滤泡辅助性T细胞促进IgAN患儿IgA抗体类别转换及Gd-IgAl生成
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摘要
第一部分
IgAN患儿外周血Tfh检测及mlgA, IL-21,TGF β1的表达
目的探讨滤泡T辅细胞(Tfh)及其细胞因子IL-21,TGF β1和mIgA,在IgAN患儿(含原发和继发性IgA肾病即紫癜性肾炎,IgAN)外周血中的表达情况。方法IgA肾病患儿根据用药情况分为初治未用药组、免疫抑制治疗组,20例初治未用药IgAN患儿,34例免疫抑制剂治疗IgAN患儿纳入研究,22例正常儿童作对照。用流式细胞术检测外周血中Tfh(CXCR5+CD4+)在CD4+T淋巴细胞中的比例,淋巴细胞膜表面mIgA在CD19+细胞中的表达水平,采用RT-PCR检测淋巴细胞IgA基因CHα1和CHα2表达水平,elisa检测血清Tfh细胞分泌因子IL-21和TGF β1的表达。结果(1)未用药组患儿外周血Tfh为(19.87%±1.00%),免疫抑制治疗组为(13.87%±0.83%),正常对照组为(10.28%±0.68%)。统计检验表明,三者间均数差异均有显著意义(P<0.001)。(2)IgA肾病患儿CD19阳性淋巴细胞中mIgA表达(13.21±0.85)显著高于正常对照组(8.75±0.32), P<0.0001。 IgA肾病患儿外周血淋巴细胞IgA基因CHα1和CHα2表达高于对照患儿.(3)IgA肾病患儿血清细胞因子IL-21为102.2±9.5(pg/ml),明显高于正常儿童74.38±2.6(pg/ml), P＜0.05. TGFβ1为80392±2274(pg/ml),显著高于正常儿童29384±1828(pg/ml), P＜0.05。结论初步发现在IgAN患儿外周血中Tfh和细胞分泌因子以及mIgA的表达显著增多,提示Tfh可能在该疾病IgA产生中起作用,免疫抑制治疗可以明显降低Tfh在CD4+T淋巴细胞中的比例。
第二部分
IgAN患儿Tfh促进B细胞IgA抗体类别转换
目的体外探讨IgAN患儿Tfh诱导B细胞IgA抗体类别转换的作用。方法磁珠分选初治未用药IgAN患儿及正常儿童外周血中的Tfh和初始B细胞(Naive B cells, NB)共培养,通过real-time RT-PCR检测共培养体系基因TGF-β1、IL-21、Bcl-6、Blimp-1、 AID、IαlCαl、Iα2Cα2和Ir3Cr3以及普通RT-PCR检测IgM(CHμ), IgA(CHal,CHa2)和IgG(CHr)基因动态表达情况。ELISA检测共培养上清液IL-21, TGF-β1和IgA在不同时间点的表达量,流式细胞术检测共培养淋巴细胞mIgA, mIgM在CD19+淋巴细胞中的表达变化。激光共聚焦显微镜观察共培养细胞及单纯NB分别添加Tfh细胞因子TGF-β1、IL-21、IL-4后mIgA的表达。结果IgAN患儿组TGF-β1, IL-21, Bcl-6, Blimp-1, AID, Ia2Ca2, IalCal基因表达均在第6小时最强,并随时间减弱；抗体类别转换产物CHμ、CHa1、CHa2、 CHγ在第6小时表达最强,并随时间表达逐渐减少,对照组基因无时序表达差异。患者组和对照组共培养的细胞mIgA、IL-21, TGF-β1及IgA表达随时间而增多,在第9天以后与对照组相比分别为8.16±0.07vs.5.1±0.77(%),15.17±1.6vs.5.5±1.3(pg/ml),1059±64.86vs.528±36.05(pg/ml),4.2±1.1vs.1.8±0.9(pg/ml)(P均<0.05)。共聚焦结果显示Tfh细胞因子TGF-β1、IL-21、IL-4促进NB细胞IgA表达；Tfh与NB共培养显著促使IgA表达。结论体外实验显示IgAN患儿Tfh细胞有促进NB细胞发生IgA抗体类别转换,促其向分化为IgA分泌细胞分化的作用,Tfh细胞分泌的细胞因子IL-21, TGF-β1, IL-4等可能参与这一诱生过程,因此,Tfh在IgAN发病中起重要作用。
第三部分
IgAN患儿Tfh及其细胞因子诱导B细胞分泌半乳糖缺乏的IgA1
目的观察IgA肾病患儿体内外半乳糖缺乏的IgAl的表达情况,探讨Tfh细胞及其细胞因子致IgA缺陷的可能机制。方法收集IgAN患儿和正常儿童外周血,磁珠分选IgA肾病患儿外周血NB和Tfh细胞,elisa测定NB和Tfh共培养组,单独NB细胞加IL-21或TGF-β1或IL-4等Tfh细胞因子培养组12天培养上清液及IgAN肾病患儿和正常儿童外周血血清IgA和半乳糖缺乏的IgAl(galactose-deficient IgAl, Gd-IgAl)水平。结果IgAN患儿外周血血清Gd-IgAl水平为2573±540.2(U/ml),显著高于正常儿童1021±132.5(U/ml), P=0.03。IgAN患儿血清IgA为2881±611(ug/ml),稍高于正常儿童2337±428(ug/m1),但无统计学差异(p=0.47)。IgAN患儿NB和Tfh共培养细胞上清液IgA水平4.82±0.39(ug/ml),显著高于NB与IL-21培养组2.28±0.26(ug/ml),NB与TGF-β1培养组2.4±0.27(ug/ml), NB与工L-4培养组2.02±0.32(ug/ml),P值均<0.001。IgA肾病患儿NB和Tfh共培养组Gd-IgAl与IgA比值为4.04±0.32(U/ug),显著低于NB与IL-21培养组7.73±1.31(U/ug),NB与TGF-B1培养组7.56±1.13(U/ug), NB与IL-4培养组8.64±1.23(U/ug),P值均<0.05.结论IgA肾病患儿存在明显的IgAl分子半乳糖缺陷,Tfh细胞及相关细胞因子在诱生B细胞产生半乳糖缺陷IgAl过程中起关健的调节作用,可能参与IgAN发病。
Part Ⅰ. Tfh and Expression of Tfh-related Cytokines of IL-21, TGFβ1and mIgA in Peripheral Blood in IgAN Patients
Objective To investigate Tfh and the expression of Tfh-related cytokines of IL-21and TGF β1and mIgA from peripheral blood in IgAN patients. Methods Tfh in CD4+lymphocytes and mIgA in CD19+lymphocytes from peripheral blood were quantitated by flow cytometry in immunosuppressive agent-treated or untreated IgAN children and healthy controls. Meanwhile, expressions of CHal, CHa2(IgA gene) were determined by RT-PCR and expression of Tfh-related cytokines including IL-21and TGFβ1were measured in plasma of immunosuppressive agent-untreated IgAN children and healthy controls by Elisa. Results Tfh proportion were (19.87±1.00)%in20untreated IgAN,(13.87±0.83)%in34immunosuppressive agent-treated IgAN and (10.28±0.68)%in22controls and all p values between each two groups<0.001. mlgA ratio in CD19+B cells was (13.21±0.85)%in IgAN but (8.75±0.32)%, p<0.0001. Tfh-related cytokines IL-21and TGFβ1were (102.2±9.5) pg/ml and (80392±2274) pg/ml in immunosuppressive agent-untreated IgAN children, both of them were significantly higher than controls with (74.38±2.6) pg/ml and (29384±1828) pg/ml, P values<0.05. Conclusion It was found that the expression of mIgA, Tfh and Tfh-related cytokines IL-21and TGF β1from peripheral blood significantly upregulated in children with IgAN which indicating enhanced IgA class switching may occur in IgAN patients and immunosuppressive agent treatment showed their effects on lowering Tfh quantitation in IgAN.
Part II. T Follicular Helper Cells Enhance IgA Class Switching of B cells in Children with IgAN
Objective To investigate if T follicular helper cells(Tfh) enhance IgA class switching in B cells of children with IgAN. Methods Magnetic bead was performed to sort Tfh cells. and naive B cells from untreated IgAN and healthy children and then co-cultured Tfh cells with naive B cells in each group. Genes expression of TGF-β1、IL-21Bcl-6. PRDM-1, AID. Ir3Cr3, Iα1Cα1, Ia2Ca2were determined by real-time RT-PCR and IgA class switching products of CHαl、 CHα2genes were detected by conventional RT-PCR and secretory expression of IL-21, TGF-β1, IgA were measured in co-cultured supernatants by Elisa. The isotype changes of immunoglobulins on CD19+B cells were detected by flow cytometry and confocal microscopy was used to determine IgA expression in Tfh and Naive B co-cultured cells and isolated Naive B cells cultured with cytokines of IL-21or TGF-β1or IL-4. Results CHal and CHa2expression were most significant at the6th hour, accompanied with similar trends in expression of Ir3Cr3, IalCαl, Ia2Ca2, TGF-β1, IL-21, Bcl-6, PRDM-1and AID genes, all of them declined over time thereafter. At the9th day, the proteins expressions of mIgA, IL-21, TGF-β1and IgA were significantly increased with declined mIgM in IgAN than in control (all P values<0.05). Confocal microscope showed IgA expressions were higher in Tfh and Naive-B co-cultured cells as well as naive B cells treated with TGF-β1or IL-21or IL-4than cytokine-untreated naive B cells. Conclusions This study first demonstrated that Tfh cells enhance IgA class switching in B cells of children with IgAN, probably through upregulated expression of IL-21and TGFβ1.
Part Ⅲ. Tfh Cells and Tfh Related Cytokines Promote the Secretion of Galactose-deficient IgAl from B cells in Children with IgAN
Objective To explore the galactose-deficient IgAl(Gd-IgAl) secretion from B cells induced by Tfh or Tfh related-cytokines in children with IgA nephropathy Methods Magnetic bead was performed to sort peripheral blood Naive B cells (CD27"IgD+) and follicular T helper cells(CD4+CXCR5+) in IgA nephropathy children and healthy controls and co-cultured them. Meanwhile, Naive B cells were cultured respectively with IL-21, TGF-β1or IL-4. Supernatant was collected to detect the excretion of IgA and galactose-deficient IgAl(Gd-IgAl) by elisa. Results Excretion of IgA and level of Gd-IgAl were2881±611(ug/ml),2573±540.2(U/ml) in children with IgA, and2337±428(ug/ml),1021±132.5(U/ml) in control group, only Gd-IgAl level showed significant difference between IgA children and control group(p=0.03). The level of IgA in supernatant of co-cultured Tfh and NB cells from children with IgA were much higher than those of NB with IL-21or NB with TGF-β1or NB with IL-4or control group[4.82±0.39(ug/ml)vs.2.28±0.26(ug/ml),2.4±0.27(ug/ml),2.02±0.32(ug/ml), all P values＜0.001. In addition, the ratios of Gd-IgAl to IgA in co-cultured Tfh and NB cells from IgA nephropathy children was4.04±0.32(U/ug), which was much lower than NB with IL-21of7.73±1.31(U/ug), NB with TGF-β1of7.56±1.13(U/ug) and NB with IL-4of8.64±1.23(U/ug), all P values＜0.05. Results Tfh cells and Tfh-related cytokines may play important roles in secretionof Gd-IgAl, and participate in the pathogenesis of IgA nephropathy.
