高IgM综合征及IPEX临床与分子特征研究
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摘要
第一部分:HIGM分子与T细胞亚群特征分析
目的:建立HIGM基因及流式细胞仪检测方法,确诊HIGM患儿,分析其临床及分子特征。检测HIGM患儿中Treg、Th17、Th1细胞亚群变化规律与自身免疫发生相关性。
方法:收集两年来HIGM疑似患儿外周血,PCR扩增CD40L、CD40、AID、UNG、NEMO等基因后测序比对,并与健康对照比较,确定致病突变。流式细胞仪检测突变患儿及移植患儿移植前后CD40L、CD40蛋白表达及Treg、Th1、Th17细胞亚群变化。
结果:通过临床、免疫学筛查和基因分析,发现中国12例HIGM患儿,基因确诊8例,均为CD40L突变。其中错义突变1例,无义突变3例,缺失突变4例。其P7发生染色体微缺失(缺失5369bp)。8例突变中发现新型突变6例。突变分布于各外显子及启动子区域,主要集中在羧基末端胞外区。4例疑诊患儿未发现上述基因突变。8例CD40L突变患儿其CD40L均无表达。同时发现XHIM患儿中Treg明显下降(1.265±0.4801 N=6 VS 2.718±0.3963 N=12 P=0.04),Th17呈下降趋势(0.4200±0.1525 N=6 VS 0.9600±0.2076 N=12 P=0.1)。同时Th1/Treg细胞比例在XHIM中亦呈上升趋势(21.39±14.64 N=6 VS 10.50±2.596 N=12)。对移植前后2例XHIM患儿Treg、Th1、Th17检测发现,移植后Th17/Treg/Th1均较移植前呈上升趋势。
结论:通过临床及其基因蛋白筛查手段,确诊中国较大宗HIGM患儿,发现6例CD40L新型突变。调节性T细胞降低与Th1/Treg比上升可能与XHIM患儿自身免疫发生相关。第二部分:IPEX临床及其分子特征分析
目的:探讨表现为顽固性腹泻、有或无胰岛素依赖性糖尿病以及皮疹的疑似IPEX患儿FOXP3基因变异及其蛋白表达水平。
方法:对近两年来我院收治的5例表现为早发性顽固性腹泻、有或无胰岛素依赖性糖尿病、以及皮疹的疑似IPEX男性患儿进行FOXP3基因扩增及测序分析,将发现的可疑突变位点通过数据库查询及与100例健康儿童相同位点序列比较,采用流式细胞仪检测CD4+CD25+FOXP3+调节性T细胞比例和FOXP3蛋白表达。
结果:5例疑似患儿中发现3例FOXP3突变,P1为FOXP3基因13098与13099位碱基之间插入碱基A(g.13098-13099 ins A),随后立即形成终止密码子。CD4+CD25+ FOXP3+调节性T细胞缺失。其临床表现为典型IPEX三联征。P2为13128位碱基错义突变(g.13128 G>A),导致FOXP3蛋白370位氨基酸由甲硫氨酸替换为异亮氨酸(Met370Ile),CD4+CD25+ FOXP3+调节性T细胞比例升高,患儿母亲为携带者。患儿临床表现为不完全症状。100例正常儿童FOXP3基因相同位点未见变异,故可排除该位点多态性可能。P3为此前已报道的错义突变(g.11628 T>C;p.F324L),临床表现为典型轻型症状。P1与P2为此前未见报道的新发突变。调节性T细胞比例降低。
结论:通过临床、免疫学筛查和基因分析,首次发现中国3例IPEX患儿,其中两例为新发突变。同时调节性T细胞数量与其临床严重性呈正相关关系。对早发胰岛素依赖性糖尿病、顽固性腹泻及不明原因肾脏等多系统损害婴幼儿,应考虑IPEX可能并进行FOXP3基因分析。第三部分:天然突变FOXP3蛋白抑制功能研究
目的:诱变及表达天然突变FOXP3蛋白,探索不同突变FOXP3蛋白抑制IL-2转录功能与IPEX临床表型相关关系。
方法:常规由外周血cDNA扩增FOXP3基因CDS区,构建表达载体,DpnI酶消化法在正常FOXP3表达载体基础上定点诱变产生突变FOXP3蛋白(N326Kfs1X; V408M; A384T; R337Q; F324L; 251delE; L242P; R146W; P187L; T108M; M370I),与IL-2启动子荧光素酶报告基因载体共转染Jurkat T细胞,PMA与离子霉素活化后双荧光素酶报告体系检测海肾荧光素与萤火虫荧光素。计算突变FOXP3对IL-2转录抑制活性变化。
结果:成功建立11种天然突变FOXP3蛋白表达载体,建立双荧光素酶表达检测系统。共转染体系检测发现N326Kfs1X; V408M; A384T; R337Q; F324L; 251delE; L242P; R146W; P187L; T108M; M370I突变体抑制IL-2转录功能均下降,其中严重突变类型251delE、N326Kfs1X和亮氨酸拉链区域突变L242P、R146W完全失去抑制功能。但仅251delE、N326Kfs1X等严重突变体与严重抑制功能障碍和IPEX临床三联征具有相关性。
结论:FOXP3严重突变和亮氨酸拉链区域突变常导致FOXP3抑制功能完全丧失,且仅严重突变体与严重抑制功能障碍及IPEX临床三联征具有相关性,因此基因诊断是IPEX最终确诊手段。
Part one: Analysis of Clinical and Molecular Characteristics of HIGM in 12 Patients from 12 Unrelated Chinese Families
Objective: To analyze the genes encoding the CD40L, CD40, AID, UNG, NEMO and CD40L, CD40 protein expression in 12 Chinese patients from 12 unrelated families with the hyper-IgM phenotype. To detect the relatitonship among lymphocyte sybsets of Treg, Th1 and Th17 freqency and autoimmunity in HIGM. Methods: The CD40L, CD40, AID, UNG, NEMO gene mutations were screened through direct sequencing of exon and cDNA specific polymerase chain reaction (PCR) products. Flow cytometry was used to determine the CD40L and CD40 expression on activated T lymphocytes. Treg, Th1 and Th17 freqency were detected by FCM in