人IgA/IgM Fc受体：Fcα/μR的表达和功能分析
摘要
Fcα/μR是一种新发现的IgA和IgM的Fc受体。人Fcα/μR为单基因家族成员,其基因位于1号染色体1q32区,毗邻其它FcR基因,包括FcγR1a、FcγR2、FcγR3、FcγR1a和pIgR。小鼠的Fcα/μR高亲和力的结合IgM,中等亲和力的结合IgA。人Fcα/μR为Ⅰ型跨膜蛋白,包含有522个氨基酸和3个膜外区结构域。其中Ig样结构域EC2与人、牛和小鼠的pIgR膜外区的第一个结构域有很高的序列同源性,提示这两个受体间可能存在亲缘上和功能上的关系。小鼠的Fcα/μR表达在胸腺、脾、肝、肾、小肠和大肠、睾丸和一些成熟的B细胞和单核细胞上。人的Fcα/μR表达在肾、小肠和二级淋巴器官。
为了确定Fcα/μR在免疫系统中的作用,区分Fcα/μR与pIgR的表达和功能,我们制备了抗Fcα/μR与pIgR的单克隆抗体。Fcα/μR与pIgR的膜外区分别构建到pET30a质粒中,在E.coli中表达。得到的包涵体蛋白经纯化后免疫Balb/c小鼠并进行细胞融合。产生的单克隆抗体经ELISA、流失细胞分析、Western blott和免疫组化分析鉴定。用确定的特异性抗体进行组织人多组织器官表达分析。
人多组织器官的免疫组化分析结果显示,Fcα/μR表达在肾小管上皮细胞和肾小球系膜区;胂、淋巴结和阑尾淋巴小结中的生发中心;还有散在于消化道粘膜固有层内的浆细胞上。而pIgR则主要集中在小肠、大肠、肺泡和胆囊的上皮细胞上。在其它组织,例如胃底腺、乳腺、睾丸、前列腺和心肌组织,Fcα/μR与pIgR均有不同程度的表达。Fcα/μR在脑组织表达阳性。
于pIgR的表达相比,Fcα/μR主要存在于两种组织。其一是位于呼吸、消化和泌尿生殖等通道下层的淋巴组织;另一种是也同时表达pIgR的上皮细胞,如乳腺和肾。然而即使是在这种情况下,这两个受体也会因表达在不同的侧面而执行不同的功能跨膜转运或者吞噬的功能。
IgA肾病(IgAN)是一种最常见的肾小球炎症,同时也是最主要的导致肾功能衰竭的原因。IgAN的发病机制还不清楚。我们用针对Fcα/μR的单克隆抗体检测了相关的肾细胞。其中Fcα/μR表达在原代培养的人系膜细胞(HMC)和近曲小管上皮细胞(PTEC)上。在正常人近曲小管细胞系HK-2上,同样检测到了Fcα/μR的蛋白表达。
我们的实验结果证明,表达在HK-2细胞上的Fcα/μR是一个功能性的IgA受体。用Fcα/μR的中和抗体可以特异性的阻断HK-2细胞与pIgA2和血清IgA的结合,并且阻止HK-2吞噬IgA/IgM免疫复合物。
免疫组化实验证明,Fcα/μR在IgAN病人的肾小球和肾小管内均表达增高。免疫双标实验揭示了IgA沉积和Fcα/μR表达的一致性。IgAN病人的血清IgA与HK-2结合能力增强,并且这种增强可以被抗Fcα/μR的中和抗体所抑制。HK-2和PTEC细胞孵育IgAN病人血清或纯化的血清IgA,可以导致Fcα/μR的明显上调。我们的实验结果表明,Fcα/μR在IgAN的发病机制中发挥了一定的作用。
Fcα/μR is the Fc receptor for Immunoglobulin A(IgA) and Immunoglobulin M(IgM). It is a single gene-family member encoded on Chromosome 1q32 near several other FcR genes.The mouse Fcα/μR is a high affinity receptor for IgM,intermediate affinity receptor with monolgA.The human Fcα/μR represents a typeⅠtransmembrane protein of 522 amino acids,3 extracellular domains containing one Ig-like domain(EC2).This EC2 domain contains a conserved motif present in the first EC loop of human,bovine, and murine pIgR,suggesting an ancestral link and function.
The mouse Fcα/μR is expressed on thymus,spleen,liver,kidney,small and large intestines,testis,and on hematopoietic cells,such as mature B cell and macrophages. Human Fcα/μR expressed in kidney,small intestine,and secondary lymphoid organs. In order to determine Fcα/μR precise role regarding the immune defense system,and distinguish its expression from plgR,we made monoclonal antibodies to Fcα/μR and pIgR.
