Animal model and research on pathogenesis of IgA nephropathy

doi:10.3877/cma.j.issn.2095-3216.2014.02.005

Abstract

Abstract:

Although the pathogenesis of IgA nephropathy (IgAN) is still unclear yet, multi-hit theory has become an accepted mechanism at present. Based on different pathogenetic mechanisms, a variety of IgAN animal models have been established, including passive immunity model, active immunity model,secondary IgAN model, spontaneous IgAN model, and early onset IgAN model. In this article, features of some representative animal models of IgAN will be reviewed briefly. Besides, a new animal model, namely α1K1-CD89Tg IgAN mouse model, will also be introduced. These different animal models of IgAN have played important roles in the research on IgAN pathogenesis.

Key words: IgA nephropathy, Animal model, Pathogenesis

Qianliao Wang, Guisen Li. Animal model and research on pathogenesis of IgA nephropathy[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2014, 03(02): 77-81.

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References 30

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发病机制	动物模型	建模方法	特点
免疫复合物在肾小球系膜区沉积及肾脏损伤	大分子免疫复合物沉积	DNP^[7]或右旋糖苷^[8-9]与IgA形成复合物,注射给小鼠	肾脏表现为系膜增生,IgA和C3沉积,复合物大小、电荷等均影响
	肾小球的亲和力	IgAN患者含低糖基化IgA1的复合物,经肾血管灌注给大鼠^[18]。被动或主动血清病IgAN模型^[9]	低糖基化IgA1表现出对大鼠肾脏更高的亲和力和致病力。抗原大小、电荷、抗原类型影响亲和力
	循环复合物的亲和力	小鼠UG基因敲除,或表达反义UG载体^[19-20]	小鼠体内出现IgAN,及循环内大量IgA-FN。UG可以阻止该复合物形成,防止其肾脏沉积致病。但人体内该基因的效应与小鼠不一致。
	其他免疫球蛋白和补体共同沉积	将产生lgG2a抗Thy-1.1(ER4G)杂交瘤细胞转化为产生IgA抗Thy-1.1(ER4A)的杂交瘤细胞,注射入Wistar大鼠的肾动脉^[21-22]	单纯ER4A不导致蛋白尿和肾脏补体活化,联合使用导致补体活化,肾小球系膜病变更突出
	阿霉素或BSA预处理	阿霉素或BSA预处理BALB/c雌性小鼠,然后注射IgA及抗原^[23]	阿霉素或BSA预处理会明显增强肾脏IgA和C3沉积
	sCD89促进大分子复合形成	建立CD89(人)的转基因小鼠^[24]	sCD89促进循环中含IgA的大分子复合物形成,并在肾脏大量沉积,小鼠出现肾脏损伤
	O-糖基化IgA类风湿因子(RF)	小鼠植入分泌6～19IgAanti-IgG2a的杂交瘤^[25]	6～19IgA分子绞链区出现O-连接聚糖。小鼠表现出肾小球病变,系膜区IgA,IgG2a,和C3沉积。血和肾脏中大量IgA-IgG2a复合物形成

半乳糖缺乏IgA1的自身抗体形成	重组人Gd-IgA1特异性IgG	人Gd-IgA1与重组Gd-IgA1特异性IgG,在体外形成免疫复合物,给严重联合免疫缺陷小鼠注射,形成被动小鼠模型^[26]	Gd-IgA1-IgG免疫复合物在肾脏沉积导致肾小球系膜细胞增生,系膜基质增宽
糖基化缺陷IgA1产生	O-糖基化缺陷人IgA1	IgAN患者低糖基化的IgA1复合物,经肾血管灌注给大鼠^[18]神经氨酸酶和半乳糖苷酶处理的IgA1经肾动脉注射给大鼠^[27]	低糖基化IgA1表现出对大鼠肾脏更高的亲和力和致病力
	N-半乳糖基化缺陷	建立β1,4半乳糖转移酶基因敲除小鼠(β4GalT-I^-/-)^[28]	小鼠出现蛋白尿,部分出现血尿,伴有系膜基质增生。肾脏IgA沉积突出,伴有IgG,IgM和C3沉积
	广泛低唾液酸化	Gne ^M712T/M712T敲入(该基因编码细胞内唾液酸化过程的重要限速酶GNE/MNK)^[29]	严重肾小球病变,足突融合,节段肾小球基底膜断裂。用唾液酸前体N-乙酰甘露糖胺(ManNac)可部分逆转其效应。但并类似于某种特定的肾病

