RhD-缺失型母儿血型不合新生儿溶血病的临床和实验研究
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摘要
研究目的RhD--缺失型是Rh血型系统一种极为罕见的变异体,血清学特征表现为红细胞上RhC/c、E/e抗原的完全缺乏和(或)D抗原的过量表达。目前RhD--缺失型的分子生物学机制尚不明确,国外的研究发现了两种情况:一种是RHCE基因完整但无表达活性,另一种是RHCE基因部分缺失。前者考虑是由于mRNA的转录活性降低所致,后者考虑是外显子部分缺失和基因重组两种机制。国内还没有相关报道。RhD--缺失型个体极易由输血或妊娠免疫,产生高效价的抗C/c、E/e的联合抗体(即抗Hro抗体),这种抗体除了不与RhD--、Rhnull、Rhmod细胞反应外,与一般红细胞都发生强烈的凝集反应。该抗体可以通过胎盘进入胎儿体内致敏胎儿红细胞,引起严重的胎儿或新生儿溶血病。本研究发现了两例RhD--缺失型个体,均为女性,都发生了严重的胎儿新生儿溶血病。本研究通过对两例RhD--缺失型胎儿新生儿溶血病的临床特征和治疗措施进行系统研究,探讨母体意外抗体效价动态监测和宫内B超的临床意义以及采用最小不相容血液对RhD--缺失型HDN换血治疗的临床应用价值。由于同一种血型表型,可以对应多种基因型,而且在不同种族和同一种族的不同群体中,同一种表型所对应的基因型也不尽相同。目前有关血型基因结构的资料,大多数来源于白人,不符合我国的种族群体特点。中国人群民族多,数量大,遗传杂合性大。本研究通过对两例确证为RhD--缺失型个体的血清学特征、基因结构和表达的深入研究,明确中国部分汉族人群的RhD--缺失型个体可能存在的新的发生机制。这对搞清中华民族的血型基因结构,广泛开展血型基因分型技术是十分必要的,还可能发现新的RH等位基因。
研究方法(1)采用经典的血细胞凝集法,对两位RhD--缺失型个体进行ABO和Rh血型鉴定、RhD--缺失型确认试验、直接和间接抗人球蛋白试验、意外抗体筛选与鉴定试验、母体意外抗体效价动态监测、胎儿和新生儿溶血病全套检测等,并对两个家系所有成员进行ABO和Rh血型调查。(2)对一例发生RhD--缺失型母儿血型不合HDN的新生儿进行常规内科治疗,监测溶血指标变化。在无法找到相合血源的情况下,采用最小不相容的血液为该新生儿换血。对另一例RhD--缺失型母儿血型不合HDFN,通过开展自体血储备、孕期监测、孕母服用中药治疗、孕母淋巴血浆置换、胎儿宫内输血、产后新生儿换血等综合救治方案进行干预和治疗。(3)采用序列特异性引物聚合酶链反应(PCR-SSP)的方法,对两例RhD--缺失型个体以及家系成员RHD与RHCE基因多个外显子与内含子进行Rh血型基因定型;对两例RhD--缺失型个体采用HindⅢ和SphⅠ内切酶酶切血液基因组DNA并与特异性探针进行Southern blot,并采用PCR-SSP方法扩增两个体RHCE基因多个外显子和内含子,采用RT-PCR方法检测两例RhD--缺失型个体是否有RHCE剪接体转录。
研究结果(1)两个体红细胞上RhC/c、E/e抗原完全缺乏,血清中均存在抗Hro抗体。两个体分别来自近亲和非近亲婚配的家系,亲代成员Rh表型均为纯合子,亲代成员中没有再次发现RhD--缺失型个体。(2)例1 RhD--缺失型个体的新生儿严重溶血,内科治疗无效,用最小不相容换血法为新生儿换血获得成功,及时挽救了患儿生命,经4年随访,患儿生长发育良好。例2 RhD--缺失型个体孕中期监测发现抗Hro抗体效价增高,经孕期综合治疗改善了胎儿宫内的贫血状况,有效延长了孕期。于孕32~(+2)周剖宫产下一女婴,虽经换血等积极治疗,患儿始终无自主呼吸,并存在肠道畸形,家属放弃治疗。(3)Southernblot发现两例RhD--缺失型个体RHCE基因均存在exon1,但存在中间段缺失(exon4-7缺失),进一步采用PCR-SSP方法特异性扩增RHCE基因多个外显子及内含子,证实RhD--缺失型个体RHCE intro4、exon4-7基因片段丢失,但exon3、exon9及3′端基因序列均存在。
研究结论(1)两个体均为RhD--缺失型血型,RhD--缺失型既可发生于近亲家系,也可发生于非近亲家系。(2)RhD--缺失型个体妊娠极易发生严重的HDFN,最小不相容换血法是治疗RhD--缺失型HDN的一种有效的手段。加强孕期监测及孕期综合治疗是预防和控制由RhD--缺失型导致的HDFN的重要手段。(3)中国部分汉族人群的RhD--缺失型个体的产生原因是RHCE基因exon4-7缺失,其截短的RHCE基因不表达相关活性产物,这与国外学者对白人、黑人RhD--缺失型个体发生的分子机制研究结果不同。
Objective RhD-- deletion is a rare variant in Rh-blood groupsystem which is characterized by the complete absence of RhC/c,E/eantigen and(or) overexpression of D antigen on the red blood cells. Atpresent, the molecular mechanism of RhD-- deletion is unclear, but thereare two possibilities contributing to it: first, the RHCE gene is intact butno expression at all; second, the RHCE gene is partially deleted. The firstis occurred in the mRNA transcription regulation level and the secondmay include exons deletion or gene recombination. RhD-- deletionindividuals are easily get immunized and can produce high titeranti-RhC/c,E/e antibody (i.e.anti-Hro antibody) by transfusion orpregnancy. The anti-Hro antibody produced by RhD-- deletionmothers can react with all red blood cells expect RhD--, Rhnull andRhmod cells, resulting to destruction of fetus red blood cells and causingsevere hemolytic disease. We investigated two RhD-- deletion pregnancypatients which are occurred severe HDFN. In this study by monitoringtheir anti-Hro antibody titer and using intrauterine B-ultrasound. Weproposed application of least incompatible blood exchange transfusion onRhD-- deletion induced HDFN patients. Since one blood type iscorresponding to various genotypes, and varied in different