Spontaneous large-scale lymphoid neogenesis and balanced autoimmunity versus tolerance in the stomach of H+/K+-ATPase-Reactive TCR transgenic mouse
Spontaneous large-scale lymphoid neogenesis and balanced autoimmunity versus tolerance in the stomach of H+/K+-ATPase-Reactive TCR transgenic mouse
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DOI：
10.4049/jimmunol.177.11.7858
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发表时间：
2006-12-01
影响因子：
4.4
通讯作者：
Shimizu, Akira
中科院分区：
文献类型：
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作者：
Katakai, Tomoya;Nomura, Takashi;Shimizu, Akira
自身免疫通常伴随着靶器官中异位淋巴组织的发展，并且这些组织被认为与疾病的严重程度密切相关。然而，这种淋巴结构的范围与自身反应性 T 细胞介导的免疫反应的强度或类型之间的真正关系仍不清楚。在本研究中，我们产生了表达 TCR 的转基因小鼠，该小鼠来自自身免疫性胃炎 (AIG) 诱导的 Th1 细胞克隆，该细胞克隆对主要胃自身抗原之一 H+/K+-ATPase α 亚基具有特异性。转基因小鼠在胃粘膜中自发地产生大量淋巴新生，具有高度组织化的组织结构，证明了Ag特异性、T细胞介导的淋巴组织诱导。然而，与新生儿胸腺切除术引起的典型 AIG 相比，周围组织的损伤和自身抗体的产生相当有限。这种温和的病理学可能是由于自身反应性 T 细胞的局部受限激活和 Th2 偏向，以及靶器官中天然存在的调节性 T 细胞的积累。总而言之，这些研究结果表明，慢性自身免疫性疾病中的淋巴新生并不简单地与破坏性反应相关。相反，局部环境中T细胞网络的整体激活状态，即自身反应性和耐受性的平衡有影响。
Autoimmunity is often accompanied by the development of ectopic lymphoid tissues in the target organ, and these tissues have been believed to have close relevance to the severity of the disease. However, the true relationship between the extent of such lymphoid structures and the intensity or type of immune responses mediated by self-reactive T cells has remained unclear. In the present study, we generated transgenic mice expressing TCR from an autoimmune gastritis (AIG)-inducing Th1 cell clone specific for one of the major stomach self-Ags, H+/K+-ATPase alpha subunit. The transgenic mice spontaneously develop massive lymphoid neogenesis with a highly organized tissue structure in the gastric mucosa, demonstrating Ag-specific, T cell-mediated induction of the lymphoid tissues. Nevertheless, the damage of surrounding tissue and autoantibody production were considerably limited compared with those in typical AIG induced by neonatal thymectomy. Such a moderate pathology is likely due to the locally restricted activation and Th2 skewing of self-reactive T cells, as well as the accumulation of naturally occurring regulatory T cells in the target organ. Altogether, the findings suggest that lymphoid neogenesis in chronic autoimmunity does not simply correlate with the destructive response; rather, the overall activation status of the T cell network, i.e., the balance of self-reactivity and tolerance, in the local environment has an impact.