IgAN患儿外周血Tfh检测及mlgA, IL-21,TGF β1的表达
目的探讨滤泡T辅细胞(Tfh)及其细胞因子IL-21,TGF β1和mIgA,在IgAN患儿(含原发和继发性IgA肾病即紫癜性肾炎,IgAN)外周血中的表达情况。方法IgA肾病患儿根据用药情况分为初治未用药组、免疫抑制治疗组,20例初治未用药IgAN患儿,34例免疫抑制剂治疗IgAN患儿纳入研究,22例正常儿童作对照。用流式细胞术检测外周血中Tfh(CXCR5+CD4+)在CD4+T淋巴细胞中的比例,淋巴细胞膜表面mIgA在CD19+细胞中的表达水平,采用RT-PCR检测淋巴细胞IgA基因CHα1和CHα2表达水平,elisa检测血清Tfh细胞分泌因子IL-21和TGF β1的表达。结果(1)未用药组患儿外周血Tfh为(19.87%±1.00%),免疫抑制治疗组为(13.87%±0.83%),正常对照组为(10.28%±0.68%)。统计检验表明,三者间均数差异均有显著意义(P<0.001)。(2)IgA肾病患儿CD19阳性淋巴细胞中mIgA表达(13.21±0.85)显著高于正常对照组(8.75±0.32), P<0.0001。 IgA肾病患儿外周血淋巴细胞IgA基因CHα1和CHα2表达高于对照患儿.(3)IgA肾病患儿血清细胞因子IL-21为102.2±9.5(pg/ml),明显高于正常儿童74.38±2.6(pg/ml), P＜0.05. TGFβ1为80392±2274(pg/ml),显著高于正常儿童29384±1828(pg/ml), P＜0.05。结论初步发现在IgAN患儿外周血中Tfh和细胞分泌因子以及mIgA的表达显著增多,提示Tfh可能在该疾病IgA产生中起作用,免疫抑制治疗可以明显降低Tfh在CD4+T淋巴细胞中的比例。
第二部分
IgAN患儿Tfh促进B细胞IgA抗体类别转换
目的体外探讨IgAN患儿Tfh诱导B细胞IgA抗体类别转换的作用。方法磁珠分选初治未用药IgAN患儿及正常儿童外周血中的Tfh和初始B细胞(Naive B cells, NB)共培养,通过real-time RT-PCR检测共培养体系基因TGF-β1、IL-21、Bcl-6、Blimp-1、 AID、IαlCαl、Iα2Cα2和Ir3Cr3以及普通RT-PCR检测IgM(CHμ), IgA(CHal,CHa2)和IgG(CHr)基因动态表达情况。ELISA检测共培养上清液IL-21, TGF-β1和IgA在不同时间点的表达量,流式细胞术检测共培养淋巴细胞mIgA, mIgM在CD19+淋巴细胞中的表达变化。激光共聚焦显微镜观察共培养细胞及单纯NB分别添加Tfh细胞因子TGF-β1、IL-21、IL-4后mIgA的表达。结果IgAN患儿组TGF-β1, IL-21, Bcl-6, Blimp-1, AID, Ia2Ca2, IalCal基因表达均在第6小时最强,并随时间减弱；抗体类别转换产物CHμ、CHa1、CHa2、 CHγ在第6小时表达最强,并随时间表达逐渐减少,对照组基因无时序表达差异。患者组和对照组共培养的细胞mIgA、IL-21, TGF-β1及IgA表达随时间而增多,在第9天以后与对照组相比分别为8.16±0.07vs.5.1±0.77(%),15.17±1.6vs.5.5±1.3(pg/ml),1059±64.86vs.528±36.05(pg/ml),4.2±1.1vs.1.8±0.9(pg/ml)(P均<0.05)。共聚焦结果显示Tfh细胞因子TGF-β1、IL-21、IL-4促进NB细胞IgA表达；Tfh与NB共培养显著促使IgA表达。结论体外实验显示IgAN患儿Tfh细胞有促进NB细胞发生IgA抗体类别转换,促其向分化为IgA分泌细胞分化的作用,Tfh细胞分泌的细胞因子IL-21, TGF-β1, IL-4等可能参与这一诱生过程,因此,Tfh在IgAN发病中起重要作用。
第三部分
IgAN患儿Tfh及其细胞因子诱导B细胞分泌半乳糖缺乏的IgA1
目的观察IgA肾病患儿体内外半乳糖缺乏的IgAl的表达情况,探讨Tfh细胞及其细胞因子致IgA缺陷的可能机制。方法收集IgAN患儿和正常儿童外周血,磁珠分选IgA肾病患儿外周血NB和Tfh细胞,elisa测定NB和Tfh共培养组,单独NB细胞加IL-21或TGF-β1或IL-4等Tfh细胞因子培养组12天培养上清液及IgAN肾病患儿和正常儿童外周血血清IgA和半乳糖缺乏的IgAl(galactose-deficient IgAl, Gd-IgAl)水平。结果IgAN患儿外周血血清Gd-IgAl水平为2573±540.2(U/ml),显著高于正常儿童1021±132.5(U/ml), P=0.03。IgAN患儿血清IgA为2881±611(ug/ml),稍高于正常儿童2337±428(ug/m1),但无统计学差异(p=0.47)。IgAN患儿NB和Tfh共培养细胞上清液IgA水平4.82±0.39(ug/ml),显著高于NB与IL-21培养组2.28±0.26(ug/ml),NB与TGF-β1培养组2.4±0.27(ug/ml), NB与工L-4培养组2.02±0.32(ug/ml),P值均<0.001。IgA肾病患儿NB和Tfh共培养组Gd-IgAl与IgA比值为4.04±0.32(U/ug),显著低于NB与IL-21培养组7.73±1.31(U/ug),NB与TGF-B1培养组7.56±1.13(U/ug), NB与IL-4培养组8.64±1.23(U/ug),P值均<0.05.结论IgA肾病患儿存在明显的IgAl分子半乳糖缺陷,Tfh细胞及相关细胞因子在诱生B细胞产生半乳糖缺陷IgAl过程中起关健的调节作用,可能参与IgAN发病。
Part Ⅰ. Tfh and Expression of Tfh-related Cytokines of IL-21, TGFβ1and mIgA in Peripheral Blood in IgAN Patients
Objective To investigate Tfh and the expression of Tfh-related cytokines of IL-21and TGF β1and mIgA from peripheral blood in IgAN patients. Methods Tfh in CD4+lymphocytes and mIgA in CD19+lymphocytes from peripheral blood were quantitated by flow cytometry in immunosuppressive agent-treated or untreated IgAN children and healthy controls. Meanwhile, expressions of CHal, CHa2(IgA gene) were determined by RT-PCR and expression of Tfh-related cytokines including IL-21and TGFβ1were measured in plasma of immunosuppressive agent-untreated IgAN children and healthy controls by Elisa. Results Tfh proportion were (19.87±1.00)%in20untreated IgAN,(13.87±0.83)%in34immunosuppressive agent-treated IgAN and (10.28±0.68)%in22controls and all p values between each two groups<0.001. mlgA ratio in CD19+B cells was (13.21±0.85)%in IgAN but (8.75±0.32)%, p<0.0001. Tfh-related cytokines IL-21and TGFβ1were (102.2±9.5) pg/ml and (80392±2274) pg/ml in immunosuppressive agent-untreated IgAN children, both of them were significantly higher than controls with (74.38±2.6) pg/ml and (29384±1828) pg/ml, P values<0.05. Conclusion It was found that the expression of mIgA, Tfh and Tfh-related cytokines IL-21and TGF β1from peripheral blood significantly upregulated in children with IgAN which indicating enhanced IgA class switching may occur in IgAN patients and immunosuppressive agent treatment showed their effects on lowering Tfh quantitation in IgAN.
Part II. T Follicular Helper Cells Enhance IgA Class Switching of B cells in Children with IgAN
Objective To investigate if T follicular helper cells(Tfh) enhance IgA class switching in B cells of children with IgAN. Methods Magnetic bead was performed to sort Tfh cells. and naive B cells from untreated IgAN and healthy children and then co-cultured Tfh cells with naive B cells in each group. Genes expression of TGF-β1、IL-21Bcl-6. PRDM-1, AID. Ir3Cr3, Iα1Cα1, Ia2Ca2were determined by real-time RT-PCR and IgA class switching products of CHαl、 CHα2genes were detected by conventional RT-PCR and secretory expression of IL-21, TGF-β1, IgA were measured in co-cultured supernatants by Elisa. The isotype changes of immunoglobulins on CD19+B cells were detected by flow cytometry and confocal microscopy was used to determine IgA expression in Tfh and Naive B co-cultured cells and isolated Naive B cells cultured with cytokines of IL-21or TGF-β1or IL-4. Results CHal and CHa2expression were most significant at the6th hour, accompanied with similar trends in expression of Ir3Cr3, IalCαl, Ia2Ca2, TGF-β1, IL-21, Bcl-6, PRDM-1and AID genes, all of them declined over time thereafter. At the9th day, the proteins expressions of mIgA, IL-21, TGF-β1and IgA were significantly increased with declined mIgM in IgAN than in control (all P values<0.05). Confocal microscope showed IgA expressions were higher in Tfh and Naive-B co-cultured cells as well as naive B cells treated with TGF-β1or IL-21or IL-4than cytokine-untreated naive B cells. Conclusions This study first demonstrated that Tfh cells enhance IgA class switching in B cells of children with IgAN, probably through upregulated expression of IL-21and TGFβ1.
Part Ⅲ. Tfh Cells and Tfh Related Cytokines Promote the Secretion of Galactose-deficient IgAl from B cells in Children with IgAN
Objective To explore the galactose-deficient IgAl(Gd-IgAl) secretion from B cells induced by Tfh or Tfh related-cytokines in children with IgA nephropathy Methods Magnetic bead was performed to sort peripheral blood Naive B cells (CD27"IgD+) and follicular T helper cells(CD4+CXCR5+) in IgA nephropathy children and healthy controls and co-cultured them. Meanwhile, Naive B cells were cultured respectively with IL-21, TGF-β1or IL-4. Supernatant was collected to detect the excretion of IgA and galactose-deficient IgAl(Gd-IgAl) by elisa. Results Excretion of IgA and level of Gd-IgAl were2881±611(ug/ml),2573±540.2(U/ml) in children with IgA, and2337±428(ug/ml),1021±132.5(U/ml) in control group, only Gd-IgAl level showed significant difference between IgA children and control group(p=0.03). The level of IgA in supernatant of co-cultured Tfh and NB cells from children with IgA were much higher than those of NB with IL-21or NB with TGF-β1or NB with IL-4or control group[4.82±0.39(ug/ml)vs.2.28±0.26(ug/ml),2.4±0.27(ug/ml),2.02±0.32(ug/ml), all P values＜0.001. In addition, the ratios of Gd-IgAl to IgA in co-cultured Tfh and NB cells from IgA nephropathy children was4.04±0.32(U/ug), which was much lower than NB with IL-21of7.73±1.31(U/ug), NB with TGF-β1of7.56±1.13(U/ug) and NB with IL-4of8.64±1.23(U/ug), all P values＜0.05. Results Tfh cells and Tfh-related cytokines may play important roles in secretionof Gd-IgAl, and participate in the pathogenesis of IgA nephropathy.
引文
l.Feehally J, Farrall M, Boland A, et al. HLA has strongest association with IgA nephropathy in genome-wide analysis. J Am Soc Nephrol,2010,21(10):1791-1797.
2.Gharavi AG, Kiryluk K, Choi M, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet,2011,43(4):321-327.
3.Paterson AD, Liu XQ, Wang K, et al. Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36. J Am Soc Nephrol,2007,18(8):2408-2415.
4.Nagareda CS. Antibody formation and the effect of x-radiation on circulating antibody levels in the hypophysectomized rat. J Immunol,1954,73(2):88-94.
