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中华妇幼临床医学杂志(电子版)

中华妇幼临床医学杂志(电子版) ›› 2020, Vol. 16 ›› Issue (02) : 171 -180. doi: 10.3877/cma.j.issn.1673-5250.2020.02.008

所属专题： 文献；

论著

儿童特发性肾病综合征低IgG血症机制：哺乳动物雷帕霉素靶蛋白过表达对滤泡辅助性T细胞数量的可能影响
刘光磊1, 杨军2, 李成荣2,†()   
  1. 1. 深圳市儿童医院肾脏免疫科，广东　518026[现在遵义医科大学第五附属(珠海)医院儿科，广东　519000]
    2. 深圳市儿童医院肾脏免疫科，广东　518026
  • 收稿日期:2019-05-07 修回日期:2020-02-21 出版日期:2020-04-01
  • 通信作者: 李成荣

Mechanism of hypo-IgG in children with idiopathic nephrotic syndrome: the possible influence of mammalian target of rapamycin over expression on follicular helper T cells

Guanglei Liu1, Jun Yang2, Chengrong Li2,†()   

  1. 1. Department of Nephrology and Immunology, Shenzhen Children′s Hospital, Shenzhen 518026, Guangdong Province, China (is working in the Department of Pediatrics, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, Zhuhai 519000, Guangdong Province, China)
    2. Department of Nephrology and Immunology, Shenzhen Children′s Hospital, Shenzhen 518026, Guangdong Province, China
  • Received:2019-05-07 Revised:2020-02-21 Published:2020-04-01
  • Corresponding author: Chengrong Li
  • About author:
    Corresponding author: Li Chengrong, Email:
  • Supported by:
    Special Scientific Research Project of Public Welfare Profession of National Health and Family Planning Commision(201402012)
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引用本文：

刘光磊, 杨军, 李成荣. 儿童特发性肾病综合征低IgG血症机制：哺乳动物雷帕霉素靶蛋白过表达对滤泡辅助性T细胞数量的可能影响[J]. 中华妇幼临床医学杂志(电子版), 2020, 16(02): 171-180.

Guanglei Liu, Jun Yang, Chengrong Li. Mechanism of hypo-IgG in children with idiopathic nephrotic syndrome: the possible influence of mammalian target of rapamycin over expression on follicular helper T cells[J]. Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition), 2020, 16(02): 171-180.

目的

探讨儿童特发性肾病综合征(INS)的低免疫球蛋白(Ig)G血症可能机制。

方法

选择2015年9月至2016年10月，于深圳市儿童医院接受治疗的40例激素敏感型INS患儿为研究对象。按照患儿病情，将其分为INS初发组(n＝20)和INS缓解组(n＝20)，选择同期在该院接受健康体检的同年龄健康儿童纳入对照组(n＝20)。采用流式细胞术(FCM)检测受试儿外周血单个核细胞(PBMC)中滤泡辅助性T细胞(Tfh，CD4＋CXCR5＋ICOShighT)、初始B细胞(CD19＋CD27－IgD＋B细胞)、转化前记忆B细胞(CD19＋CD27＋IgD＋ B细胞)、转化后记忆B细胞(CD19＋CD27＋IgD－ B细胞)及浆细胞(CD19＋CD27＋IgD－CD38highB细胞)百分比；采用逆转录-聚合酶链反应(RT-PCR)，检测受试儿外周血CD4＋T细胞相关基因mRNA表达水平；采用酶联免疫吸附试验、免疫荧光吸附试验，分别检测受试儿血浆白细胞介素(IL)-2水平、丙二醛浓度。采用单因素方差分析及最小显著性差异(LSD)-t法，对上述指标分别进行3组间及组间两两比较；对其中部分指标的相关性，采用Pearson相关分析法。本研究通过深圳市儿童医院伦理委员会批准(批准日期：2016-04-11)，所有受试对象监护人知情并同意。