The cDNAs of the extracellular region of human Fcα/μR and plgR were inserted into pET30a plasmid and expressed as inclusion bodies in Escherichia coli. The purified proteins were used to immunize Balb/c mice and to generate hybridomas. The monoclonal antibodies were characterized by ELISA,flow cytometry,Western blotting and immunochemical analysis.Tissue distribution analysis was done using human multiple tissue arrays.
Immunohistochemical analysis of human multiple tissues showed that the epithelial cells of renal tubules and human mesangium in glomeruli,some germinal center of spleen,lymphoid node and appendix,and some plasma cells in lamina propria of digestive tracts all express Fcα/μR.
The epithelial cells of small and large intestines or pulmonary alveolus and gall bladder were strongly stained by anti-pIgR mAbs.Other tissues,such as the fundic glands of stomach,mammary gland,testis,prostate and cardiac muscle had different degree of positive staining by both receptors.Brain was positive for Fcα/μR stain.
In brief,human Fcα/μR is wildly expressed on many tissues of human body.Compared to pIgR,Fcα/μR focus on these two kinds of tissue,the majority of lymphoid tissue located within the lining of the major tracts including respiratory,digestive and genitourinary tracts;and some epithelial cells of co-expressed with plgR,such as mammary gland and kidney.And the two tgA receptor can perform different function at the different lateral side of epithelial cells,transcytosis or receptor-mediating phagocytes. IgA nephropathy(IgAN) is the most common form of glomerulonephritis and is one of the principal causes of renal failure worldwide.The pathogenic mechanisms underlying IgAN are poorly understood.Using monoclonal antibodies specifically to Fcα/μR,we detected that the receptor could be expressed on primarily cultured human mesangial cells(HMC),human proximal tubular epithelial cells(PTEC) and HK-2 cells(a normal human proximal tubular cell line).The Fcα/μR expressed on HK-2 cells is a functional IgA receptor.The neutralizing antibody against Fcα/μR can block the binding of pIgA2 and serum IgA to HK-2 cells,and the phagocytosis for IgA/IgM immune complex.
Immunohistochemistry analysis on biopsy subjects showed that Fcα/μR expression was increased in both glomeruli and renal tubules from IgAN.Dual-labeling studies demonstrated that IgA deposits in IgAN patients were co-localized with Fcα/μR in the glomeruli and renal tubules.Compared to controls,avidity between IgA and Fcα/μR was increased in IgAN patients.The binding could be inhibited up to 80%by anti-Fcα/μR monoclonal antibodies.Sera or purified IgA from IgAN patients could significantly up-regulate Fcα/μR expression on HK-2 cells and PTEC.These data indicated that Fcα/μR might be involved in pathogenesis of IgAN.
为了确定Fcα/μR在免疫系统中的作用,区分Fcα/μR与pIgR的表达和功能,我们制备了抗Fcα/μR与pIgR的单克隆抗体。Fcα/μR与pIgR的膜外区分别构建到pET30a质粒中,在E.coli中表达。得到的包涵体蛋白经纯化后免疫Balb/c小鼠并进行细胞融合。产生的单克隆抗体经ELISA、流失细胞分析、Western blott和免疫组化分析鉴定。用确定的特异性抗体进行组织人多组织器官表达分析。
人多组织器官的免疫组化分析结果显示,Fcα/μR表达在肾小管上皮细胞和肾小球系膜区;胂、淋巴结和阑尾淋巴小结中的生发中心;还有散在于消化道粘膜固有层内的浆细胞上。而pIgR则主要集中在小肠、大肠、肺泡和胆囊的上皮细胞上。在其它组织,例如胃底腺、乳腺、睾丸、前列腺和心肌组织,Fcα/μR与pIgR均有不同程度的表达。Fcα/μR在脑组织表达阳性。
于pIgR的表达相比,Fcα/μR主要存在于两种组织。其一是位于呼吸、消化和泌尿生殖等通道下层的淋巴组织;另一种是也同时表达pIgR的上皮细胞,如乳腺和肾。然而即使是在这种情况下,这两个受体也会因表达在不同的侧面而执行不同的功能跨膜转运或者吞噬的功能。
IgA肾病(IgAN)是一种最常见的肾小球炎症,同时也是最主要的导致肾功能衰竭的原因。IgAN的发病机制还不清楚。我们用针对Fcα/μR的单克隆抗体检测了相关的肾细胞。其中Fcα/μR表达在原代培养的人系膜细胞(HMC)和近曲小管上皮细胞(PTEC)上。在正常人近曲小管细胞系HK-2上,同样检测到了Fcα/μR的蛋白表达。
我们的实验结果证明,表达在HK-2细胞上的Fcα/μR是一个功能性的IgA受体。用Fcα/μR的中和抗体可以特异性的阻断HK-2细胞与pIgA2和血清IgA的结合,并且阻止HK-2吞噬IgA/IgM免疫复合物。
免疫组化实验证明,Fcα/μR在IgAN病人的肾小球和肾小管内均表达增高。免疫双标实验揭示了IgA沉积和Fcα/μR表达的一致性。IgAN病人的血清IgA与HK-2结合能力增强,并且这种增强可以被抗Fcα/μR的中和抗体所抑制。HK-2和PTEC细胞孵育IgAN病人血清或纯化的血清IgA,可以导致Fcα/μR的明显上调。我们的实验结果表明,Fcα/μR在IgAN的发病机制中发挥了一定的作用。