5. Linterman MA, Vinuesa CG. Signals that influence T follicular helper cell differentiation and function. Semin Immunopathol,2010,32(2):183—196.
6. Velardi A, Mingafi MC, Moretta L, et al. Functional analysis of cloned germinal center CD4+cells with natural killer cell-related features. Divergence from typical T helper cell. J Immunol,1986,137(9):2808-2813.
7. Schaerli P, Willimannk, Lang AB, et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med,2000,192(11): 1553—1562.
8. Benson MJ, Erickson LD, Gleeson MW, et al. Affinity of antigen encounter and other early B-cell signals determine B-cell fate. Curr Opin Immunol,2007,19(3):275-280.
9.Allen CD, Okada T, Tang HL, et al. Imaging of germinal center selection events during affinity maturation. Science,2007,315:528—31.
lO.MacLennan IC, Liu YJ. Maturation and dispersal of B-cellclones during T celldependent antibody responses. Immunol Rev,1992,126:143—61.
ll.Kelsoe G. The germinal center reaction. Immunol. Today,1995,16:324-6.
12.Liu YJ, Malisan F, de Bouteiller O, et al. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity,1996, 4:241-250
13. Haynes NM, Allen CDC, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J Immunol 2007; 179: 5099-5108.
14. Junt T, Fink K, Forster R, Senn B, Lipp M, Muramatsu M et al. CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses. J Immunol 2005; 175:7109-7116.
15.Ruprecht, C. R., Lanzavecchia, A. (2006) Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur. J. Immunol.36,810-816.
16. Huggins, J., Pellegrin, T, Felgar, R. E., Wei, C., Brown, M., Zheng, B., Milner, E. C., Bernstein, S. H., Sanz, I., Zand, M. S. (2007) CpG DNA
activation and plasma-cell differentiation of.CD27—naive human B cells. Blood 109, 1611-1619.
17. Jiang, W., Lederman, M. M., Harding, C. V., Rodriguez, B., Mohner, R. J., Sieg, S. F. (2007) TLR9 stimulation drives nalve B cells to proliferateand to attain enhanced antigen presenting function. Eur. J. Immunol.37,2205-2213.
18. Muramatsu, M., Sankaranand, V.S., Anant, S., Sugai, M., Kinoshita, K., Davidson, N.O., and Honjo, T. (1999). Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol Chem.274,18470-18476.
19. Muto, T., Muramatsu, M., Taniwaki, M., Kinoshita, K., and Honjo, T. (2000). Isolation, tissue distribution and chromosomal localization AID of Genomics 68,85-88.
20. Ta, V.T., Nagaoka, H., Catalan, N., Durandy, A., Fischer, A., Imai, K., Nonoyama, S., Tashiro, J., Ikegawa, M., Ito, S., et al. (2003). AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat. Immunol.4,843-848.
21. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. (2002). The AID enzyme induces class switch recombine tion in fibroblasts. Nature 416, 340-345.
22. Yoshikawa, K., Okazaki, I.M., Eto, T., Kinoshita, K., Muramatsu, M.,Nagaoka, H., and Honjo, T. (2002). AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296,2033-2036.
23. Martin, A., Bardwell, P.D., Woo, C.J., Fan, M., Shulman, M.J., and Scharff, M.D. (2002). Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415,802-806.
24. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. (2002). The AID enzyme induces class switch recombine tion in fibroblasts. Nature 416, 340-345
25. Arakawa, H., and Buerstedde, J.M. (2004). Immunoglobulin gene conversion:insights from bursal B cells and the DT40 cell line. Dev. Dyn.229,458-464.
26. Linteman MA, Beaton L, Yu D, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med,2010,207(2):353-363.
27. Kassiotis G, O Garra A. Establishing the follicular helper identity. Immunity,2009, 31(3):450-452.
28. King IL, Mohrs M. IL-4 producing CD4+T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med,2009,206:1001—1007.
29. Rodrtguez Pinilla SM, Roncador G, et-al. Primary cutaneous CD4+small/ medium-sized pleomorphie T-cell lymphoma expresses follicular T-cell markers. Am J Surg Pathol,2009,33(1):81-90.
30. Tsuji M, Komatsu N, Kawamoto S, Suzuki K, Kanagawa O, Honjo T, Hori S, Fagarasan S. Preferential generation of follicular B helper T cells from Foxp3+T cells in gut Peyer's patches. Science.2009 Mar 13;323(5920):1488-92.
31. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bc26 mediates the development of T follicular helper cells. Science.2009 Aug 21;325(5943):1001-5.
32. Johnston RJ,Poholek AC,DiToro D,Yusuf I,Eto D, Barnett B, Dent AL, Craft J, Crotty S.Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science.2009 Aug 21;325(5943):1006-10.
33. Bryant VL, Ma CS,Avery DT, Li Y, Good KL, Corcoran LM,de Waal Malefyt R, Tangye SG. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells:predominant role of IL-21 produced by CXCR5+T follicular helper cells. J Immunol.2007 Dec 15; 179(12):8180-90.
34. Seo GY, Youn J, Kim PH. IL-21 ensures TGF-beta 1-induced IgA isotype expression in mouse Peyer's patches. J Leukoc Biol.2009 May;85(5):744-50.
1. Haynes NM, Allen CDC, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J Immunol 2007; 179: 5099-5108.
2. Junt T, Fink K, Forster R, Senn B, Lipp M, Muramatsu M et al. CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses. J Immunol 2005; 175:7109-7116.
3. inuesa CG, Tangye SG, Moser B, et al. Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol,2005,5(11):853-865.
4. Hardtke S, Ohl L, Forster R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood,2005,106(6):1924-1931.
5. Patakas A, Platt AM, Butcher JP, et al. Putative existence of reciprocal dialogue between Tfh and B cells and its impact on infectious and autoimmune disease. Immunol Lett, 2011,138(1):38-46.
6. Hu YL, Metz DP, Chung J, et al. B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. J Immunol,2009,182(3):1421-1428.
7. Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM et al. A RINGtype
ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 2005; 435:452-458.
8. Linterman MA, Vinuesa CG. Signals that influence T follicular helper cell differentiation and function. Semin Immunopathol 2010; in press.
9.Deenick EK, Ma CS. The regulation and role of T follicular helper cells in immunity. Immunology,2011,134(4):361-367.
10. Conley ME, Dobbs AK, Farmer DM, et al. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol.2009,27:199-227.
11. Elgueta R, Benson MJ, de Vries VC, et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev,2009, 229(1):152-172.
12. Ma CS, Avery DT, Chan A, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood,2012,8. [Epub ahead of print]
13. Kroenke MA, Eto D, Locci M, et al. Bcl-6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol.2012 Mar 16. [Epub ahead of print]
14. M. Colleen Hastings, Zina Moldoveanu, Bruce A. Julian, Jan Novak, John T. Sanders, Kim R. McGlothan, Ali G. Gharavi, Robert J. Wyatt. Galactose-Deficient IgAl in African Americans with IgA Nephropathy:Serum Levels and Heritability. Clin J Am SocNephrol 2010,5:2069-2074.
15. Z Moldoveanu, RJ Wyatt, JY Lee, M Tomana, BA Julian, J Mestecky, W-Q Huang, SR Anreddy, S Hall, MC Hastings, KK Lau, WJ Cook, J Novak. Patients with IgA nephropathy have increased serum galactose-deficient IgAl levels. Kidney International 2007,71;1148-1154.
16. Novak J, Renfrow MB, Gharavi AG, Julian BA.Pathogenesis of immunoglobulin A nephropathy. Curr Opin Nephrol Hypertens.2013 Mar 18. [Epub ahead of print}
17. Roza I Nurieva and Yeonseok Chung. Understanding the development and function of T follicular helper cells. Cellular & Molecular Immunology (2010) 7,190-197.
18. Sawalha AH, Kaufman KM, Kelly JA, Adler AJ, Aberle T, Kilpatrick J et al. Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus. Ann Rheum Dis 2008; 67:458-61.
19. Odegard JM, Marks BR, DiPlacido LD, Poholek AC, Kono DH, Dong C et al. ICOS dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med 2008; 205:2873-2886.
20. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006;24:99—146. [PubMed:16551245]
21.Corthay A. How do regulatory T cells work? Scand J Immunol,2009,70(4):326—336.
22. Martin, A., Bardwell, P.D., Woo, C.J., Fan, M., Shulman, M.J., and Scharff, M.D. (2002). Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415,802-806
23. Junt T, Fink K, Forster R, Senn B, Lipp M, Muramatsu M et al. CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses. J Immunol 2005; 175:7109-7116.
1. Ebert LM, Hom MP, Lang AB, et al. B cells alter the phenotype and function of follicular homing CXCR5 T cells. Eur J Imm unol,2004,34:3562-71.
2. Qi H, Cannons JL, Klauschen F, et al. SAP-controlled T-B cell interactions underlie germinal centre formation. Namre,2008,455:764—9.
3. Fazilleau N, McHeyzer-Williams LJ, Rosen H, et al. The function of follicular helper Tcells is regulated by the strength of T cell antigen receptor binding. Namre Immunol, 2009,10:375—84.
4. Nurieva RI, Chung Y, Hwang D, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1,2, or 17 cell lineages. Immunity,2008,29:138—49.
5. Yu D, Rao S, Tsai LM, et al. The transcriptional repressor BCL--6 directs T follicular helper cell lineage comm itment. Immunity.2009.31:457—68
6. Johnston RJ, Poholek AC, DiToro D, et al. Bcl-6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science,2009,325: 1006—10.
7.Nurieva RI, Chung Y, Martinez GJ, et al. Bc16 mediates the development of T follicular helper cells. Science,2009,325:1001—5.
8.Grimbacher B, Hutlof A, Schlesier M, et al. Homozygous loss of IC0S is associated with adult—onset common variable immunodeficiency. Nat Immunol,2003,4:261—8.
9.Bossaller L, Burger J, Draeger R, et al. ICOS deficiency is associated with a severe reduction of CXCR5 +CD4+ germinal center Th cells. J Immunol,2006,177: 4927—32.
10. Akiba H, Takeda K, Kojima Y, et al. The role of ICOS in the CXCR5 follicular B helper T cel maintenance in vivo. J Immunol,2005,175:2340—48.
11. Mak TW, Shahinian A, Yoshinaga SK, et al. Costimulation through the inducible costimulator ligand is essential for bothT helper and B cell functions in T cell-dependent B cell responses. Nat Immuno 1,2003,4:765—72.
12.Hams E, McCarron MJ, Amu S, et al. Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells. J Immunol,2011,186(10):5648-5655.
13.Kajita M, Okazawa T, Ikeda M, et al. Efficient affinity maturation of antibodies in an engineered chicken B cell line DT40-SW by increasing point mutation. J Biosci Bioeng, 2010,110(3):351-358.
14.Deenick EK, Ma CS. The regulation and role of T follicular helper cells in immunity. Immunology,2011,134(4):361-367.
15. Tsuji M, Komatsu N, Kawamoto S, Suzuki K, Kanagawa O, Honjo T, Hori S, Fagarasan S. Preferential generation of follicular B helper T cells from Foxp3+T cells in gut Peyer's patches. Science.2009 Mar 13;323(5920):1488-92.
16. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bc16 mediates the development of T follicular helper cells. Science.2009 Aug 21;325(5943):1001-5.
17. Johnston RJ,Poholek AC, DiToro D,Yusuf I,Eto D,Barnett B,Dent AL, Craft J, Crotty S.Bc16 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science.2009 Aug 21;325(5943):1006-10.