结果

①INS初发组患儿血清总蛋白及白蛋白水平，以及血浆总IgG、IgG1、IgG2、IgG4水平等6项指标，均显著低于对照组健康儿童，血清总胆固醇浓度，则显著高于对照组，并且差异均有统计学意义(P<0.05)。②INS初发组患儿PBMC中Tfh百分比为(3.9±1.2)%，显著低于对照组的(5.2±1.1)%及INS缓解组的(4.9±1.2)%，并且差异均有统计学意义(P＝0.001，P＝0.021)。③INS初发组患儿PBMC中，转化后记忆B细胞、浆细胞百分比为(8.4±3.6)%、(7.5±2.0)%，均低于INS缓解组患儿的(11.6±2.7)%、(11.4±3.9)%及对照组健康儿童的(12.2±3.7)%、(12.5±3.4)%，并且差异均有统计学意义(均为P<0.001)。④INS初发组患儿的8项指标，如CD4＋T细胞相关基因B淋巴细胞诱导成熟蛋白(Blimp)-1、IL-2Rα、IL-2Rβ、IL-2Rγ、磷脂酰肌醇3激酶(PI3K)、丝氨酸/苏氨酸蛋白激酶(AKT)、哺乳动物雷帕霉素靶蛋白(mTOR)及雷帕霉素结合蛋白复合物(mTORC)1mRNA表达水平为(3.2±1.1)、(14.4±5.7)、(18.5±4.6)、(7.2±1.7)、(10.3±3.6)、(2.2±0.3)、(1.84±0.68)、(7.2±1.4)，均高于INS缓解组患儿的(2.4±1.1)、(10.5±2.5)、(15.5±3.5)、(5.5±1.1)、(8.5±2.2)、(1.8±0.5)、(1.44±0.29)、(6.1±1.2)及对照组健康儿童的(2.4±1.1)、(10.3±5.5)、(14.6±4.8)、(5.6±2.5)、(1.56±0.42)、(2.4±1.1)、(10.3±5.5)、(14.6±4.8)；而B细胞淋巴瘤因子(BCL)-6 mRNA表达水平为(1.22±0.29)，则低于INS缓解组患儿的(1.49±0.35)及对照组健康儿童的(1.56±0.42)，并且上述差异均有统计学意义(均为P<0.05)。⑤INS初发组患儿血浆IL-2水平及丙二醛浓度为(28.9±6.1) ng/L、(15.0±9.2) μmol/L，均高于INS缓解组患儿的(18.0±5.9) ng/L、(7.3±5.4) μmol/L及对照组健康儿童的(16.2±7.6) ng/L、(8.8±5.1) μmol/L，并且差异均有统计学意义(P<0.001、P＝0.022，P<0.001、P＝0.004)。⑥INS缓解组患儿与对照组健康儿童上述21项指标比较，差异均无统计学意义(P>0.05)。⑦60例受试儿PBMC中Tfh百分比与血浆IgG水平、浆细胞百分比，均呈正相关关系(r＝0.692、0.809，P<0.001)。INS初发组20例患儿血浆丙二醛浓度与mTOR、mTORC1mRNA表达水平，亦均呈正相关关系(r＝0.627、P＝0.003，r＝0.794、P<0.001)。

结论

INS患儿PBMC中Tfh百分比下降影响B细胞分化成熟，可能是导致患儿低IgG血症的原因之一。血浆IL-2水平升高和高脂血症导致的mTOR和mTORC1过表达，可能是抑制INS患儿Tfh分化的重要原因。

关键词: 肾病综合征, 丙种球蛋白缺乏血症, 免疫，体液, 免疫球蛋白G, T淋巴细胞，辅助诱导, 雷帕霉素靶蛋白复合物1, 雷帕霉素靶蛋白复合物2, 儿童
Objective

To investigate the possible mechanism of hypogammaglobulinemia in pediatric idiopathic nephrotic syndrome (INS).