races ordifferent population among one race. The current gene structureinformation of blood types is dissected on white people, which isinconsistent with Chinese people. Through this study, We detected thetwo RhD-- deletion individuals' serology characteristics, geneconstruction, and expression regulation, and explored the new mechanismbehind Chinese Han population RhD-- deletion disease, which providednew insights of Chinese blood type gene construction, new Rh allelesinformation, and the importance of genetyping on the RhD-- deletion individuals.
Methods (1) ABO and Rh blood typing, RhD-- deletion comfirming test, Coombs' test, accident antibody screening and identification, dynamic monitor of maternity antibody title and HDFN tests were carried out in the two RhD-- deletion individuals as well as ABO/Rh blood typing on their family members. (2) One newborn patient of HDFN was applied to common medical therapy and hemolysis monitoring. The least incompatible blood exchange transfusion was performed since the antigen-negative blood was unavailable. Another newborn patient of HDFN was applied to antoblood storage, pregnancy monitoring, traditional Chinese medicine, lymphocyte plasma exchanging, intrauterine transfusion and exchange transfusion. (3) Multiple exons and introns of RHD and RHCE gene of RhD-- deletion individuals and their family members were assayed by PCR-SSP. Southern blotting was employed on HindIII and sph I digested genome DNA of two RhD--deletion individuals. RT-PCR was used to analyze the RHCE gene transcript splicing.
Result (1) RhC/c, E/e antigens were complete absent in the red blood cells and anti-Hro antibody is existed in the serum of the two RhD-- deletion individuals which come from consanguineous and non-consanguineous family, respectively. The parental generation individuals are homozygote of Rh and no other RhD-- deletion patients were observed. (2) The first newborn is survived by the application of least incompatible blood exchange after unsuccessful medical therapy. The child developed normally in the four years follow-up. In the second case, although the anemia of the fetus was approved greatly and the date of pregnancy was prolonged, the newborn was born as premature infant in the 32~(+2) gestation by cesarean delivery. The relatives gave up rescuing since there was no independent breath and abnormity of bowel after intensive treatment was applied to this infant. (3) Southern blotting confirmed that the exonl of RHCE gene is existed in the two RhD--deletion individuals, but the exon4-7 is deleted. PCR-SSP also found that intron4, exon4-7 are deleted, while exon3 and 9 are existed.
Conclusion (1) The two pregnancy patients both are RhD--deletion which could occure in consanguineous and non-consanguineous family. (2) Severe HDFN may occur in RhD-- deletion with high probability and the least incompatibility blood exchange transfusion is an effective treatment. Enforcing monitoring and comprehensive therapy through the pregnancy is the most effective way to prevent HDFN. (3) RHCE gene exon4-7 deletion induced loss of function may contribute to the Chinese Han population RhD-- deletion. It is different from the result of mechanism of RhD-- deletion in White people and Black people.