18. Bryant VL,Ma CS,Avery DT, Li Y, Good KL, Corcoran LM,de Waal Malefyt R, Tangye SG. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells:predominant role of IL-21 produced by CXCR5+T follicular helper cells. J Immunol.2007 Dec 15; 179(12):8180-90.
19. Seo GY, Youn J, Kim PH. IL-21 ensures TGF-beta 1-induced IgA isotype expression in mouse Peyer's patches. J Leukoc Biol.2009 May;85(5):744-50.
20. Ozaki, K., K. Kikly, D. Michalovich, P. R. Young, and W. J. Leonard. Cloning of a type I cytokine receptor most related to the IL-2 receptor βkhain. Proc. Natl. Acad. Sci. 2000.97:11439.
21. Parrish-Novak, J., S. R. Dillon, A. Nelson, A. Hammond, C. Sprecher, J. A. Gross, J. Johnston, K. Madden, W. Xu, J. West, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature,2000,408:57.
22. Leonard, W. J. Cytokines and immunodeficiency diseases. Nat. Rev. Immunol.2001, 1:200.
23. Asao, H., H. C. Okuyama, S. Kumaki, N. Ishii, S. Tsuchiya, D. Foster, and K. Sugamura.. The common γ_chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol.2001,167:1.
24. Ozaki, K., R. Spolski, C. G. Feng, J. Cheng, A. Sher, C. Liu, P. L. Schwarzberg, and W. J. Leonard. A critical role for IL-21 in regulating immunoglobulin production. Science, 2002,298:1630.
25. Suto, A., H. Nakajima, K. Hirose, K. Suzuki, S. Kagami, Y. Seto, A. Hoshimoto, Y. Saito, D. C. Foster, and I. Iwamoto. Interleukin 21 prevents antigeninduced IgE production by inhibiting germ line C_ transcription of IL-4-stimulated B cells. Blood, 2002,100:4565.
26. Mehta, D. S., A. L. Wurster, M. J. Whitters, D. A. Young, M. Collins, and M. J. Grusby. IL-21 induces the apoptosis of resting and activated primary B cells. J. Immunol.2003, 170:4111.
27.Ruprecht, C. R., Lanzavecchia, A. (2006) Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur. J. Immunol.36,810-816.
28. Huggins, J., Pellegrin, T., Felgar, R. E., Wei, C., Brown, M., Zheng, B., Milner, E. C., Bernstein, S. H., Sanz, I., Zand, M. S. (2007) CpG DNA
29. Katsutoshi Ozaki, Rosanne Spolski, Rachel Ettinger, et al. Regulation of B Cell Differentiation and Plasma Cell Generation by IL-21, a Novel Inducer of Blimp-1 and Bcl-6. J Immunol 2004;173;5361-5371
30. Linteman MA, Beaton L, Yu D, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med,2010,207(2):353-363.
31. Kassiotis G, O Garra A. Establishing the follicular helper identity. Immunity,2009, 31(3):450-452.
32. King IL, Mohrs M. IL-4 producing CD4+T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med,2009,206:1001—1007.
33. Rodrtguez Pinilla SM, Roncador G> et-al. Primary cutaneous CD4+ small medium-sized pleomorphie T-cell lymphoma expresses follicular T-cell markers. Am J Surg Pathol,2009,33(1):81-90.
34. Chattha KS, Firth MA, Hodgins DC, et al. Age related variation in expression of CD21 and CD32 on bovine lymphocytes:a cross-sectional study. Vet Immunol Immunopathol, 2009,130(1-2):70-78.
35. Corfe SA, Paige CJ. The many roles of IL-7 in B cell development; Mediator of survival, proliferation and differentiation. Semin Immunol,2012 Mar 13. [Epub ahead of print]
36. Muramatsu, M., Sankaranand, V.S., Anant, S., Sugai, M., Kinoshita, K., Davidson, N.O., and Honjo, T. (1999). Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol Chem.274,18470-18476.
37. Muto, T., Muramatsu, M., Taniwaki, M., Kinoshita, K., and Honjo, T. (2000). Isolation, tissue distribution and chromosomal localization AID of Genomics 68,85—88.
38. Ta, V.T., Nagaoka, H., Catalan, N., Durandy, A., Fischer, A., Imai, K., Nonoyama, S., Tashiro, J., Ikegawa, M., Ito, S., et al. (2003). AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat. Immunol.4,843-848.
39. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. (2002). The AID enzyme induces class switch recombine tion in fibroblasts. Nature 416, 340-345.
40. Yoshikawa, K., Okazaki, I.M., Eto, T., Kinoshita, K., Muramatsu, M.,Nagaoka, H., and Honjo, T. (2002). AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296,2033-2036.
41. Martin, A., Bardwell, P.D., Woo, C.J., Fan, M., Shulman, M.J., and Scharff, M.D. (2002). Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415,802-806.
42. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. (2002). The AID enzyme induces class switch recombine tion in fibroblasts. Nature 416, 340-345
43. Arakawa, H., and Buerstedde, J.M. (2004). Immunoglobulin gene conversion:insights from bursal B cells and the DT40 cell line. Dev. Dyn.229,458-64.
44.Honjo, T., K. Kinoshita, and M. Muaramatsu.2002. Molecular mechanism of class switch recombination:linkage with somatic hypermutation. Annu. Rev. Immunol. 20:165.
45. Banchereau, J., F. Bazan, D. Blanchard, F. Briere, J. P. Galizzi, C. van Kooten, Y. J. Liu, F. Rousset, and S. Saeland.1994. The CD40 antigen and its ligand. Annu. Rev. Immunol.12:881.
46. Manis, J. P., M. Tian, and F. W. Alt.2002. Mechanism and control of class-switch recombination. Trends Immunol.23:31.
47. Haynes NM, Allen CDC, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J Immunol 2007; 179: 5099-5108.
1.潘敏,王伟铭.IgA型ANCA与过敏性紫癜[J].中国中西医结合肾病杂志,2009,6(10)：934-936.
2.KEITH K, LAU&ROBERT J.Serum levels of galactose—deficient IgA in children with IgA nephropathy and Henoch-Schnlein purpura[J].Pediatr Nephrol,2009,22(9):2067-2072.
3. NOVAK J, MOLDOVEANU Z, RENFROW MB.IgA nephropathy and Henoch-Schoenlein purpura nephritis:aberrant glycosylation of IgAl, formation of IgAl -ontaining immune complexes, and activation of mesangial cells. Contrib Nephrol,2007,157 (9):134-138.
4.刘冰.儿童紫癜性肾炎治疗研究现状.临床儿科杂志,2006,12(6)：534-537.
5.Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol,2011,22(10):1795-1803.
6.Glassock RJ. The pathogenesis of IgA nephropathy. Curr Opin Nephrol Hypertens,2011, 20(2):153-160.
7.Emancipator SN. Prospects and perspectives on IgA nephropathy from animal models. Contrib Nephrol,2011,169:126-152.
8.Van der Boog PJ, van Kooten C, van Seggelen A, et al. An increased polymeric IgA level is not a prognostic marker for progressive IgA nephropathy. Nephrol Dial Transplant,2004, 19(10):2487-2493.
9. Moura IC, Arcos-Fajardo M, Sadaka C, et al. Glycosylation and size of IgAl are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J Am Soc Nephrol, 2004,15(3):622-634.
10.Camilla R, Suzuki H, Dapra V, et al. Oxidative stress and galactose-deficient IgAl as markers of progression in IgA nephropathy. Clin J Am Soc Nephrol,2011, 6(8):1903-1911.
11. Iwasaki, H., et al.2003. Initiation of O-glycan synthesis in IgAl hinge region is determined by a single enzyme, UDP-N-acetyl-a-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2.J. Biol. Chem.278:5613-5621.
12. Ju, T., Brewer, K., D'Souza, A., Cummings, R.D.,and Canfield, W.M.2002. Cloning and expression of human core 1 βi,3-galactosyltransferase. J. Biol. Chem.277:178-186.
13. Ju, T., and Cummings, R.D.2002. A unique molecular chaperone Cosmc required for activity of the mammalian core 1 β3-galactosyltransferase. Proc. Natl. Acad. Sci. U. S. A.99:16613-16618.
14. Ju, T., and Cummings, R.D.2005. Protein glycosylation:chaperone mutation in Tn syndrome. Nature,437:1252.
15. Ikehara, Y., et al.1999. Cloning and expression of a human gene encoding an N-acetylgalactosamine-a2,6-sialyltransferase (ST6GalNAc I):a candidate for synthesis of cancer-associated sialyl-Tn antigens. Glycobiology.9:1213-1224.
16. Raska, M., et al.2007. Identification and characterization of CMP-NeuAc:GalNAc-IgAl a2,6-sialyltransferase in IgAl-producing cells. J. Mol. Biol. 369:69-78.
17. Marcos, N.T., et al.2004. Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen. Cancer Res.64:7050—7057.
18. Gillespie, W., Kelm, S., and Paulson, J.C.1992. Cloning and expression of the Gal βi,3-GalNAc a2,3-sialyltransferase. J. Biol. Chem.267:21004-21010.
19. Priatel, J.J., et al.2000. The ST3Gal-I sialyltransferase controls CD8+ T lymphocyte homeostasis by modulating O-glycan biosynthesis. Immunity. 12:273-283.
20. Schachter, H., McGuire, E.J., and Roseman, S.1971. Sialic acids. XIII. A uridine diphosphate D-galactose:mucin galactosyltransferase from porcine submaxillary gland. J. Biol. Chem.246:5321-5328
21. Novak, J., Julian, B.A., Tomana, M., and Mestecky, J.2001. Progress in molecular and genetic studies of IgA nephropathy. J. Clin. Immunol.21:310-327.
22. Z Moldoveanu, RJ Wyatt, JY Lee, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgAl levels. Kidney International (2007) 71,1148-1154.
23. Hitoshi Suzuki, lZina Moldoveanu, Stacy Hall, et al. IgAl-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgAl. The-Journal of Clinical Investigation,2008,118:629-639.
24. Xiaojie Lin, Jiaxiang Ding, Li Zhu, et al. Aberrant galactosylation of IgAl is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. Nephrol Dial Transplant (2009) 24:3372-3375.
25. M. Colleen Hastings, Zina Moldoveanu, Bruce A. Julian, et al.Galactose-Deficient IgAl in African Americans with IgA Nephropathy:Serum Levels and Heritability. Clin J Am Soc Nephrol,2010.5:2069-2074.
26. Arratt J, Feehally J, Smith AC. Pathogenesis of IgA nephropathy. Semin Nephrol,2004, 24(3):197-217.
27. Narita I, Gejyo F. Pathogenetic significance of aberrant glycosylation of IgAl in IgA nephropathy. Clin Exp Nephrol,2008,12(5):332-338.
28. Moldoveanu Z, Wyatt RJ, Lee JY, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgAl levels. Kidney Int,2007,71(11):1148-1154.
29.Shimozato S, Hiki Y, Odani H, et al. Serum under-galactosylated IgAl is increased in Japanese patients with IgA nephropathy. Nephrol Dial Transplant,2008,23(6):1931-1939.
30.JUT, BREWER K, D'SOUZA A, CUMMINGS RD, et al. Cloning and expression of human core 1 betal,3-galactosyltransferase. Biol Chemm,2002,277(1):178— 186.
31.SENIOR BW, WOOF JM. The influences of hinge length and composition on the susceptibility of human IgA to cleavage by diverse bacterial IgAl proteases Immunol,2005,17 (4):7792—7799.
32.丁务高,谢茹,陈景,等.小儿过敏性紫癜76例临床分析[J].亚太传统医药,2009,5(11)：109.