Methods

A total of 40 children with steroid-sensitive INS from September 2015 to October 2016 in Shenzhen Children′s Hospital were selected as research subjects. According to pathogenetic condition, they were divided into new onset INS group (n=20) and remission INS group (n=20). Meanwhile, in the same hospital there were 20 undergoing physical examination children with age matching the research subjects were enrolled into control group (n=20). The percentage of follicular helper T cell(Tfh, CD4+ CXCR5+ ICOShigh T cell), naive B cells (CD19+ CD27-IgD+ B cells), pre-transformed memory B cells (CD19+ CD27+ IgD+ B cells), transformed memory B cells (CD19+ CD27+ IgD- B cells) and plasma cells (CD19+ CD27+ IgD-CD38high B cells) in peripheral blood mononuclear cell (PBMC) were analyzed by flow cytometry (FCM). Reverse transcription-polymerase chain reaction (RT-PCR) was performed to analyze mRNA expression level of CD4+ T cells related genes in peripheral blood. Plasma level of interleukin (IL)-2 and plasma concentrations of malondialdehyde were detected by enzyme linked immunosorbent assay and immunofluorescence adsorption test, respectively. Clinical data were compared among three groups and pairwise compared between two groups using one-way ANOVA and least significant difference (LSD)-t test, respectively. And Pearson′s correlation analysis was used to analyze the correlation between some of two indexes.The study was approved by the Ethics Committee of Shenzhen Children′s Hospital (Approval date: April 11, 2016), and all guardians of children signed the informed consent forms for clinical study.

Results

①The serum levels of total protein and albumin, also plasma immunoglobulin (Ig)G, IgG1, IgG2 and IgG4 of children with INS in new onset INS group were lower than those of control group, while serum total cholesterol concentration was higher than that of control group, and the differences were statistically significant (P<0.05). ②The percentage of Tfh in PBMC of children with INS in new onset INS group was (3.9±1.2)%, which was lower than that of (5.2±1.1)% in control group and (4.9±1.2)% in remission INS group, and the differences were statistically significant (P=0.001, P=0.021). ③The percentage of transformed memory B cells and plasma cells in PBMC of children with INS in new onset INS group were (8.4±3.6)% and (7.5±2.0)%, which were lower than those of (11.6±2.7)% and (11.4±3.9)% in remission INS group and (12.2±3.7)% and (12.5±3.4)% in control group, and the differences were statistically significant (all P<0.001). ④The mRNA expression levels of CD4+ T cells related genes of B lymphocyte induced maturation protein (Blimp)-1, IL-2Rα, IL-2Rβ, IL-2Rγ, phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase (AKT), mammalian target of rapamycin (mTOR) and mechanistic target of rapamycin complex (mTORC)1 of children with INS in new onset INS group were (3.2±1.1), (14.4±5.7), (18.5±4.6), (7.2±1.7), (10.3±3.6), (2.2±0.3), (1.84±0.68) and (7.2±1.4), which were higher than those of (2.4±1.1), (10.5±2.5), (15.5±3.5), (5.5±1.1), (8.5±2.2), (1.8±0.5), (1.44±0.29) and (6.1±1.2) in remission INS group and (2.4±1.1), (10.3±5.5), (14.6±4.8), (5.6±2.5), (1.56±0.42), (2.4±1.1), (10.3±5.5) and (14.6±4.8) in control group; while mRNA expression level of B-cell lymphoma (BCL)-6 in new onset INS group was (1.22±0.29), which was lower than that of (1.49±0.35) in remission INS group and (1.56±0.42) in control group, and all the differences above were statistically significant (all P<0.05). ⑤Plasma level of IL-2 and concentration of malondialdehyde of children with INS in new onset INS group were (28.9±6.1) ng/L, (15.0±9.2) μmol/L, which were higher than those of (18.0±5.9) ng/L, (7.3±5.4) μmol/L in remission INS group and (16.2±7.6) ng/L, (8.8±5.1) μmol/L in control group, and the differences were statistically significant(P<0.001, P=0.022; P<0.001, P=0.004). ⑥There were no significant differences between remission INS group and control group in all these above mentioned 21 indexes (P>0.05). ⑦ The percentage of Tfh in PBMC of 60 participants were positively correlated with their plasma IgG levels and the percentage of plasma cells (r=0.692, 0.809; P<0.001). Plasma concentration of malondialdehyde of 20 children with INS in new onset INS group were positively correlated with mRNA expression levels of mTOR and mTORC1 genes (r=0.627, P=0.003; r=0.794, P<0.001).