研究方法(1)采用经典的血细胞凝集法,对两位RhD--缺失型个体进行ABO和Rh血型鉴定、RhD--缺失型确认试验、直接和间接抗人球蛋白试验、意外抗体筛选与鉴定试验、母体意外抗体效价动态监测、胎儿和新生儿溶血病全套检测等,并对两个家系所有成员进行ABO和Rh血型调查。(2)对一例发生RhD--缺失型母儿血型不合HDN的新生儿进行常规内科治疗,监测溶血指标变化。在无法找到相合血源的情况下,采用最小不相容的血液为该新生儿换血。对另一例RhD--缺失型母儿血型不合HDFN,通过开展自体血储备、孕期监测、孕母服用中药治疗、孕母淋巴血浆置换、胎儿宫内输血、产后新生儿换血等综合救治方案进行干预和治疗。(3)采用序列特异性引物聚合酶链反应(PCR-SSP)的方法,对两例RhD--缺失型个体以及家系成员RHD与RHCE基因多个外显子与内含子进行Rh血型基因定型;对两例RhD--缺失型个体采用HindⅢ和SphⅠ内切酶酶切血液基因组DNA并与特异性探针进行Southern blot,并采用PCR-SSP方法扩增两个体RHCE基因多个外显子和内含子,采用RT-PCR方法检测两例RhD--缺失型个体是否有RHCE剪接体转录。
研究结果(1)两个体红细胞上RhC/c、E/e抗原完全缺乏,血清中均存在抗Hro抗体。两个体分别来自近亲和非近亲婚配的家系,亲代成员Rh表型均为纯合子,亲代成员中没有再次发现RhD--缺失型个体。(2)例1 RhD--缺失型个体的新生儿严重溶血,内科治疗无效,用最小不相容换血法为新生儿换血获得成功,及时挽救了患儿生命,经4年随访,患儿生长发育良好。例2 RhD--缺失型个体孕中期监测发现抗Hro抗体效价增高,经孕期综合治疗改善了胎儿宫内的贫血状况,有效延长了孕期。于孕32~(+2)周剖宫产下一女婴,虽经换血等积极治疗,患儿始终无自主呼吸,并存在肠道畸形,家属放弃治疗。(3)Southernblot发现两例RhD--缺失型个体RHCE基因均存在exon1,但存在中间段缺失(exon4-7缺失),进一步采用PCR-SSP方法特异性扩增RHCE基因多个外显子及内含子,证实RhD--缺失型个体RHCE intro4、exon4-7基因片段丢失,但exon3、exon9及3′端基因序列均存在。
研究结论(1)两个体均为RhD--缺失型血型,RhD--缺失型既可发生于近亲家系,也可发生于非近亲家系。(2)RhD--缺失型个体妊娠极易发生严重的HDFN,最小不相容换血法是治疗RhD--缺失型HDN的一种有效的手段。加强孕期监测及孕期综合治疗是预防和控制由RhD--缺失型导致的HDFN的重要手段。(3)中国部分汉族人群的RhD--缺失型个体的产生原因是RHCE基因exon4-7缺失,其截短的RHCE基因不表达相关活性产物,这与国外学者对白人、黑人RhD--缺失型个体发生的分子机制研究结果不同。
Objective RhD-- deletion is a rare variant in Rh-blood groupsystem which is characterized by the complete absence of RhC/c,E/eantigen and(or) overexpression of D antigen on the red blood cells. Atpresent, the molecular mechanism of RhD-- deletion is unclear, but thereare two possibilities contributing to it: first, the RHCE gene is intact butno expression at all; second, the RHCE gene is partially deleted. The firstis occurred in the mRNA transcription regulation level and the secondmay include exons deletion or gene recombination. RhD-- deletionindividuals are easily get immunized and can produce high titeranti-RhC/c,E/e antibody (i.e.anti-Hro antibody) by transfusion orpregnancy. The anti-Hro antibody produced by RhD-- deletionmothers can react with all red blood cells expect RhD--, Rhnull andRhmod cells, resulting to destruction of fetus red blood cells and causingsevere hemolytic disease. We investigated two RhD-- deletion pregnancypatients which are occurred severe HDFN. In this study by monitoringtheir anti-Hro antibody titer and using intrauterine B-ultrasound. Weproposed application of least incompatible blood exchange transfusion onRhD-- deletion induced HDFN patients. Since one blood type iscorresponding to various genotypes, and varied in different races ordifferent population among one race. The current gene structureinformation of blood types is dissected on white people, which isinconsistent with Chinese people. Through this study, We detected thetwo RhD-- deletion individuals' serology characteristics, geneconstruction, and expression regulation, and explored the new mechanismbehind Chinese Han population RhD-- deletion disease, which providednew insights of Chinese blood type gene construction, new Rh allelesinformation, and the importance of genetyping on the RhD-- deletion individuals.