33. Hiki Y. O-linked oligosaccharides of the IgAl hinge region:roles of its aberrant structure in the occurrence and/or progression of IgA nephropathy. Clin Exp Nephrol, 2009,13(5):415-423.
34.Ma CS, Avery DT, Chan A, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood,2012 Mar 8. [Epub ahead of print]
35. Eto D, Lao C, DiToro D, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One,2011,6(3):e 17739.
36. Pau E, Chang NH, Loh C, et al. Abrogation of pathogenic IgG autoantibody production in CD40L gene-deleted lupus-prone New Zealand Black mice. Clin Immunol,2011, 139(2):215-227.
37. Mulder A, Kardol MJ, Kamp J, et al. Determination of the frequency of HLA antibody secreting B-lymphocytes in alloantigen sensitized individuals. Clin Exp Immunol,2001, 124(1):9-15.
38. Ali G. Gharavi, Zina Moldoveanu, Robert J. Wyatt, et al. Aberrant IgAl Glycosylation Is Inherited in Familial and Sporadic IgA Nephropathy. J Am Soc Nephrol 19: 1008-1014,2008
l.Casadevall, A. & Pirofski, L. A. A new synthesis for antibody-mediated immunity. Nature Immunol.13,21-28 (2011).
2.Wingren, C., Hansson, U.-B. & Alkner, U. in Van Nostrand's Scientific Encyclopedia (ed. Considine, G. D.) (Wiley-Interscience,2007).
3.Mond, J. J., Lees, A. & Snapper, C. M. T cell-independent antigens type 2. Annu. Rev. Immunol.13,655-692 (1995).
4.Gould, H. J. & Sutton, B. J. IgE in allergy and asthma today. Nature Rev. Immunol.8, 205-217 (2008).
5.Cerutti, A., Chen, K. & Chorny, A. Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol.29,273-293 (2011).
6.Stavnezer, J., Guikema, J. E. & Schrader, C. E. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol.26,261-292 (2008). A comprehensive review of the molecular mechanisms of CSR.
7.Honjo, T. A memoir of AID, which engraves antibody memory on DNA. Nature Immunol.9,335-337 (2008).
8.Casali, P. in Lewin's Genes X (eds Krebs, J. E., Goldstein, E. S. & Kilpatrick, S. T.) 570-623 (Jones & Bartlett,2009).
9.Goodnow, C. C, Vinuesa, C. G., Randall, K. L., Mackay, F. & Brink, R. Control systems and decision making for antibody production. Nature Immunol.11,681-688 (2010).
lO.Casadevall, A., Dadachova, E. & Pirofski, L. A. Passive antibody therapy for infectious diseases. Nature Rev. Microbiol.2,695-703 (2004).
11.Pulendran, B. & Ahmed, R. Translating innate immunity into immunological memory: implications for vaccine development. Cell 124,849-863 (2006).
12.Plotkin, S. A. Vaccines:correlates of vaccine-induced immunity. Clin. Infect. Dis.47, 401-409(2008).
13.Delker, R. K., Fugmann, S. D. & Papavasiliou, F. N. A coming-of-age story: activation-induced cytidine deaminase turns 10. Nature Immunol.10,1147-1153 (2009).
14.Zan, H. & Casali, P. AID-and Ung-dependent generation of staggered double-strand DNA breaks in immunoglobulin class switch DNA recombination:a post-cleavage role for AID. Mol. Immunol.46,45-61 (2008).
15.Zan, H. et al. Endonuclease G plays a role in immunoglobulin class switch DNA recombination by introducing double-strand breaks in switch regions. Mol. Immunol.48, 610-622(2011).
16.Kobayashi, M. et al. AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination. Proc. Natl Acad. Sci. USA 106,22375-22380 (2009).
17.Stavnezer, J. Complex regulation and function of activation-induced cytidine deaminase. Trends Immunol.32,194-201 (2011).
18.Rada, C., Di Noia, J. M. & Neuberger, M. S. Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol. Cell 16,163-171 (2004).
19.Min, I. M. et al. The Sμ tandem repeat region is critical for Ig isotype switching in the absence of Msh2. Immunity 19,515-524 (2003).
20.Petersen, S. et al. AID is required to initiate Nbsl/y-H2AX focus formation and mutations at sites of class switching. Nature 414,660-665 (2001).
21.Lee-Theilen, M., Matthews, A. J., Kelly, D., Zheng, S. & Chaudhuri, J. CtIP promotes microhomology-mediated alternative end joining during class-switch recombination. Nature Struct. Mol. Biol.18,75-79 (2011).
22.Klein, U. & Dalla-Favera, R. Germinal centres:role in B-cell physiology and malignancy. Nature Rev. Immunol.8,22-33 (2008).
23.McHeyzer-Williams, M., Okitsu, S., Wang, N. & McHeyzer-Williams, L. Molecular programming of B cell memory. Nature Rev. Immunol.12,24-34 (2012).
24.Pone, E. J. et al. Toll-like receptors and B-cell receptors synergize to induce immunoglobulin class-switch DNA recombination:relevance to microbial antibody responses. Crit. Rev. Immunol.30,1-29 (2010).
25.Casanova, J. L., Abel, L. & Quintana-Murci, L. Human TLRs and IL-1Rs in host defense:natural insights from evolutionary, epidemiological, and clinical genetics. Annu. Rev. Immunol.29,447-491 (2011).
26.Barton, G. M. & Kagan, J. C. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nature Rev. Immunol.9,535-542 (2009).
27.He, B. et al. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nature Immunol.11, 836-845 (2010).
28.Pone, E. J. et al. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-кB pathway. Nature Commun.3,767 (2012).
29.Rawlings, D. J., Schwartz, M. A., Jackson, S. W. & Meyer-Bahlburg, A. Integration of B cell responses through Toll-like receptors and antigen receptors. Nature Rev. Immunol. 12,282-294 (2012).
30.Wesemann, D. R. et al. Immature B cells preferentially switch to IgE with increased direct Sμ to Se recombination. J. Exp. Med.208,2733-2746 (2011).
31.Fritz, E. L. & Papavasiliou, F. N. Cytidine deaminases:AIDing DNA demethylation? Genes Dev.24,2107-2114 (2010).
32.Bhutani, N., Burns, D. M. & Blau, H. M. DNA demethylation dynamics. Cell 146, 866-872(2011).
33.Guo, J. U., Su, Y., Zhong, C., Ming, G. L. & Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145,423-434(2011).
34.Robbiani, D. F. et al. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Mol. Cell 36, 631-641 (2009).
35.Hasham, M. G. et al. Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination. Nature Immunol.11, 820-826 (2010).
36.Xu, Z. et al. Regulation of aicda expression and AID activity:relevance to somatic hypermutation and class switch DNA recombination. Crit. Rev. Immunol.27,367-397 (2007).
37.Hasler, J., Rada, C. & Neuberger, M. S. Cytoplasmic activation-induced cytidine deaminase (AID) exists in stoichiometric complex with translation elongation factor la (eEF1A). Proc. Natl Acad. Sci. USA108,18366-18371 (2011).
38.Uchimura, Y., Barton, L. F., Rada, C. & Neuberger, M. S. REG-y associates with and modulates the abundance of nuclear activation-induced deaminase. J. Exp. Med.208, 2385-2891 (2011).
39.Li, G. et al. Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination. J. Biol. Chem.3 May 2012 (doi:10.1074/jbc.Ml 12.366732).
40.He, B., Qiao, X. & Cerutti, A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J. Immunol.173,4479-491 (2004).
41.Tran, T. H. et al. B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. Nature Immunol.11,148-154 (2010).
42.Smale, S. T. Hierarchies of NF-кB target-gene regulation. Nature Immunol.12,689-694 (2011).
43.Baltimore, D. NF-кB is 25. Nature Immunol.12,683-685 (2011).
44.Pauklin, S., Semandez, I. V., Bachmann, G., Ramiro, A. R. & Petersen-Mahrt, S. K. Estrogen directly activates AID transcription and function. J. Exp. Med.206,99-111 (2009).
45.Mai, T. et al. Estrogen receptors bind to and activate the HOXC4/HoxC4 promoter to potentiate HoxC4-mediated activation-induced cytosine deaminase induction, immunoglobulin class switch DNA recombination, and somatic hypermutation. J. Biol. Chem.285,37797-37810 (2010).
46.White, C. A. et al. AID dysregulation in lupus-prone MRL/Faslpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations:modulation by HoxC4. Autoimmunity 44,585-598 (2011).
47.Sayegh, C. E., Quong, M. W., Agata, Y. & Murre, C. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nature Immunol.4, 586-593 (2003).
48.Ise, W. et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nature Immunol.12,536-543 (2011).
49.Betz, B. C. et al. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J. Exp. Med.207,933-942 (2010).
50.Cerutti, A. & Rescigno, M. The biology of intestinal immunoglobulin A responses. Immunity 28,740-750 (2008).
51.Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut:T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 28,243-273 (2010).
52.Daniel, J. A. et al. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science 329,917-923 (2010).
53.Yu, K., Chedin, F., Hsieh, C. L., Wilson, T. E. & Lieber, M. R. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nature Immunol.4,442-451 (2003).
54.Chaudhuri, J. & Alt, F. W. Class-switch recombination:interplay of transcription, DNA deamination and DNA repair. Nature Rev. Immunol.4,541-552 (2004).
55.Basu, U. et al. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 144,353-363 (2011).
56.Sellars, M., Reina-San-Martin, B., Kastner, P. & Chan, S. Ikaros controls isotype selection during immunoglobulin class switch recombination. J. Exp. Med.206, 1073-1087(2009).
57.Perlot, T. & Alt, F. W. Cis-regulatory elements and epigenetic changes control genomic rearrangements of the IgH locus. Adv. Immunol.99,1-32 (2008).
58.Dunnick, W. A. et al. Switch recombination and somatic hypermutation are controlled by the heavy chain 3'enhancer region. J. Exp. Med.206,2613-2623 (2009).
59.Kim, E. C., Edmonston, C. R., Wu, X., Schaffer, A. & Casali, P. The HoxC4 homeodomain protein mediates activation of the immunoglobulin heavy chain 3'hs1,2 enhancer in human B cells. Relevance to class switch DNA jecombination. J. Biol. Chem. 279,42258-2269(2004).
60.Wuerffel, R. et al. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity 27,711-722(2007).
61.Hackney, J. A. et al. DNA targets of AID evolutionary link between antibody somatic hypermutation and class switch recombination. Adv. Immunol.101,163-189 (2009).
62.Xu, Z. et al.14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination. Nature Struct. Mol. Biol.17,1124-1135 (2010).
63.Zarrin, A. A. et al. An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nature Immunol.5,1275-1281 (2004).
64.Park, S. R. et al. HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. Nature Immunol.10,540-550 (2009)
65.Aoufouchi, S. et al. Proteasomal degradation restricts the nuclear lifespan of AID. J. Exp. Med.205,1357-1368 (2008).
2.Gharavi AG, Kiryluk K, Choi M, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet,2011,43(4):321-327.
3.Paterson AD, Liu XQ, Wang K, et al. Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36. J Am Soc Nephrol,2007,18(8):2408-2415.
4.Nagareda CS. Antibody formation and the effect of x-radiation on circulating antibody levels in the hypophysectomized rat. J Immunol,1954,73(2):88-94.
5. Linterman MA, Vinuesa CG. Signals that influence T follicular helper cell differentiation and function. Semin Immunopathol,2010,32(2):183—196.
6. Velardi A, Mingafi MC, Moretta L, et al. Functional analysis of cloned germinal center CD4+cells with natural killer cell-related features. Divergence from typical T helper cell. J Immunol,1986,137(9):2808-2813.