Conclusions

Decrease of percentage of Tfh in PBMC of children with INS effected on differentiation and maturation of B cells, which might be one of the reasons that resulted in hypogammaglobulinemia. Over expression of mTOR and mTORC1 caused by increased plasma IL-2 level and hyperlipidemia could be an important reason to inhibit the differentiation of Tfh in children with INS.

Key words: Nephrotic syndrome, Agammaglobulinemia, Immunity, humoral, Immunoglobulin G, T-lymphocytes, helper-inducer, Mechanistic target of rapamycin complex 1, Mechanistic target of rapamycin complex 2, Child
表1 本研究CD4＋T细胞相关基因引物信息
基因 正向引物(5′→3′) 反向引物(5′→3′) 退火温度(℃) 扩充片段长度(bp)
BCL-6 ATGAGGAGTTTCGGATGTC CCTCTTCTGGGATTGTTTCC 58 177
Blimp-1 CTTAAATTGTGAGCCAAGCCATGTA GTAGGCAAGGGTGCCCAATC 60 148
mTOR ATGCTTGGAACCGGACCTG TCTTGACTCATCTCGGAGTT 60 173
mTORC1 GCGAATTGAGACGGACTTTGA GAGTCTGCGCGTGTTGTTTAC 60 90
mTORC2 CAGAAACCCTAAAGCTGCATTGTAA GTCTGTTCAGTGACCTACAAACACC 60 180
IL-2Rα ATGAATGAGGTCCCAGGCAGAG TAGTGCAGGCCAAATTCAGGGTA 60 126
IL-2Rβ AGGACCTTGGGTTCCCAATACA ATTCAGGACCCTATGGCAGGAG 60 187
IL-2Rγ TGAACCACTGTTTGGAGCACTTG GTAGCGTTTCTGCCCATCCAC 60 122
PI3K AGCATTGGGACCTCACATTACACA ACTGGAAACACAGTCCATGCACATA 60 138
AKT CTTGCTTTCAGGGCTGCTCA TACACGTGCTGCCACACGATAC 60 117
GAPDH CAAGAAGGTGGTGAAGCAGG AGGTGGAGGAGTGGGTGTCG 54～60 110
表2 3组受试儿一般临床资料比较
组别 例数 性别[例数(%)] 年龄(月，±s) 血清总蛋白水平(g/L, ±s) 血清白蛋白水平(g/L, ±s) 血清总胆固醇浓度(μmol/L, ±s)
男 女
INS初发组 20 12(60.0) 8(40.0) 38±16 41.5±5.4 16.0±5.0 10.5±2.7
INS缓解组 20 13(65.0) 7(35.0) 41±18 66.2±4.9 42.9±2.2 4.5±1.4
对照组 20 14(70.0) 6(30.0) 40±15 68.3±3.9 43.6±3.2 4.3±1.5
检验值 ? χ2＝12.000 F＝0.103 F＝192.141 F＝341.150 F＝66.836
P值 ? 0.285 0.902 <0.001 <0.001 <0.001
表3 3组受试儿血浆免疫球蛋白水平比较(g/L，±s)
组别 例数 总IgG IgG1 IgG2 IgG3 IgG4 IgA IgM
INS初发组 20 3.2±1.9 3.9±1.7 1.2±0.7 0.34±0.16 0.26±0.19 1.2±0.8 1.8±0.5
INS缓解组 20 8.2±2.1 5.7±1.7 1.7±1.0 0.40±0.24 0.54±0.45 1.1±0.7 1.4±0.5
对照组 20 8.4±2.2 6.8±2.2 2.1±0.9 0.43±0.25 0.81±0.79 1.1±0.9 1.3±0.5
