Local transgenic expression of granulocyte macrophage-colony stimulating factor initiates autoimmunity
Local transgenic expression of granulocyte macrophage-colony stimulating factor initiates autoimmunity
复制标题
DOI：
10.4049/jimmunol.166.3.2090
复制
发表时间：
2001-02-01
影响因子：
4.4
通讯作者：
Alderuccio, F
中科院分区：
文献类型：
--
作者：
Biondo, M;Nasa, Z;Alderuccio, F
导致免疫耐受崩溃和启动自身免疫的机制尚不清楚。实验性自身免疫性胃炎是一种器官特异性自身免疫的典范，源于对胃WK-ATPase的病理性自身免疫反应，胃炎伴随着胃WK-ATPase的自身抗体，最典型的实验性自身免疫性胃炎模型需要新生儿胸腺切除，这一过程扰乱了免疫谱系，限制了其在免疫系统完整的动物中如何发生的有效性。在此，我们测试了促炎细胞因子GM-CSF的局部产生是否足以打破耐受并启动自身免疫。我们建立了胃内表达GM-CSF的转基因小鼠，这些转基因小鼠在与胃炎易感的BALBc/Crslc Mire进行6次回交后自发发生胃炎，发病率约为80%。胃炎伴有胃粘膜肥大、引流淋巴结肿大和抗胃WK-ATPase自身抗体，树突状细胞和巨噬细胞先于CD4T细胞渗入胃粘膜，引流淋巴结中的T细胞特异性地增殖到胃WK-ATPase，而CD8-T细胞不向裸鼠受体转移胃炎。来自脾的CD4(+)CD25(+)T细胞保留了被IL-2逆转的无能抑制特性。我们认为局部表达GM-CSF足以打破免疫耐受，启动由CD4T细胞介导的自身免疫。这种新的小鼠模型对于器官特异性自身免疫的研究应该是有用的。
Mechanisms leading to breakdown of immunological tolerance and initiation of autoimmunity are poorly understood. Experimental autoimmune gastritis is a paradigm of organ-specific autoimmunity arising from a pathogenic autoimmune response to gastric WK ATPase, The gastritis is accompanied by autoantibodies to the gastric WK ATPase, The best characterized model of experimental autoimmune gastritis requires neonatal thymectomy, This procedure disrupts the immune repertoire, limiting its usefulness in understanding how autoimmunity arises in animals with intact immune systems, Here we tested whether local production of GM-CSF, a pro-inflammatory cytokine, is sufficient to break tolerance and initiate autoimmunity. We generated transgenic mice expressing GM-CSF in the stomach, These transgenic mice spontaneously developed gastritis with an incidence of about 80% after six backcrosses to gastritis-susceptible BALBc/CrSlc mire. The gastritis is accompanied by mucosal hypertrophy, enlargement of draining lymph nodes and autoantibodies to gastric WK ATPase, An infiltrate of dendritic cells and macrophages preceded CD4 T cells into the gastric mucosa, T cells from draining lymph nodes specifically proliferated to the gastric WK ATPase, CD4 but not CD8 T cells transferred gastritis to nude mouse recipients. CD4(+) CD25(+) T cells from the spleen retained anergic suppressive properties that were reversed by IL-2. We conclude that local expression of GM-CSF is sufficient to break tolerance and initiate autoimmunity mediated by CD4 T cells. This new mouse model should be useful for studies of organ-specific autoimmunity.