7. Schaerli P, Willimannk, Lang AB, et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med,2000,192(11): 1553—1562.
8. Benson MJ, Erickson LD, Gleeson MW, et al. Affinity of antigen encounter and other early B-cell signals determine B-cell fate. Curr Opin Immunol,2007,19(3):275-280.
9.Allen CD, Okada T, Tang HL, et al. Imaging of germinal center selection events during affinity maturation. Science,2007,315:528—31.
lO.MacLennan IC, Liu YJ. Maturation and dispersal of B-cellclones during T celldependent antibody responses. Immunol Rev,1992,126:143—61.
ll.Kelsoe G. The germinal center reaction. Immunol. Today,1995,16:324-6.
12.Liu YJ, Malisan F, de Bouteiller O, et al. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity,1996, 4:241-250
13. Haynes NM, Allen CDC, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J Immunol 2007; 179: 5099-5108.
14. Junt T, Fink K, Forster R, Senn B, Lipp M, Muramatsu M et al. CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses. J Immunol 2005; 175:7109-7116.
15.Ruprecht, C. R., Lanzavecchia, A. (2006) Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur. J. Immunol.36,810-816.
16. Huggins, J., Pellegrin, T, Felgar, R. E., Wei, C., Brown, M., Zheng, B., Milner, E. C., Bernstein, S. H., Sanz, I., Zand, M. S. (2007) CpG DNA
activation and plasma-cell differentiation of.CD27—naive human B cells. Blood 109, 1611-1619.
17. Jiang, W., Lederman, M. M., Harding, C. V., Rodriguez, B., Mohner, R. J., Sieg, S. F. (2007) TLR9 stimulation drives nalve B cells to proliferateand to attain enhanced antigen presenting function. Eur. J. Immunol.37,2205-2213.
18. Muramatsu, M., Sankaranand, V.S., Anant, S., Sugai, M., Kinoshita, K., Davidson, N.O., and Honjo, T. (1999). Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol Chem.274,18470-18476.
19. Muto, T., Muramatsu, M., Taniwaki, M., Kinoshita, K., and Honjo, T. (2000). Isolation, tissue distribution and chromosomal localization AID of Genomics 68,85-88.
20. Ta, V.T., Nagaoka, H., Catalan, N., Durandy, A., Fischer, A., Imai, K., Nonoyama, S., Tashiro, J., Ikegawa, M., Ito, S., et al. (2003). AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat. Immunol.4,843-848.
21. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. (2002). The AID enzyme induces class switch recombine tion in fibroblasts. Nature 416, 340-345.
22. Yoshikawa, K., Okazaki, I.M., Eto, T., Kinoshita, K., Muramatsu, M.,Nagaoka, H., and Honjo, T. (2002). AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296,2033-2036.
23. Martin, A., Bardwell, P.D., Woo, C.J., Fan, M., Shulman, M.J., and Scharff, M.D. (2002). Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415,802-806.
24. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. (2002). The AID enzyme induces class switch recombine tion in fibroblasts. Nature 416, 340-345
25. Arakawa, H., and Buerstedde, J.M. (2004). Immunoglobulin gene conversion:insights from bursal B cells and the DT40 cell line. Dev. Dyn.229,458-464.
26. Linteman MA, Beaton L, Yu D, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med,2010,207(2):353-363.
27. Kassiotis G, O Garra A. Establishing the follicular helper identity. Immunity,2009, 31(3):450-452.
28. King IL, Mohrs M. IL-4 producing CD4+T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med,2009,206:1001—1007.
29. Rodrtguez Pinilla SM, Roncador G, et-al. Primary cutaneous CD4+small/ medium-sized pleomorphie T-cell lymphoma expresses follicular T-cell markers. Am J Surg Pathol,2009,33(1):81-90.
30. Tsuji M, Komatsu N, Kawamoto S, Suzuki K, Kanagawa O, Honjo T, Hori S, Fagarasan S. Preferential generation of follicular B helper T cells from Foxp3+T cells in gut Peyer's patches. Science.2009 Mar 13;323(5920):1488-92.
31. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bc26 mediates the development of T follicular helper cells. Science.2009 Aug 21;325(5943):1001-5.
32. Johnston RJ,Poholek AC,DiToro D,Yusuf I,Eto D, Barnett B, Dent AL, Craft J, Crotty S.Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science.2009 Aug 21;325(5943):1006-10.
33. Bryant VL, Ma CS,Avery DT, Li Y, Good KL, Corcoran LM,de Waal Malefyt R, Tangye SG. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells:predominant role of IL-21 produced by CXCR5+T follicular helper cells. J Immunol.2007 Dec 15; 179(12):8180-90.
34. Seo GY, Youn J, Kim PH. IL-21 ensures TGF-beta 1-induced IgA isotype expression in mouse Peyer's patches. J Leukoc Biol.2009 May;85(5):744-50.
1. Haynes NM, Allen CDC, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J Immunol 2007; 179: 5099-5108.
2. Junt T, Fink K, Forster R, Senn B, Lipp M, Muramatsu M et al. CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses. J Immunol 2005; 175:7109-7116.
3. inuesa CG, Tangye SG, Moser B, et al. Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol,2005,5(11):853-865.
4. Hardtke S, Ohl L, Forster R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood,2005,106(6):1924-1931.
5. Patakas A, Platt AM, Butcher JP, et al. Putative existence of reciprocal dialogue between Tfh and B cells and its impact on infectious and autoimmune disease. Immunol Lett, 2011,138(1):38-46.
6. Hu YL, Metz DP, Chung J, et al. B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. J Immunol,2009,182(3):1421-1428.
7. Vinuesa CG, Cook MC, Angelucci C, Athanasopoulos V, Rui L, Hill KM et al. A RINGtype
ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 2005; 435:452-458.
8. Linterman MA, Vinuesa CG. Signals that influence T follicular helper cell differentiation and function. Semin Immunopathol 2010; in press.
9.Deenick EK, Ma CS. The regulation and role of T follicular helper cells in immunity. Immunology,2011,134(4):361-367.
10. Conley ME, Dobbs AK, Farmer DM, et al. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol.2009,27:199-227.
11. Elgueta R, Benson MJ, de Vries VC, et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev,2009, 229(1):152-172.
12. Ma CS, Avery DT, Chan A, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood,2012,8. [Epub ahead of print]
13. Kroenke MA, Eto D, Locci M, et al. Bcl-6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J Immunol.2012 Mar 16. [Epub ahead of print]
14. M. Colleen Hastings, Zina Moldoveanu, Bruce A. Julian, Jan Novak, John T. Sanders, Kim R. McGlothan, Ali G. Gharavi, Robert J. Wyatt. Galactose-Deficient IgAl in African Americans with IgA Nephropathy:Serum Levels and Heritability. Clin J Am SocNephrol 2010,5:2069-2074.
15. Z Moldoveanu, RJ Wyatt, JY Lee, M Tomana, BA Julian, J Mestecky, W-Q Huang, SR Anreddy, S Hall, MC Hastings, KK Lau, WJ Cook, J Novak. Patients with IgA nephropathy have increased serum galactose-deficient IgAl levels. Kidney International 2007,71;1148-1154.
16. Novak J, Renfrow MB, Gharavi AG, Julian BA.Pathogenesis of immunoglobulin A nephropathy. Curr Opin Nephrol Hypertens.2013 Mar 18. [Epub ahead of print}
17. Roza I Nurieva and Yeonseok Chung. Understanding the development and function of T follicular helper cells. Cellular & Molecular Immunology (2010) 7,190-197.
18. Sawalha AH, Kaufman KM, Kelly JA, Adler AJ, Aberle T, Kilpatrick J et al. Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus. Ann Rheum Dis 2008; 67:458-61.
19. Odegard JM, Marks BR, DiPlacido LD, Poholek AC, Kono DH, Dong C et al. ICOS dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med 2008; 205:2873-2886.
20. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006;24:99—146. [PubMed:16551245]
21.Corthay A. How do regulatory T cells work? Scand J Immunol,2009,70(4):326—336.
22. Martin, A., Bardwell, P.D., Woo, C.J., Fan, M., Shulman, M.J., and Scharff, M.D. (2002). Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415,802-806
23. Junt T, Fink K, Forster R, Senn B, Lipp M, Muramatsu M et al. CXCR5-dependent seeding of follicular niches by B and Th cells augments antiviral B cell responses. J Immunol 2005; 175:7109-7116.
1. Ebert LM, Hom MP, Lang AB, et al. B cells alter the phenotype and function of follicular homing CXCR5 T cells. Eur J Imm unol,2004,34:3562-71.
2. Qi H, Cannons JL, Klauschen F, et al. SAP-controlled T-B cell interactions underlie germinal centre formation. Namre,2008,455:764—9.
3. Fazilleau N, McHeyzer-Williams LJ, Rosen H, et al. The function of follicular helper Tcells is regulated by the strength of T cell antigen receptor binding. Namre Immunol, 2009,10:375—84.
4. Nurieva RI, Chung Y, Hwang D, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1,2, or 17 cell lineages. Immunity,2008,29:138—49.
5. Yu D, Rao S, Tsai LM, et al. The transcriptional repressor BCL--6 directs T follicular helper cell lineage comm itment. Immunity.2009.31:457—68
6. Johnston RJ, Poholek AC, DiToro D, et al. Bcl-6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science,2009,325: 1006—10.
7.Nurieva RI, Chung Y, Martinez GJ, et al. Bc16 mediates the development of T follicular helper cells. Science,2009,325:1001—5.
8.Grimbacher B, Hutlof A, Schlesier M, et al. Homozygous loss of IC0S is associated with adult—onset common variable immunodeficiency. Nat Immunol,2003,4:261—8.
9.Bossaller L, Burger J, Draeger R, et al. ICOS deficiency is associated with a severe reduction of CXCR5 +CD4+ germinal center Th cells. J Immunol,2006,177: 4927—32.
10. Akiba H, Takeda K, Kojima Y, et al. The role of ICOS in the CXCR5 follicular B helper T cel maintenance in vivo. J Immunol,2005,175:2340—48.
11. Mak TW, Shahinian A, Yoshinaga SK, et al. Costimulation through the inducible costimulator ligand is essential for bothT helper and B cell functions in T cell-dependent B cell responses. Nat Immuno 1,2003,4:765—72.
12.Hams E, McCarron MJ, Amu S, et al. Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells. J Immunol,2011,186(10):5648-5655.
13.Kajita M, Okazawa T, Ikeda M, et al. Efficient affinity maturation of antibodies in an engineered chicken B cell line DT40-SW by increasing point mutation. J Biosci Bioeng, 2010,110(3):351-358.
14.Deenick EK, Ma CS. The regulation and role of T follicular helper cells in immunity. Immunology,2011,134(4):361-367.
15. Tsuji M, Komatsu N, Kawamoto S, Suzuki K, Kanagawa O, Honjo T, Hori S, Fagarasan S. Preferential generation of follicular B helper T cells from Foxp3+T cells in gut Peyer's patches. Science.2009 Mar 13;323(5920):1488-92.
16. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bc16 mediates the development of T follicular helper cells. Science.2009 Aug 21;325(5943):1001-5.
17. Johnston RJ,Poholek AC, DiToro D,Yusuf I,Eto D,Barnett B,Dent AL, Craft J, Crotty S.Bc16 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science.2009 Aug 21;325(5943):1006-10.
18. Bryant VL,Ma CS,Avery DT, Li Y, Good KL, Corcoran LM,de Waal Malefyt R, Tangye SG. Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells:predominant role of IL-21 produced by CXCR5+T follicular helper cells. J Immunol.2007 Dec 15; 179(12):8180-90.