Methods (1) ABO and Rh blood typing, RhD-- deletion comfirming test, Coombs' test, accident antibody screening and identification, dynamic monitor of maternity antibody title and HDFN tests were carried out in the two RhD-- deletion individuals as well as ABO/Rh blood typing on their family members. (2) One newborn patient of HDFN was applied to common medical therapy and hemolysis monitoring. The least incompatible blood exchange transfusion was performed since the antigen-negative blood was unavailable. Another newborn patient of HDFN was applied to antoblood storage, pregnancy monitoring, traditional Chinese medicine, lymphocyte plasma exchanging, intrauterine transfusion and exchange transfusion. (3) Multiple exons and introns of RHD and RHCE gene of RhD-- deletion individuals and their family members were assayed by PCR-SSP. Southern blotting was employed on HindIII and sph I digested genome DNA of two RhD--deletion individuals. RT-PCR was used to analyze the RHCE gene transcript splicing.
Result (1) RhC/c, E/e antigens were complete absent in the red blood cells and anti-Hro antibody is existed in the serum of the two RhD-- deletion individuals which come from consanguineous and non-consanguineous family, respectively. The parental generation individuals are homozygote of Rh and no other RhD-- deletion patients were observed. (2) The first newborn is survived by the application of least incompatible blood exchange after unsuccessful medical therapy. The child developed normally in the four years follow-up. In the second case, although the anemia of the fetus was approved greatly and the date of pregnancy was prolonged, the newborn was born as premature infant in the 32~(+2) gestation by cesarean delivery. The relatives gave up rescuing since there was no independent breath and abnormity of bowel after intensive treatment was applied to this infant. (3) Southern blotting confirmed that the exonl of RHCE gene is existed in the two RhD--deletion individuals, but the exon4-7 is deleted. PCR-SSP also found that intron4, exon4-7 are deleted, while exon3 and 9 are existed.
Conclusion (1) The two pregnancy patients both are RhD--deletion which could occure in consanguineous and non-consanguineous family. (2) Severe HDFN may occur in RhD-- deletion with high probability and the least incompatibility blood exchange transfusion is an effective treatment. Enforcing monitoring and comprehensive therapy through the pregnancy is the most effective way to prevent HDFN. (3) RHCE gene exon4-7 deletion induced loss of function may contribute to the Chinese Han population RhD-- deletion. It is different from the result of mechanism of RhD-- deletion in White people and Black people.
引文
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[55]Okuda H,Suganuma H,Kamesaki T,Kumada M,et al.The analysis of nucleotide substitutions,gaps,and recombination events between RHD and RHCE genes through complete sequencing.Biochemical and Biophysical Research Communication,2000,274:670-683.
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[57]朱发明,严力行.序列特异性引物PCR法检测Rh血型C/c基因型.临床检验杂志,2002,20:204-205.
[58]Wijk PA,Faas BHW,Ruijter JAM,Overbeeke MAM,et al.Genotyping of RHD by multiplex polymerase chain reaction analysis of six RHD-specific exons,transfusion,1998,38:1015-1021.
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[60]朱发明,严力行.序列特异性引物PCR法检测Rh血型E/e基因型.临床输血和检验,2002,4:5-7.
[61]Cherif-Zahar B,Raynal v,Le Van Kim C,et al.Structure and expression of the RH locus in the Rh-deficiency syndrome.Blood,1993,82:656-662.
[62]Huang CH,Reid ME,Chen Y,Coghlan G,et al.Molecular definition of red cell Rh haplotypes by tightly linked Sphl RFLPs.Am J Hum Genet,1996,58:133-142.
[63]Huang CH,Peng J,Chen HC,et al.RH locus contraction in a novel Dc-/D--genotype resulting from separate genetic recombination events. Transfusion,2004,44:853-859.
[64]Blunt T,Steers F,Daniels G,et al.Lack of RH C/E expression in the Rhesus D--phenotype is the result of a gene deletion.Ann Hum Genet,1994,58:19-24.