patient with HIGM including the petients after bone marrow transplantation. Results: In the present study, molecular defects involved in the HIGM in 12 patients were investigated. We identified 8 distinct CD40L mutations, 6 of which had not been previously described. All 8 patients with CD40L mutation showed no production of CD40L protein on activated T cells. The frequency of regulatory T cells decresed when compared with healthy control (1.265±0.4801 N=6 VS 2.718±0.3963 N=12 P=0.04), so the proportion of Th1/Treg also decreased (21.39±14.64 N=6 VS 10.50±2.596 N=12). Besides, the frequency of Th17 also trend to dcreased. Two out of the eight genetically defined patients received umbilical cord blood stem cell transplantation from unrelated donor and achieved clinical remission. The expression of CD40L on the PBMC restored. The Treg and Th17 cells increased. Conclusion: We demonstrated 8 XHIM patients with CD40L mutations, six of wich were novel mutations. All of the mutations led to null protein expression of CD40L. The decreased Treg frequency and proportion of Th1/Treg may associate with antoimmunity in XHIM patients. Part two: Analysis of Clinical and Molecular Characteristics of IPEX in 3 Patients from 3 Unrelated Chinese Families
Objective To investigate variations in FOXP3 gene and its expression in male children presented with IPEX phenotype. Methods Five male children presented with early-onset severe enteropathy, rash, with or without insulin-dependent diabetes mellitus (IDDM) were subjected to the detection of FOXP3 expression on CD4+CD25+ T cells and frequency of regulatory T cells (Tregs) by flow cytometry. The cDNA and relative coding exons including promoter region of FOXP3 gene were amplified by PCR and sequenced. The candidate mutation sites were compared with those of 100 healthy controls to exclude polymorphism. Results Genetic analysis revealed 1 insertion and 2 missense mutations out of the total 5 children. P1 presented classical IPEX clinical phenotype. A novel frameshift insertion occurred in exon 11 (p.N361KfsX1) which led to complete abrogation of Tregs. P2 showed incomplete IPEX form and carryied a missense mutation in exon 11 (p.M370I) with slightly increased frequency of Tregs, whereas P3 presented relatively mild classical manifestations of IPEX and was demonstrated a previously reported missense mutation in exon 10 (p.F324L) with decreased frequency of Tregs. Conclusions: Three cases of IPEX presented as different clinical form with 2 novel mutations were identified from three unrelated families in China. Our limited data indicates somewhat correlation between genotype and phenotype of this disease as well. Part three: the relationships between suppression function of natural mutated FOXP3 and IPEX clinical characterizations
Objective To analyze the relationship between the suppression function of natural mutated FOXP3 and IPEX clinical characterizations.