19. Seo GY, Youn J, Kim PH. IL-21 ensures TGF-beta 1-induced IgA isotype expression in mouse Peyer's patches. J Leukoc Biol.2009 May;85(5):744-50.
20. Ozaki, K., K. Kikly, D. Michalovich, P. R. Young, and W. J. Leonard. Cloning of a type I cytokine receptor most related to the IL-2 receptor βkhain. Proc. Natl. Acad. Sci. 2000.97:11439.
21. Parrish-Novak, J., S. R. Dillon, A. Nelson, A. Hammond, C. Sprecher, J. A. Gross, J. Johnston, K. Madden, W. Xu, J. West, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature,2000,408:57.
22. Leonard, W. J. Cytokines and immunodeficiency diseases. Nat. Rev. Immunol.2001, 1:200.
23. Asao, H., H. C. Okuyama, S. Kumaki, N. Ishii, S. Tsuchiya, D. Foster, and K. Sugamura.. The common γ_chain is an indispensable subunit of the IL-21 receptor complex. J. Immunol.2001,167:1.
24. Ozaki, K., R. Spolski, C. G. Feng, J. Cheng, A. Sher, C. Liu, P. L. Schwarzberg, and W. J. Leonard. A critical role for IL-21 in regulating immunoglobulin production. Science, 2002,298:1630.
25. Suto, A., H. Nakajima, K. Hirose, K. Suzuki, S. Kagami, Y. Seto, A. Hoshimoto, Y. Saito, D. C. Foster, and I. Iwamoto. Interleukin 21 prevents antigeninduced IgE production by inhibiting germ line C_ transcription of IL-4-stimulated B cells. Blood, 2002,100:4565.
26. Mehta, D. S., A. L. Wurster, M. J. Whitters, D. A. Young, M. Collins, and M. J. Grusby. IL-21 induces the apoptosis of resting and activated primary B cells. J. Immunol.2003, 170:4111.
27.Ruprecht, C. R., Lanzavecchia, A. (2006) Toll-like receptor stimulation as a third signal required for activation of human naive B cells. Eur. J. Immunol.36,810-816.
28. Huggins, J., Pellegrin, T., Felgar, R. E., Wei, C., Brown, M., Zheng, B., Milner, E. C., Bernstein, S. H., Sanz, I., Zand, M. S. (2007) CpG DNA
29. Katsutoshi Ozaki, Rosanne Spolski, Rachel Ettinger, et al. Regulation of B Cell Differentiation and Plasma Cell Generation by IL-21, a Novel Inducer of Blimp-1 and Bcl-6. J Immunol 2004;173;5361-5371
30. Linteman MA, Beaton L, Yu D, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med,2010,207(2):353-363.
31. Kassiotis G, O Garra A. Establishing the follicular helper identity. Immunity,2009, 31(3):450-452.
32. King IL, Mohrs M. IL-4 producing CD4+T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J Exp Med,2009,206:1001—1007.
33. Rodrtguez Pinilla SM, Roncador G> et-al. Primary cutaneous CD4+ small medium-sized pleomorphie T-cell lymphoma expresses follicular T-cell markers. Am J Surg Pathol,2009,33(1):81-90.
34. Chattha KS, Firth MA, Hodgins DC, et al. Age related variation in expression of CD21 and CD32 on bovine lymphocytes:a cross-sectional study. Vet Immunol Immunopathol, 2009,130(1-2):70-78.
35. Corfe SA, Paige CJ. The many roles of IL-7 in B cell development; Mediator of survival, proliferation and differentiation. Semin Immunol,2012 Mar 13. [Epub ahead of print]
36. Muramatsu, M., Sankaranand, V.S., Anant, S., Sugai, M., Kinoshita, K., Davidson, N.O., and Honjo, T. (1999). Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol Chem.274,18470-18476.
37. Muto, T., Muramatsu, M., Taniwaki, M., Kinoshita, K., and Honjo, T. (2000). Isolation, tissue distribution and chromosomal localization AID of Genomics 68,85—88.
38. Ta, V.T., Nagaoka, H., Catalan, N., Durandy, A., Fischer, A., Imai, K., Nonoyama, S., Tashiro, J., Ikegawa, M., Ito, S., et al. (2003). AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat. Immunol.4,843-848.
39. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. (2002). The AID enzyme induces class switch recombine tion in fibroblasts. Nature 416, 340-345.
40. Yoshikawa, K., Okazaki, I.M., Eto, T., Kinoshita, K., Muramatsu, M.,Nagaoka, H., and Honjo, T. (2002). AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296,2033-2036.
41. Martin, A., Bardwell, P.D., Woo, C.J., Fan, M., Shulman, M.J., and Scharff, M.D. (2002). Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature 415,802-806.
42. Okazaki, I.M., Kinoshita, K., Muramatsu, M., Yoshikawa, K., and Honjo, T. (2002). The AID enzyme induces class switch recombine tion in fibroblasts. Nature 416, 340-345
43. Arakawa, H., and Buerstedde, J.M. (2004). Immunoglobulin gene conversion:insights from bursal B cells and the DT40 cell line. Dev. Dyn.229,458-64.
44.Honjo, T., K. Kinoshita, and M. Muaramatsu.2002. Molecular mechanism of class switch recombination:linkage with somatic hypermutation. Annu. Rev. Immunol. 20:165.
45. Banchereau, J., F. Bazan, D. Blanchard, F. Briere, J. P. Galizzi, C. van Kooten, Y. J. Liu, F. Rousset, and S. Saeland.1994. The CD40 antigen and its ligand. Annu. Rev. Immunol.12:881.
46. Manis, J. P., M. Tian, and F. W. Alt.2002. Mechanism and control of class-switch recombination. Trends Immunol.23:31.
47. Haynes NM, Allen CDC, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J Immunol 2007; 179: 5099-5108.
1.潘敏,王伟铭.IgA型ANCA与过敏性紫癜[J].中国中西医结合肾病杂志,2009,6(10)：934-936.
2.KEITH K, LAU&ROBERT J.Serum levels of galactose—deficient IgA in children with IgA nephropathy and Henoch-Schnlein purpura[J].Pediatr Nephrol,2009,22(9):2067-2072.
3. NOVAK J, MOLDOVEANU Z, RENFROW MB.IgA nephropathy and Henoch-Schoenlein purpura nephritis:aberrant glycosylation of IgAl, formation of IgAl -ontaining immune complexes, and activation of mesangial cells. Contrib Nephrol,2007,157 (9):134-138.
4.刘冰.儿童紫癜性肾炎治疗研究现状.临床儿科杂志,2006,12(6)：534-537.
5.Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol,2011,22(10):1795-1803.
6.Glassock RJ. The pathogenesis of IgA nephropathy. Curr Opin Nephrol Hypertens,2011, 20(2):153-160.
7.Emancipator SN. Prospects and perspectives on IgA nephropathy from animal models. Contrib Nephrol,2011,169:126-152.
8.Van der Boog PJ, van Kooten C, van Seggelen A, et al. An increased polymeric IgA level is not a prognostic marker for progressive IgA nephropathy. Nephrol Dial Transplant,2004, 19(10):2487-2493.
9. Moura IC, Arcos-Fajardo M, Sadaka C, et al. Glycosylation and size of IgAl are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J Am Soc Nephrol, 2004,15(3):622-634.
10.Camilla R, Suzuki H, Dapra V, et al. Oxidative stress and galactose-deficient IgAl as markers of progression in IgA nephropathy. Clin J Am Soc Nephrol,2011, 6(8):1903-1911.
11. Iwasaki, H., et al.2003. Initiation of O-glycan synthesis in IgAl hinge region is determined by a single enzyme, UDP-N-acetyl-a-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2.J. Biol. Chem.278:5613-5621.
12. Ju, T., Brewer, K., D'Souza, A., Cummings, R.D.,and Canfield, W.M.2002. Cloning and expression of human core 1 βi,3-galactosyltransferase. J. Biol. Chem.277:178-186.
13. Ju, T., and Cummings, R.D.2002. A unique molecular chaperone Cosmc required for activity of the mammalian core 1 β3-galactosyltransferase. Proc. Natl. Acad. Sci. U. S. A.99:16613-16618.
14. Ju, T., and Cummings, R.D.2005. Protein glycosylation:chaperone mutation in Tn syndrome. Nature,437:1252.
15. Ikehara, Y., et al.1999. Cloning and expression of a human gene encoding an N-acetylgalactosamine-a2,6-sialyltransferase (ST6GalNAc I):a candidate for synthesis of cancer-associated sialyl-Tn antigens. Glycobiology.9:1213-1224.
16. Raska, M., et al.2007. Identification and characterization of CMP-NeuAc:GalNAc-IgAl a2,6-sialyltransferase in IgAl-producing cells. J. Mol. Biol. 369:69-78.
17. Marcos, N.T., et al.2004. Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialyl-Tn antigen. Cancer Res.64:7050—7057.
18. Gillespie, W., Kelm, S., and Paulson, J.C.1992. Cloning and expression of the Gal βi,3-GalNAc a2,3-sialyltransferase. J. Biol. Chem.267:21004-21010.
19. Priatel, J.J., et al.2000. The ST3Gal-I sialyltransferase controls CD8+ T lymphocyte homeostasis by modulating O-glycan biosynthesis. Immunity. 12:273-283.
20. Schachter, H., McGuire, E.J., and Roseman, S.1971. Sialic acids. XIII. A uridine diphosphate D-galactose:mucin galactosyltransferase from porcine submaxillary gland. J. Biol. Chem.246:5321-5328
21. Novak, J., Julian, B.A., Tomana, M., and Mestecky, J.2001. Progress in molecular and genetic studies of IgA nephropathy. J. Clin. Immunol.21:310-327.
22. Z Moldoveanu, RJ Wyatt, JY Lee, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgAl levels. Kidney International (2007) 71,1148-1154.
23. Hitoshi Suzuki, lZina Moldoveanu, Stacy Hall, et al. IgAl-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgAl. The-Journal of Clinical Investigation,2008,118:629-639.
24. Xiaojie Lin, Jiaxiang Ding, Li Zhu, et al. Aberrant galactosylation of IgAl is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. Nephrol Dial Transplant (2009) 24:3372-3375.
25. M. Colleen Hastings, Zina Moldoveanu, Bruce A. Julian, et al.Galactose-Deficient IgAl in African Americans with IgA Nephropathy:Serum Levels and Heritability. Clin J Am Soc Nephrol,2010.5:2069-2074.
26. Arratt J, Feehally J, Smith AC. Pathogenesis of IgA nephropathy. Semin Nephrol,2004, 24(3):197-217.
27. Narita I, Gejyo F. Pathogenetic significance of aberrant glycosylation of IgAl in IgA nephropathy. Clin Exp Nephrol,2008,12(5):332-338.
28. Moldoveanu Z, Wyatt RJ, Lee JY, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgAl levels. Kidney Int,2007,71(11):1148-1154.
29.Shimozato S, Hiki Y, Odani H, et al. Serum under-galactosylated IgAl is increased in Japanese patients with IgA nephropathy. Nephrol Dial Transplant,2008,23(6):1931-1939.
30.JUT, BREWER K, D'SOUZA A, CUMMINGS RD, et al. Cloning and expression of human core 1 betal,3-galactosyltransferase. Biol Chemm,2002,277(1):178— 186.
31.SENIOR BW, WOOF JM. The influences of hinge length and composition on the susceptibility of human IgA to cleavage by diverse bacterial IgAl proteases Immunol,2005,17 (4):7792—7799.
