KO mice compared to WT and GRKO mice. The incidence and mean severity of EAU were significantly higher in GRKO and fyn KO mice than in WT mice, suggesting that endogenous IFN-gamma R and fyn negatively regulate the development of EAU. The different cytokine production patterns by the GRKO and fyn KO mice indicate that the negative regulatory mechanism mediated by IFN-gamma R and fyn may differ.