Methods FOXP3 gene CDS region was amplified by PCR with the template of normal cDNA and then cloned into pReceiver-12 vector. The mutated FOXP3 expression vectors were constructed by site-directed mutagenesis. The pReceiver-12 vector and IL-2 promoter luciferase reporter vector were cotransfected to Jurkat T cells and stimulated with 50 ng/ml of phorbol myristate acetate and 500 ng/ml ionomycin for 6–7 hrs before lysing cells and analyzed by means of dual luciferase assay normalized with Renilla luciferase activity according to the manufacturer’s protocol. Results Eleven mutated foxp3 protein were constructed and expressed (N326Kfs1X; V408M; A384T; R337Q; F324L; 251delE; L242P; R146W; P187L; T108M; M370I). The mutated FOXP3 of 251delE, N326Kfs1, L242P, M370I and R146W absolutely lost suppression function and the others partly lost. The analysis of clinical characterization shows no relationship with the FOXP3 suppression function except that the severe mutation 251delE, N326Kfs1 always showed triad of IPEX and severely suppression function defect. Conclusions: Severe FOXP3 mutations are associated with severe suppression function defect and triad of IPEX. The clinical phenotype was determined by gene bachground and environment and FOXP3 gene analysis was the final diagnosis.
目的:建立HIGM基因及流式细胞仪检测方法,确诊HIGM患儿,分析其临床及分子特征。检测HIGM患儿中Treg、Th17、Th1细胞亚群变化规律与自身免疫发生相关性。
方法:收集两年来HIGM疑似患儿外周血,PCR扩增CD40L、CD40、AID、UNG、NEMO等基因后测序比对,并与健康对照比较,确定致病突变。流式细胞仪检测突变患儿及移植患儿移植前后CD40L、CD40蛋白表达及Treg、Th1、Th17细胞亚群变化。
结果:通过临床、免疫学筛查和基因分析,发现中国12例HIGM患儿,基因确诊8例,均为CD40L突变。其中错义突变1例,无义突变3例,缺失突变4例。其P7发生染色体微缺失(缺失5369bp)。8例突变中发现新型突变6例。突变分布于各外显子及启动子区域,主要集中在羧基末端胞外区。4例疑诊患儿未发现上述基因突变。8例CD40L突变患儿其CD40L均无表达。同时发现XHIM患儿中Treg明显下降(1.265±0.4801 N=6 VS 2.718±0.3963 N=12 P=0.04),Th17呈下降趋势(0.4200±0.1525 N=6 VS 0.9600±0.2076 N=12 P=0.1)。同时Th1/Treg细胞比例在XHIM中亦呈上升趋势(21.39±14.64 N=6 VS 10.50±2.596 N=12)。对移植前后2例XHIM患儿Treg、Th1、Th17检测发现,移植后Th17/Treg/Th1均较移植前呈上升趋势。
结论:通过临床及其基因蛋白筛查手段,确诊中国较大宗HIGM患儿,发现6例CD40L新型突变。调节性T细胞降低与Th1/Treg比上升可能与XHIM患儿自身免疫发生相关。第二部分:IPEX临床及其分子特征分析
目的:探讨表现为顽固性腹泻、有或无胰岛素依赖性糖尿病以及皮疹的疑似IPEX患儿FOXP3基因变异及其蛋白表达水平。
方法:对近两年来我院收治的5例表现为早发性顽固性腹泻、有或无胰岛素依赖性糖尿病、以及皮疹的疑似IPEX男性患儿进行FOXP3基因扩增及测序分析,将发现的可疑突变位点通过数据库查询及与100例健康儿童相同位点序列比较,采用流式细胞仪检测CD4+CD25+FOXP3+调节性T细胞比例和FOXP3蛋白表达。
结果:5例疑似患儿中发现3例FOXP3突变,P1为FOXP3基因13098与13099位碱基之间插入碱基A(g.13098-13099 ins A),随后立即形成终止密码子。CD4+CD25+ FOXP3+调节性T细胞缺失。其临床表现为典型IPEX三联征。P2为13128位碱基错义突变(g.13128 G>A),导致FOXP3蛋白370位氨基酸由甲硫氨酸替换为异亮氨酸(Met370Ile),CD4+CD25+ FOXP3+调节性T细胞比例升高,患儿母亲为携带者。患儿临床表现为不完全症状。100例正常儿童FOXP3基因相同位点未见变异,故可排除该位点多态性可能。P3为此前已报道的错义突变(g.11628 T>C;p.F324L),临床表现为典型轻型症状。P1与P2为此前未见报道的新发突变。调节性T细胞比例降低。
结论:通过临床、免疫学筛查和基因分析,首次发现中国3例IPEX患儿,其中两例为新发突变。同时调节性T细胞数量与其临床严重性呈正相关关系。对早发胰岛素依赖性糖尿病、顽固性腹泻及不明原因肾脏等多系统损害婴幼儿,应考虑IPEX可能并进行FOXP3基因分析。第三部分:天然突变FOXP3蛋白抑制功能研究
目的:诱变及表达天然突变FOXP3蛋白,探索不同突变FOXP3蛋白抑制IL-2转录功能与IPEX临床表型相关关系。
