Dual roles of immunoregulatory cytokine TGF-β in the pathogenesis of autoimmunity-mediated organ damage
Dual roles of immunoregulatory cytokine TGF-β in the pathogenesis of autoimmunity-mediated organ damage
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DOI：
10.4049/jimmunol.180.3.1903
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发表时间：
2008-02-01
影响因子：
4.4
通讯作者：
Singh, Ram Raj
中科院分区：
文献类型：
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作者：
Saxena, Vijay;Lienesch, Douglas W.;Singh, Ram Raj
大量证据表明TGF-β在预防自身免疫中的作用。多器官炎性疾病、自身反应性T细胞的自发活化和自身抗体产生是自身免疫性疾病（如狼疮）的标志。这些特征使人联想到TGF-β 1缺陷小鼠的免疫病理学表现。在这项研究中，我们发现，狼疮倾向（新西兰黑人和白色）F（1）小鼠淋巴组织中TGF-β 1的表达减少，TGF-β 1或产生TGF-β 1的T细胞抑制自身抗体的产生。相反，TGF-β 1蛋白和mRNA以及TGF-β信号传导蛋白（II型TGF-β受体和磷酸化SMAD 3）的表达在靶器官中增加，即，肾脏，这些小鼠的年龄和发展进行性器官损伤。事实上，肾组织和尿液中TGF-β 1的水平与代表局部组织纤维化的慢性病变的程度相关。通过用抗TGF-β Ab治疗这些小鼠的体内TGF-β阻断选择性地抑制慢性纤维化病变，而不影响自身抗体产生和组织损伤的炎性组分。因此，TGF-β在多器官自身免疫性疾病中的器官损伤的发展中起着双重的、看似矛盾的作用。根据我们的工作模型，免疫细胞中TGF-β的减少容易导致免疫失调和自身抗体的产生，这会导致组织炎症，从而触发靶器官中抗炎细胞因子（如TGF-β）的产生以对抗炎症。反过来，靶器官中TGF-β的增强可导致组织修复失调、进行性纤维化和最终的终末器官损伤。
Ample evidence suggests a role of TGF-beta in preventing autoimmunity. Multiorgan inflammatory disease, spontaneous activation of self-reactive T cells, and autoantibody production are hallmarks of autoimmune diseases, such as lupus. These features are reminiscent of the immunopathology manifest in TGF-beta 1-deficient mice. In this study, we show that lupus-prone (New Zealand Black and White)F(1) mice have reduced expression of TGF-beta 1 in lymphoid tissues, and TGF-beta 1 or TGF-beta 1-producing T cells suppress autoantibody production. In contrast, the expression of TGF-beta 1 protein and mRNA and TGF-beta signaling proteins (TGF-beta receptor type II and phosphorylated SMAD3) increases in the target organs, i.e., kidneys, of these mice as they age and develop progressive organ damage. In fact, the levels of TGF-beta 1 in kidney tissue and urine correlate with the extent of chronic lesions that represent local tissue fibrosis. In vivo TGF-beta blockade by treatment of these mice with an anti-TGF-beta Ab selectively inhibits chronic fibrotic lesions without affecting autoantibody production and the inflammatory component of tissue injury. Thus, TGF-beta plays a dual, seemingly paradoxical, role in the development of organ damage in multiorgan autoimmune diseases. According to our working model, reduced TGF-beta in immune cells predisposes to immune dysregulation and autoantibody production, which causes tissue inflammation that triggers the production of anti-inflammatory cytokines such as TGF-beta in target organs to counter inflammation. Enhanced TGF-beta in target organs, in turn, can lead to dysregulated tissue repair, progressive fibrogenesis, and eventual end-organ damage.