Sharma Rahul, Deshmukh Umesh S, Zheng Lingjie, Fu Shu Man, Ju Shyr-Te
Center for Inflammation, Immunity, and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA 22908-0412, USA.
J Immunol. 2009 Sep 1;183(5):3212-8. doi: 10.4049/jimmunol.0804355. Epub 2009 Jul 31.
Scurfy (Foxp3(Sf)/Y), Il2(-/-), and Il2ralpha(-/-) mice are deficient in CD4(+)Foxp3(+) regulatory T cells (Treg), but only the latter two develop inflammation in the submandibular gland (SMG), a critical target of Sjögren's syndrome. In this study, we investigated the reason that SMG of Scurfy (Sf), Sf.Il2(-/-), Sf.Il2ralpha(-/-), and the long-lived Sf.Fas(lpr/lpr) mice remained free of inflammation, even though their lymph node cells induced SMG inflammation in Rag1(-/-) recipients. A strong correlation was observed between the development of the granular convoluted tubules (GCT) of the SMG in these mice and SMG resistance to inflammation. Moreover, GCT development in Sf.Rag1(-/-) mice was not impeded, indicating a role of adaptive immunity. In the Sf.Fas(lpr/lpr) mice, this block was linked to atrophy and inflammation in the accessory reproductive organs. Testosterone treatment restored GCT expression, but did not induce SMG inflammation, indicating GCT is not required for inflammation and additional mechanisms were controlling SMG inflammation. Conversely, oral application of LPS induced SMG inflammation, but not GCT expression. LPS treatment induced up-regulation of several chemokines in SMG with little effect on the chemokine receptors on CD4(+) T cells in Sf mice. Our study demonstrates that Sf mutation affects SMG development through adaptive immunity against accessory reproductive organs, and the manifestation of SMG inflammation in Sf mice is critically controlled through innate immunity.
毛发蓬松（Foxp3(Sf)/Y）、Il2基因敲除（Il2(-/-)）和Il2受体α链基因敲除（Il2ralpha(-/-)）小鼠缺乏CD4(+)Foxp3(+)调节性T细胞（Treg），但只有后两者会在下颌下腺（SMG）发生炎症，下颌下腺是干燥综合征的关键靶器官。在本研究中，我们探究了毛发蓬松（Sf）、Sf.Il2(-/-)、Sf.Il2ralpha(-/-)以及长寿的Sf.Fas(lpr/lpr)小鼠的下颌下腺为何没有炎症，尽管它们的淋巴结细胞能在Rag1(-/-)受体中诱导下颌下腺炎症。在这些小鼠中，下颌下腺颗粒曲管（GCT）的发育与下颌下腺对炎症的抵抗力之间存在很强的相关性。此外，Sf.Rag1(-/-)小鼠的GCT发育并未受到阻碍，这表明适应性免疫发挥了作用。在Sf.Fas(lpr/lpr)小鼠中，这种阻碍与附属生殖器官的萎缩和炎症有关。睾酮治疗可恢复GCT表达，但不会诱导下颌下腺炎症，这表明炎症并不需要GCT，且存在其他机制控制下颌下腺炎症。相反，口服脂多糖（LPS）可诱导下颌下腺炎症，但不会诱导GCT表达。LPS治疗可诱导下颌下腺中几种趋化因子上调，对毛发蓬松小鼠CD4(+) T细胞上的趋化因子受体影响很小。我们的研究表明，Sf突变通过针对附属生殖器官的适应性免疫影响下颌下腺发育，且毛发蓬松小鼠下颌下腺炎症的表现受到固有免疫的严格控制。