32.丁务高,谢茹,陈景,等.小儿过敏性紫癜76例临床分析[J].亚太传统医药,2009,5(11)：109.
33. Hiki Y. O-linked oligosaccharides of the IgAl hinge region:roles of its aberrant structure in the occurrence and/or progression of IgA nephropathy. Clin Exp Nephrol, 2009,13(5):415-423.
34.Ma CS, Avery DT, Chan A, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood,2012 Mar 8. [Epub ahead of print]
35. Eto D, Lao C, DiToro D, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS One,2011,6(3):e 17739.
36. Pau E, Chang NH, Loh C, et al. Abrogation of pathogenic IgG autoantibody production in CD40L gene-deleted lupus-prone New Zealand Black mice. Clin Immunol,2011, 139(2):215-227.
37. Mulder A, Kardol MJ, Kamp J, et al. Determination of the frequency of HLA antibody secreting B-lymphocytes in alloantigen sensitized individuals. Clin Exp Immunol,2001, 124(1):9-15.
38. Ali G. Gharavi, Zina Moldoveanu, Robert J. Wyatt, et al. Aberrant IgAl Glycosylation Is Inherited in Familial and Sporadic IgA Nephropathy. J Am Soc Nephrol 19: 1008-1014,2008
l.Casadevall, A. & Pirofski, L. A. A new synthesis for antibody-mediated immunity. Nature Immunol.13,21-28 (2011).
2.Wingren, C., Hansson, U.-B. & Alkner, U. in Van Nostrand's Scientific Encyclopedia (ed. Considine, G. D.) (Wiley-Interscience,2007).
3.Mond, J. J., Lees, A. & Snapper, C. M. T cell-independent antigens type 2. Annu. Rev. Immunol.13,655-692 (1995).
4.Gould, H. J. & Sutton, B. J. IgE in allergy and asthma today. Nature Rev. Immunol.8, 205-217 (2008).
5.Cerutti, A., Chen, K. & Chorny, A. Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol.29,273-293 (2011).
6.Stavnezer, J., Guikema, J. E. & Schrader, C. E. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol.26,261-292 (2008). A comprehensive review of the molecular mechanisms of CSR.
7.Honjo, T. A memoir of AID, which engraves antibody memory on DNA. Nature Immunol.9,335-337 (2008).
8.Casali, P. in Lewin's Genes X (eds Krebs, J. E., Goldstein, E. S. & Kilpatrick, S. T.) 570-623 (Jones & Bartlett,2009).
9.Goodnow, C. C, Vinuesa, C. G., Randall, K. L., Mackay, F. & Brink, R. Control systems and decision making for antibody production. Nature Immunol.11,681-688 (2010).
lO.Casadevall, A., Dadachova, E. & Pirofski, L. A. Passive antibody therapy for infectious diseases. Nature Rev. Microbiol.2,695-703 (2004).
11.Pulendran, B. & Ahmed, R. Translating innate immunity into immunological memory: implications for vaccine development. Cell 124,849-863 (2006).
12.Plotkin, S. A. Vaccines:correlates of vaccine-induced immunity. Clin. Infect. Dis.47, 401-409(2008).
13.Delker, R. K., Fugmann, S. D. & Papavasiliou, F. N. A coming-of-age story: activation-induced cytidine deaminase turns 10. Nature Immunol.10,1147-1153 (2009).
14.Zan, H. & Casali, P. AID-and Ung-dependent generation of staggered double-strand DNA breaks in immunoglobulin class switch DNA recombination:a post-cleavage role for AID. Mol. Immunol.46,45-61 (2008).
15.Zan, H. et al. Endonuclease G plays a role in immunoglobulin class switch DNA recombination by introducing double-strand breaks in switch regions. Mol. Immunol.48, 610-622(2011).
16.Kobayashi, M. et al. AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination. Proc. Natl Acad. Sci. USA 106,22375-22380 (2009).
17.Stavnezer, J. Complex regulation and function of activation-induced cytidine deaminase. Trends Immunol.32,194-201 (2011).
18.Rada, C., Di Noia, J. M. & Neuberger, M. S. Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol. Cell 16,163-171 (2004).
19.Min, I. M. et al. The Sμ tandem repeat region is critical for Ig isotype switching in the absence of Msh2. Immunity 19,515-524 (2003).
20.Petersen, S. et al. AID is required to initiate Nbsl/y-H2AX focus formation and mutations at sites of class switching. Nature 414,660-665 (2001).
21.Lee-Theilen, M., Matthews, A. J., Kelly, D., Zheng, S. & Chaudhuri, J. CtIP promotes microhomology-mediated alternative end joining during class-switch recombination. Nature Struct. Mol. Biol.18,75-79 (2011).
22.Klein, U. & Dalla-Favera, R. Germinal centres:role in B-cell physiology and malignancy. Nature Rev. Immunol.8,22-33 (2008).
23.McHeyzer-Williams, M., Okitsu, S., Wang, N. & McHeyzer-Williams, L. Molecular programming of B cell memory. Nature Rev. Immunol.12,24-34 (2012).
24.Pone, E. J. et al. Toll-like receptors and B-cell receptors synergize to induce immunoglobulin class-switch DNA recombination:relevance to microbial antibody responses. Crit. Rev. Immunol.30,1-29 (2010).
25.Casanova, J. L., Abel, L. & Quintana-Murci, L. Human TLRs and IL-1Rs in host defense:natural insights from evolutionary, epidemiological, and clinical genetics. Annu. Rev. Immunol.29,447-491 (2011).
26.Barton, G. M. & Kagan, J. C. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nature Rev. Immunol.9,535-542 (2009).
27.He, B. et al. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nature Immunol.11, 836-845 (2010).
28.Pone, E. J. et al. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-кB pathway. Nature Commun.3,767 (2012).
29.Rawlings, D. J., Schwartz, M. A., Jackson, S. W. & Meyer-Bahlburg, A. Integration of B cell responses through Toll-like receptors and antigen receptors. Nature Rev. Immunol. 12,282-294 (2012).
30.Wesemann, D. R. et al. Immature B cells preferentially switch to IgE with increased direct Sμ to Se recombination. J. Exp. Med.208,2733-2746 (2011).
31.Fritz, E. L. & Papavasiliou, F. N. Cytidine deaminases:AIDing DNA demethylation? Genes Dev.24,2107-2114 (2010).
32.Bhutani, N., Burns, D. M. & Blau, H. M. DNA demethylation dynamics. Cell 146, 866-872(2011).
33.Guo, J. U., Su, Y., Zhong, C., Ming, G. L. & Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145,423-434(2011).
34.Robbiani, D. F. et al. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Mol. Cell 36, 631-641 (2009).
35.Hasham, M. G. et al. Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination. Nature Immunol.11, 820-826 (2010).
36.Xu, Z. et al. Regulation of aicda expression and AID activity:relevance to somatic hypermutation and class switch DNA recombination. Crit. Rev. Immunol.27,367-397 (2007).
37.Hasler, J., Rada, C. & Neuberger, M. S. Cytoplasmic activation-induced cytidine deaminase (AID) exists in stoichiometric complex with translation elongation factor la (eEF1A). Proc. Natl Acad. Sci. USA108,18366-18371 (2011).
38.Uchimura, Y., Barton, L. F., Rada, C. & Neuberger, M. S. REG-y associates with and modulates the abundance of nuclear activation-induced deaminase. J. Exp. Med.208, 2385-2891 (2011).
39.Li, G. et al. Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination. J. Biol. Chem.3 May 2012 (doi:10.1074/jbc.Ml 12.366732).
40.He, B., Qiao, X. & Cerutti, A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J. Immunol.173,4479-491 (2004).
41.Tran, T. H. et al. B cell-specific and stimulation-responsive enhancers derepress Aicda by overcoming the effects of silencers. Nature Immunol.11,148-154 (2010).
42.Smale, S. T. Hierarchies of NF-кB target-gene regulation. Nature Immunol.12,689-694 (2011).
43.Baltimore, D. NF-кB is 25. Nature Immunol.12,683-685 (2011).
44.Pauklin, S., Semandez, I. V., Bachmann, G., Ramiro, A. R. & Petersen-Mahrt, S. K. Estrogen directly activates AID transcription and function. J. Exp. Med.206,99-111 (2009).
45.Mai, T. et al. Estrogen receptors bind to and activate the HOXC4/HoxC4 promoter to potentiate HoxC4-mediated activation-induced cytosine deaminase induction, immunoglobulin class switch DNA recombination, and somatic hypermutation. J. Biol. Chem.285,37797-37810 (2010).
46.White, C. A. et al. AID dysregulation in lupus-prone MRL/Faslpr/lpr mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations:modulation by HoxC4. Autoimmunity 44,585-598 (2011).
47.Sayegh, C. E., Quong, M. W., Agata, Y. & Murre, C. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nature Immunol.4, 586-593 (2003).
48.Ise, W. et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nature Immunol.12,536-543 (2011).
49.Betz, B. C. et al. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J. Exp. Med.207,933-942 (2010).
50.Cerutti, A. & Rescigno, M. The biology of intestinal immunoglobulin A responses. Immunity 28,740-750 (2008).
51.Fagarasan, S., Kawamoto, S., Kanagawa, O. & Suzuki, K. Adaptive immune regulation in the gut:T cell-dependent and T cell-independent IgA synthesis. Annu. Rev. Immunol. 28,243-273 (2010).
52.Daniel, J. A. et al. PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science 329,917-923 (2010).
53.Yu, K., Chedin, F., Hsieh, C. L., Wilson, T. E. & Lieber, M. R. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nature Immunol.4,442-451 (2003).
54.Chaudhuri, J. & Alt, F. W. Class-switch recombination:interplay of transcription, DNA deamination and DNA repair. Nature Rev. Immunol.4,541-552 (2004).
55.Basu, U. et al. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 144,353-363 (2011).
56.Sellars, M., Reina-San-Martin, B., Kastner, P. & Chan, S. Ikaros controls isotype selection during immunoglobulin class switch recombination. J. Exp. Med.206, 1073-1087(2009).
57.Perlot, T. & Alt, F. W. Cis-regulatory elements and epigenetic changes control genomic rearrangements of the IgH locus. Adv. Immunol.99,1-32 (2008).
58.Dunnick, W. A. et al. Switch recombination and somatic hypermutation are controlled by the heavy chain 3'enhancer region. J. Exp. Med.206,2613-2623 (2009).
59.Kim, E. C., Edmonston, C. R., Wu, X., Schaffer, A. & Casali, P. The HoxC4 homeodomain protein mediates activation of the immunoglobulin heavy chain 3'hs1,2 enhancer in human B cells. Relevance to class switch DNA jecombination. J. Biol. Chem. 279,42258-2269(2004).
60.Wuerffel, R. et al. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity 27,711-722(2007).
61.Hackney, J. A. et al. DNA targets of AID evolutionary link between antibody somatic hypermutation and class switch recombination. Adv. Immunol.101,163-189 (2009).
62.Xu, Z. et al.14-3-3 adaptor proteins recruit AID to 5'-AGCT-3'-rich switch regions for class switch recombination. Nature Struct. Mol. Biol.17,1124-1135 (2010).
63.Zarrin, A. A. et al. An evolutionarily conserved target motif for immunoglobulin class-switch recombination. Nature Immunol.5,1275-1281 (2004).
64.Park, S. R. et al. HoxC4 binds to the promoter of the cytidine deaminase AID gene to induce AID expression, class-switch DNA recombination and somatic hypermutation. Nature Immunol.10,540-550 (2009)
65.Aoufouchi, S. et al. Proteasomal degradation restricts the nuclear lifespan of AID. J. Exp. Med.205,1357-1368 (2008).