方法:常规由外周血cDNA扩增FOXP3基因CDS区,构建表达载体,DpnI酶消化法在正常FOXP3表达载体基础上定点诱变产生突变FOXP3蛋白(N326Kfs1X; V408M; A384T; R337Q; F324L; 251delE; L242P; R146W; P187L; T108M; M370I),与IL-2启动子荧光素酶报告基因载体共转染Jurkat T细胞,PMA与离子霉素活化后双荧光素酶报告体系检测海肾荧光素与萤火虫荧光素。计算突变FOXP3对IL-2转录抑制活性变化。
结果:成功建立11种天然突变FOXP3蛋白表达载体,建立双荧光素酶表达检测系统。共转染体系检测发现N326Kfs1X; V408M; A384T; R337Q; F324L; 251delE; L242P; R146W; P187L; T108M; M370I突变体抑制IL-2转录功能均下降,其中严重突变类型251delE、N326Kfs1X和亮氨酸拉链区域突变L242P、R146W完全失去抑制功能。但仅251delE、N326Kfs1X等严重突变体与严重抑制功能障碍和IPEX临床三联征具有相关性。
结论:FOXP3严重突变和亮氨酸拉链区域突变常导致FOXP3抑制功能完全丧失,且仅严重突变体与严重抑制功能障碍及IPEX临床三联征具有相关性,因此基因诊断是IPEX最终确诊手段。
Part one: Analysis of Clinical and Molecular Characteristics of HIGM in 12 Patients from 12 Unrelated Chinese Families
Objective: To analyze the genes encoding the CD40L, CD40, AID, UNG, NEMO and CD40L, CD40 protein expression in 12 Chinese patients from 12 unrelated families with the hyper-IgM phenotype. To detect the relatitonship among lymphocyte sybsets of Treg, Th1 and Th17 freqency and autoimmunity in HIGM. Methods: The CD40L, CD40, AID, UNG, NEMO gene mutations were screened through direct sequencing of exon and cDNA specific polymerase chain reaction (PCR) products. Flow cytometry was used to determine the CD40L and CD40 expression on activated T lymphocytes. Treg, Th1 and Th17 freqency were detected by FCM in patient with HIGM including the petients after bone marrow transplantation. Results: In the present study, molecular defects involved in the HIGM in 12 patients were investigated. We identified 8 distinct CD40L mutations, 6 of which had not been previously described. All 8 patients with CD40L mutation showed no production of CD40L protein on activated T cells. The frequency of regulatory T cells decresed when compared with healthy control (1.265±0.4801 N=6 VS 2.718±0.3963 N=12 P=0.04), so the proportion of Th1/Treg also decreased (21.39±14.64 N=6 VS 10.50±2.596 N=12). Besides, the frequency of Th17 also trend to dcreased. Two out of the eight genetically defined patients received umbilical cord blood stem cell transplantation from unrelated donor and achieved clinical remission. The expression of CD40L on the PBMC restored. The Treg and Th17 cells increased. Conclusion: We demonstrated 8 XHIM patients with CD40L mutations, six of wich were novel mutations. All of the mutations led to null protein expression of CD40L. The decreased Treg frequency and proportion of Th1/Treg may associate with antoimmunity in XHIM patients. Part two: Analysis of Clinical and Molecular Characteristics of IPEX in 3 Patients from 3 Unrelated Chinese Families
