Yoshioka Takeshi, Imura Kinichi, Hikita Ichiro, Hirasawa Tsutomu, Sakata Tsuneaki, Matsutani Takaji, Horikawa Tatsuya, Arimura Akinori
Shionogi Discovery Research Laboratories, Shionogi & Co. Ltd, Osaka, Japan.
Immunology. 2007 May;121(1):51-61. doi: 10.1111/j.1365-2567.2007.02536.x. Epub 2007 Feb 20.
Although the pathogenic role of interleukin-13 (IL-13) is a key for atopic dermatitis (AD), the mechanism of IL-13 production in AD remains unclear. To investigate the role of the T-cell receptor Vbeta (TCR Vbeta) haplotype in the development of dermatitis and the production of IL-13 in the naturally occurring dermatitis model by staphylococcal enterotoxin C (SEC)-producing Staphylococcus aureus, we raised DS-Nh mice harbouring the TCR Vbeta(a) haplotype with a central deletion in the TCRBV gene segments, including TCR Vbeta8S2. Observation and histopathological analysis of the two mouse substrains with spontaneous dermatitis indicated that later onset and weaker severity of AD-like dermatitis were identified in mice with TCR Vbeta(a) compared to those with TCR Vbeta(b). Immunohistochemical examination revealed the infiltration of a large number of CD4-bearing T cells in the skin lesions in mice with TCR Vbeta(b) but not in those with TCR Vbeta(a). Interestingly, much lower levels of serum IL-13 were detected in mice with the TCR Vbeta(a) than in those with the TCR Vbeta(b) haplotype. In vitro, synthetic ligands (Pam(2)CSK4) of toll-like receptor 2 (TLR2) synergistically produced IL-13 with SEC in splenocytes of mice with TCR Vbeta(b) but not of those with TCR Vbeta(a), and natural killer T cells were essential for this synergism. Our findings suggested that this TCR Vbeta-haplotype-dependent synergism with TLR2 plays an important role in the development of AD-like dermatitis in DS-Nh mice.
尽管白细胞介素-13（IL-13）的致病作用是特应性皮炎（AD）的关键，但AD中IL-13产生的机制仍不清楚。为了研究T细胞受体Vβ（TCR Vβ）单倍型在由产生葡萄球菌肠毒素C（SEC）的金黄色葡萄球菌引起的自然发生性皮炎模型中皮炎发展和IL-13产生中的作用，我们培育了携带TCR Vβ（a）单倍型且TCRBV基因片段（包括TCR Vβ8S2）有中央缺失的DS-Nh小鼠。对两种自发性皮炎小鼠亚系的观察和组织病理学分析表明，与具有TCR Vβ（b）的小鼠相比，具有TCR Vβ（a）的小鼠AD样皮炎发病较晚且严重程度较轻。免疫组织化学检查显示，具有TCR Vβ（b）的小鼠皮肤病变中有大量含CD4的T细胞浸润，而具有TCR Vβ（a）的小鼠则没有。有趣的是，检测到具有TCR Vβ（a）的小鼠血清IL-13水平远低于具有TCR Vβ（b）单倍型的小鼠。在体外，Toll样受体2（TLR2）的合成配体（Pam（2）CSK4）与SEC在具有TCR Vβ（b）的小鼠脾细胞中协同产生IL-13，但在具有TCR Vβ（a）的小鼠脾细胞中则不能，并且自然杀伤T细胞对于这种协同作用至关重要。我们的研究结果表明，这种与TLR2的TCR Vβ单倍型依赖性协同作用在DS-Nh小鼠AD样皮炎的发展中起重要作用。