F值 ? 8.157 6.388 4.690 0.604 3.016 0.023 0.867
P值 ? <0.001 0.001 0.007 0.616 0.039 0.978 0.467
图1 3组受试儿外周血中的Tfh流式细胞术检测示意图[图1A：CD4＋T细胞的SSC与FSC散点图；图1B：CD4＋CXCR5＋T细胞(方框内)；图1C：3组受试儿PBMC中Tfh百分比(对照组为5.2%、INS初发组为3.9%、INS缓解组为4.9%)]
图2 60例受试儿PBMC中Tfh百分比与血浆IgG水平相关性分析的散点图
图3 3组受试儿外周血单个核细胞中不同分化阶段B细胞流式细胞术检测示意图[图3A：SSC与FSC散点图；图3B：外周血中B细胞(方框内)；图3C：3组受试儿FBMC中不同分化阶段B细胞百分比；图3D：3组受试儿PBMC中浆细胞百分比]
图4 60例受试儿PBMC中Tfh百分比与浆细胞百分比相关性分析的散点图
表4 3组受试儿外周血单个核细胞中不同分化阶段B细胞百分比比较(%，±s)
组别 例数 初始B细胞 转化前记忆B细胞 转化后记忆B细胞 浆细胞
INS初发组 20 62.9±11.2 12.9±8.1 8.4±3.6 7.5±2.0
INS缓解组 20 67.7±6.1 13.7±8.4 11.6±2.7 11.4±3.9
对照组 20 69.2±10.5 13.5±9.8 12.2±3.7 12.5±3.4
F值 ? 1.185 0.468 16.928 41.622
P值 ? 0.313 0.629 <0.001 <0.001
表5 3组受试儿外周血CD4＋T细胞相关基因mRNA相对表达水平比较(±s)
组别 例数 BCL-6基因(×10－2) Blimp-1基因(×10－2) IL-2Rα基因(×10－3) IL-2Rβ基因(×10－3) IL-2Rγ基因(×10－1)
①INS初发组 20 1.22±0.29 3.2±1.1 14.4±5.7 18.5±4.6 7.2±1.7
②INS缓解组 20 1.49±0.35 2.4±1.1 10.5±2.5 15.5±3.5 5.5±1.1
③对照组 20 1.56±0.42 2.4±1.1 10.3±5.5 14.6±4.8 5.6±2.5
总体比较 ? ? ? ? ? ?
? F值 ? 3.382 10.439 6.404 4.027 4.418
? P值 ? 0.027 <0.001 0.004 0.024 0.016
组间两两比较P值a ? ? ? ? ? ?
? ① vs ② ? 0.019 0.001 0.007 0.041 0.010
? ① vs ③ ? 0.018 <0.001 0.001 0.009 0.011
? ② vs ③ ? 0.723 0.408 0.296 0.521 0.922
组别 例数 PI3K基因(×10－3) AKT基因(×10－3) mTOR基因(×10－3) mTORC1基因(×10－2) mTORC2基因(×10－1)
①INS初发组 20 10.3±3.6 2.2±0.3 1.84±0.68 7.2±1.4 1.9±0.7
②INS缓解组 20 8.5±2.2 1.8±0.5 1.44±0.29 6.1±1.2 1.6±0.5
③对照组 20 7.5±2.5 1.8±0.4 1.30±0.45 5.5±1.7 1.7±0.6
总体比较 ? ? ? ? ? ?
? F值 ? 6.561 9.782 4.622 6.999 1.768
? P值 ? 0.003 <0.001 0.014 0.002 0.180
组间两两比较P值a ? ? ? ? ? ?
? ① vs ② ? 0.015 0.004 0.028 0.018 0.072
? ① vs ③ ? 0.001 <0.001 0.005 <0.001 0.169
? ② vs ③ ? 0.306 0.209 0.643 0.166 0.626
图5 20例INS初发组患儿血浆丙二醛浓度与mTOR、mTORC1基因mRNA相对表达水平相关性分析的散点图
表6 3组受试儿血浆IL-2水平及丙二醛浓度比较(±s)
组别 例数 血浆IL-2水平(ng/L) 血浆丙二醛浓度(μmol/L)
INS初发组 20 28.9±6.1 15.0±9.2
INS缓解组 20 18.0±5.9 7.3±5.4
对照组 20 16.2±7.6 8.8±5.1
F值 ? 21.659 4.944
P值 ? <0.001 0.011
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