Objective To investigate variations in FOXP3 gene and its expression in male children presented with IPEX phenotype. Methods Five male children presented with early-onset severe enteropathy, rash, with or without insulin-dependent diabetes mellitus (IDDM) were subjected to the detection of FOXP3 expression on CD4+CD25+ T cells and frequency of regulatory T cells (Tregs) by flow cytometry. The cDNA and relative coding exons including promoter region of FOXP3 gene were amplified by PCR and sequenced. The candidate mutation sites were compared with those of 100 healthy controls to exclude polymorphism. Results Genetic analysis revealed 1 insertion and 2 missense mutations out of the total 5 children. P1 presented classical IPEX clinical phenotype. A novel frameshift insertion occurred in exon 11 (p.N361KfsX1) which led to complete abrogation of Tregs. P2 showed incomplete IPEX form and carryied a missense mutation in exon 11 (p.M370I) with slightly increased frequency of Tregs, whereas P3 presented relatively mild classical manifestations of IPEX and was demonstrated a previously reported missense mutation in exon 10 (p.F324L) with decreased frequency of Tregs. Conclusions: Three cases of IPEX presented as different clinical form with 2 novel mutations were identified from three unrelated families in China. Our limited data indicates somewhat correlation between genotype and phenotype of this disease as well. Part three: the relationships between suppression function of natural mutated FOXP3 and IPEX clinical characterizations
Objective To analyze the relationship between the suppression function of natural mutated FOXP3 and IPEX clinical characterizations.
Methods FOXP3 gene CDS region was amplified by PCR with the template of normal cDNA and then cloned into pReceiver-12 vector. The mutated FOXP3 expression vectors were constructed by site-directed mutagenesis. The pReceiver-12 vector and IL-2 promoter luciferase reporter vector were cotransfected to Jurkat T cells and stimulated with 50 ng/ml of phorbol myristate acetate and 500 ng/ml ionomycin for 6–7 hrs before lysing cells and analyzed by means of dual luciferase assay normalized with Renilla luciferase activity according to the manufacturer’s protocol. Results Eleven mutated foxp3 protein were constructed and expressed (N326Kfs1X; V408M; A384T; R337Q; F324L; 251delE; L242P; R146W; P187L; T108M; M370I). The mutated FOXP3 of 251delE, N326Kfs1, L242P, M370I and R146W absolutely lost suppression function and the others partly lost. The analysis of clinical characterization shows no relationship with the FOXP3 suppression function except that the severe mutation 251delE, N326Kfs1 always showed triad of IPEX and severely suppression function defect. Conclusions: Severe FOXP3 mutations are associated with severe suppression function defect and triad of IPEX. The clinical phenotype was determined by gene bachground and environment and FOXP3 gene analysis was the final diagnosis.
引文
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