Fcα/μR is the Fc receptor for Immunoglobulin A(IgA) and Immunoglobulin M(IgM). It is a single gene-family member encoded on Chromosome 1q32 near several other FcR genes.The mouse Fcα/μR is a high affinity receptor for IgM,intermediate affinity receptor with monolgA.The human Fcα/μR represents a typeⅠtransmembrane protein of 522 amino acids,3 extracellular domains containing one Ig-like domain(EC2).This EC2 domain contains a conserved motif present in the first EC loop of human,bovine, and murine pIgR,suggesting an ancestral link and function.
The mouse Fcα/μR is expressed on thymus,spleen,liver,kidney,small and large intestines,testis,and on hematopoietic cells,such as mature B cell and macrophages. Human Fcα/μR expressed in kidney,small intestine,and secondary lymphoid organs. In order to determine Fcα/μR precise role regarding the immune defense system,and distinguish its expression from plgR,we made monoclonal antibodies to Fcα/μR and pIgR.
The cDNAs of the extracellular region of human Fcα/μR and plgR were inserted into pET30a plasmid and expressed as inclusion bodies in Escherichia coli. The purified proteins were used to immunize Balb/c mice and to generate hybridomas. The monoclonal antibodies were characterized by ELISA,flow cytometry,Western blotting and immunochemical analysis.Tissue distribution analysis was done using human multiple tissue arrays.
Immunohistochemical analysis of human multiple tissues showed that the epithelial cells of renal tubules and human mesangium in glomeruli,some germinal center of spleen,lymphoid node and appendix,and some plasma cells in lamina propria of digestive tracts all express Fcα/μR.
The epithelial cells of small and large intestines or pulmonary alveolus and gall bladder were strongly stained by anti-pIgR mAbs.Other tissues,such as the fundic glands of stomach,mammary gland,testis,prostate and cardiac muscle had different degree of positive staining by both receptors.Brain was positive for Fcα/μR stain.
In brief,human Fcα/μR is wildly expressed on many tissues of human body.Compared to pIgR,Fcα/μR focus on these two kinds of tissue,the majority of lymphoid tissue located within the lining of the major tracts including respiratory,digestive and genitourinary tracts;and some epithelial cells of co-expressed with plgR,such as mammary gland and kidney.And the two tgA receptor can perform different function at the different lateral side of epithelial cells,transcytosis or receptor-mediating phagocytes. IgA nephropathy(IgAN) is the most common form of glomerulonephritis and is one of the principal causes of renal failure worldwide.The pathogenic mechanisms underlying IgAN are poorly understood.Using monoclonal antibodies specifically to Fcα/μR,we detected that the receptor could be expressed on primarily cultured human mesangial cells(HMC),human proximal tubular epithelial cells(PTEC) and HK-2 cells(a normal human proximal tubular cell line).The Fcα/μR expressed on HK-2 cells is a functional IgA receptor.The neutralizing antibody against Fcα/μR can block the binding of pIgA2 and serum IgA to HK-2 cells,and the phagocytosis for IgA/IgM immune complex.
Immunohistochemistry analysis on biopsy subjects showed that Fcα/μR expression was increased in both glomeruli and renal tubules from IgAN.Dual-labeling studies demonstrated that IgA deposits in IgAN patients were co-localized with Fcα/μR in the glomeruli and renal tubules.Compared to controls,avidity between IgA and Fcα/μR was increased in IgAN patients.The binding could be inhibited up to 80%by anti-Fcα/μR monoclonal antibodies.Sera or purified IgA from IgAN patients could significantly up-regulate Fcα/μR expression on HK-2 cells and PTEC.These data indicated that Fcα/μR might be involved in pathogenesis of IgAN.
引文
2 Restricted Expression(contributing more than half of the EST frequency)。
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