Barrett S P, van Driel I R, Tan S S, Alderuccio F, Toh B H, Gleeson P A
Department of Pathology and Immunology, Monash University Medical School, Alfred Hospital, Melbourne, Australia.
Eur J Immunol. 1995 Sep;25(9):2686-94. doi: 10.1002/eji.1830250943.
Autoimmune gastritis, induced by day-3 thymectomy of BALB/c mice, is a destructive CD4+ T cell-mediated disease characterized by leukocyte infiltrates in the gastric mucosa, loss of parietal and chief cells and anti-gastric H/K ATPase autoantibodies. Our previous studies have indicated that a T cell response to the H/K ATPase beta subunit is required for the onset of autoimmune gastritis (Alderuccio, F., Toh, B. H., Tan, S. S., Gleeson, P. A. and van Driel, I. R., J. Exp. Med. 1993. 178: 419). To determine whether a response to the beta subunit autoantigen is alone sufficient to induce autoimmunity, or whether other tissue-specific factors are required, we have generated transgenic mice expressing the gastric H/K ATPase beta subunit in beta islet cells of the pancreas (RIP-H/K beta). RIP-H/K beta mice developed autoimmune gastritis and insulitis after day-3 thymectomy. Significantly, insulitis, observed as a peri-islet infiltrate, was only detected in thymectomized mice with autoimmune gastritis. There was no apparent immune destruction of the pancreas as insulitis did not progress to invasion of the islets or diabetes. Double transgenic mice, expressing the gastric H/K ATPase beta subunit in the thymus and in the pancreas, were protected from both gastritis and insulitis after day-3 thymectomy. Therefore, insulitis in the RIP-H/K beta mice appears to be dependent on a T cell response to the H/K ATPase beta subunit. This is the first example where an organ-specific initiating autoantigen has been expressed in another peripheral tissue. Autoimmune destruction in the stomach, but not the pancreas, indicates that tissue-specific factors play a fundamental role in the development of organ-specific autoimmunity.
自身免疫性胃炎由BALB/c小鼠在出生后第3天进行胸腺切除诱导产生，是一种由CD4+ T细胞介导的破坏性疾病，其特征为胃黏膜白细胞浸润、壁细胞和主细胞丧失以及抗胃H/K ATP酶自身抗体。我们之前的研究表明，对H/K ATP酶β亚基的T细胞反应是自身免疫性胃炎发病所必需的（阿尔德鲁乔，F.，托，B. H.，谭，S. S.，格利森，P. A.和范德里尔，I. R.，《实验医学杂志》。1993年。178: 419）。为了确定对β亚基自身抗原的反应是否足以单独诱导自身免疫，或者是否需要其他组织特异性因子，我们构建了在胰腺β胰岛细胞中表达胃H/K ATP酶β亚基的转基因小鼠（RIP-H/Kβ）。RIP-H/Kβ小鼠在出生后第3天胸腺切除后出现自身免疫性胃炎和胰岛炎。值得注意的是，仅在患有自身免疫性胃炎的胸腺切除小鼠中检测到作为胰岛周围浸润的胰岛炎。由于胰岛炎未发展为胰岛侵犯或糖尿病，胰腺没有明显的免疫破坏。在胸腺和胰腺中均表达胃H/K ATP酶β亚基的双转基因小鼠在出生后第3天胸腺切除后对胃炎和胰岛炎均有抵抗力。因此，RIP-H/Kβ小鼠中的胰岛炎似乎依赖于对H/K ATP酶β亚基的T细胞反应。这是器官特异性起始自身抗原在另一个外周组织中表达的首个实例。胃部而非胰腺的自身免疫破坏表明，组织特异性因子在器官特异性自身免疫的发展中起根本作用。