发病机制	动物模型	建模方法	特点
免疫复合物在肾小球系膜区沉积及肾脏损伤	大分子免疫复合物沉积	DNP^[7]或右旋糖苷^[8-9]与IgA形成复合物,注射给小鼠	肾脏表现为系膜增生,IgA和C3沉积,复合物大小、电荷等均影响
	肾小球的亲和力	IgAN患者含低糖基化IgA1的复合物,经肾血管灌注给大鼠^[18]。被动或主动血清病IgAN模型^[9]	低糖基化IgA1表现出对大鼠肾脏更高的亲和力和致病力。抗原大小、电荷、抗原类型影响亲和力
	循环复合物的亲和力	小鼠UG基因敲除,或表达反义UG载体^[19-20]	小鼠体内出现IgAN,及循环内大量IgA-FN。UG可以阻止该复合物形成,防止其肾脏沉积致病。但人体内该基因的效应与小鼠不一致。
	其他免疫球蛋白和补体共同沉积	将产生lgG2a抗Thy-1.1(ER4G)杂交瘤细胞转化为产生IgA抗Thy-1.1(ER4A)的杂交瘤细胞,注射入Wistar大鼠的肾动脉^[21-22]	单纯ER4A不导致蛋白尿和肾脏补体活化,联合使用导致补体活化,肾小球系膜病变更突出
	阿霉素或BSA预处理	阿霉素或BSA预处理BALB/c雌性小鼠,然后注射IgA及抗原^[23]	阿霉素或BSA预处理会明显增强肾脏IgA和C3沉积
	sCD89促进大分子复合形成	建立CD89(人)的转基因小鼠^[24]	sCD89促进循环中含IgA的大分子复合物形成,并在肾脏大量沉积,小鼠出现肾脏损伤
	O-糖基化IgA类风湿因子(RF)	小鼠植入分泌6～19IgAanti-IgG2a的杂交瘤^[25]	6～19IgA分子绞链区出现O-连接聚糖。小鼠表现出肾小球病变,系膜区IgA,IgG2a,和C3沉积。血和肾脏中大量IgA-IgG2a复合物形成

半乳糖缺乏IgA1的自身抗体形成	重组人Gd-IgA1特异性IgG	人Gd-IgA1与重组Gd-IgA1特异性IgG,在体外形成免疫复合物,给严重联合免疫缺陷小鼠注射,形成被动小鼠模型^[26]	Gd-IgA1-IgG免疫复合物在肾脏沉积导致肾小球系膜细胞增生,系膜基质增宽
糖基化缺陷IgA1产生	O-糖基化缺陷人IgA1	IgAN患者低糖基化的IgA1复合物,经肾血管灌注给大鼠^[18]神经氨酸酶和半乳糖苷酶处理的IgA1经肾动脉注射给大鼠^[27]	低糖基化IgA1表现出对大鼠肾脏更高的亲和力和致病力
	N-半乳糖基化缺陷	建立β1,4半乳糖转移酶基因敲除小鼠(β4GalT-I^-/-)^[28]	小鼠出现蛋白尿,部分出现血尿,伴有系膜基质增生。肾脏IgA沉积突出,伴有IgG,IgM和C3沉积
	广泛低唾液酸化	Gne ^M712T/M712T敲入(该基因编码细胞内唾液酸化过程的重要限速酶GNE/MNK)^[29]	严重肾小球病变,足突融合,节段肾小球基底膜断裂。用唾液酸前体N-乙酰甘露糖胺(ManNac)可部分逆转其效应。但并类似于某种特定的肾病

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