[65]Cherif-Zahar B,Raynal V,Cartron JP.Lack of RHCE-encoded proteins in the D--phenotype may result from homologous recombination between the two RH genes.Blood,1996,88:1518-1520.
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[51]Tse WT,Gallaghter PG,Pothier B,Costa FF,et al.An insertional frameshift mutation of the β-spectrin gene associated with elliptocytosis in spectrin nice (β 220/216).Blood,1991,78:517-523.
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[54]Randen I,sorensen K,Hauge R,Dahlberg AB.Accurate Rh phenotype determination by reticulocyte rnRNA typing shortly after multiple transfusions.Haematologica,2008,93:627-630.
[55]Okuda H,Suganuma H,Kamesaki T,Kumada M,et al.The analysis of nucleotide substitutions,gaps,and recombination events between RHD and RHCE genes through complete sequencing.Biochemical and Biophysical Research Communication,2000,274:670-683.
[56]Faas BH,Simsek S,Bleeker PM,Overbeeke,et al.RhE/e genotyping by allele-specific primer amplification.Blood,1995,85:829-832.
[57]朱发明,严力行.序列特异性引物PCR法检测Rh血型C/c基因型.临床检验杂志,2002,20:204-205.
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[60]朱发明,严力行.序列特异性引物PCR法检测Rh血型E/e基因型.临床输血和检验,2002,4:5-7.
[61]Cherif-Zahar B,Raynal v,Le Van Kim C,et al.Structure and expression of the RH locus in the Rh-deficiency syndrome.Blood,1993,82:656-662.
[62]Huang CH,Reid ME,Chen Y,Coghlan G,et al.Molecular definition of red cell Rh haplotypes by tightly linked Sphl RFLPs.Am J Hum Genet,1996,58:133-142.
[63]Huang CH,Peng J,Chen HC,et al.RH locus contraction in a novel Dc-/D--genotype resulting from separate genetic recombination events. Transfusion,2004,44:853-859.
[64]Blunt T,Steers F,Daniels G,et al.Lack of RH C/E expression in the Rhesus D--phenotype is the result of a gene deletion.Ann Hum Genet,1994,58:19-24.
[65]Cherif-Zahar B,Raynal V,Cartron JP.Lack of RHCE-encoded proteins in the D--phenotype may result from homologous recombination between the two RH genes.Blood,1996,88:1518-1520.
[1]Landsteiner K,Wiener AS.An agglutinable factor in human blood recognized by immune sere for rhesus blood.Pro soc Exp Biol NY,1940,43:223.
[2]Landsteiner K,Wiener AS.Studies on an aggiutinogen(Rh) in human blood reacting with anti-rhesus sera and with human isoantibodies.J Exp Med,1941,74:309-320.
[3](Geoff Daniels.人类血型学.第二版.北京:科学出版社,2007.
[4]Darrow RR.Icterus gravis(erythroblastosis neonatorum,examination of etiologic considerations).Arch Pathol,1938,25:378-417.
[5]Urbaniak SJ,Greiss MA.RhD haemolytic disease of the fetus and the newborn.Blood Reviews,2000,14:44-61.
[6]Fisher RA.Note on the calculation of the frequencices of the Rhesus allelomorphs.Ann Eugen,1947,23:223-224.
[7]Tipper P.A speculative model for the Rh blood groups.Ann Hum Genet,1986,50:241-247.
[8]Avent ND,Ridgwell K,Tanner MJ,Anstee DJ.cDNA cloning of a 30kDa erythrocyte membrane protein associated with Rh blood-group antigen expression.Biochem J,1990,271:821-825.
[9]Cherif-Zahar B,Bloy C,Le Van Kim,Blanchard D,et al.Molecular cloning and protein structure of a human blood group Rh polypeptide.Proc Nail Acad Sci,1990,87:6243-6247.
[10]Smythe JS,Avent ND,Judson PA,Parsons SF,et al.Expression of RHD and RHCE gene products using retroviral transduction of K562 cells establishes the molecular basis of Rh blood group antigens.Blood,1996,87:2968-2973.
[11]Okuda H,Suganuma H,Kamesaki T,Kumada M,et al.The analysis of nucleotide substitutions,gaps,and recombination events between RHD and RHCE genes through complete sequencing.Biochemical and Biophysical Research Communication,2000,274:670-683.
[12]Colin Y,Cherif-Zahar B,Le Van Kim C,Raynal V,et al.Genetic basis of the RhD-positive and RhD-negative blood group polymorphism as determined by southern analysis.Blood,1991,78:2747-2752.
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