Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Immunity. 2012 Sep 21;37(3):563-73. doi: 10.1016/j.immuni.2012.06.017. Epub 2012 Sep 13.
Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r(-/-)Rag1(-/-) mice to acute colitis. Although negligible contributions of adaptive immunity in F11r(+/+)Rag1(-/-) mice were observed, F11r(-/-)Rag1(-/-) mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4(+) T cells in F11r(-/-) mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4(+) T cells and TGF-β. Absence of IgA in F11r(+/+)Igha(-/-) mice did not affect disease, whereas F11r(-/-)Igha(-/-) mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.
缺乏连接黏附分子 A（JAM-A，由 F11r 编码）的小鼠表现出增强的肠道上皮通透性、细菌易位和结肠淋巴细胞数量升高，但不会发展为结肠炎。为了研究适应性免疫补偿对增加的肠道上皮通透性的贡献，我们研究了 F11r(-/-)Rag1(-/-) 小鼠对急性结肠炎的易感性。尽管在 F11r(+/+)Rag1(-/-) 小鼠中观察到适应性免疫的可忽略不计的贡献，但 F11r(-/-)Rag1(-/-) 小鼠表现出增加的微生物依赖性结肠炎。T 细胞亚群的消除和细胞因子分析表明，TGF-β 产生的 CD4(+) T 细胞在 F11r(-/-) 小鼠中具有保护作用。此外，JAM-A 的缺失导致黏膜和血清 IgA 升高，这依赖于 CD4(+) T 细胞和 TGF-β。F11r(+/+)Igha(-/-) 小鼠中缺乏 IgA 并不影响疾病，而 F11r(-/-)Igha(-/-) 小鼠对急性损伤诱导的结肠炎表现出明显增加的易感性。这些数据确立了在肠道上皮屏障受损的情况下，适应性免疫介导的对急性结肠炎的保护作用。
