1例CIITA新发突变致MHC-Ⅱ类分子缺陷病的临床与分子特征
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摘要
目的探讨1例CIITA基因突变所致MHCⅡ类分子(major histocompatibility complex classⅡ,MHCⅡ)缺陷病患儿临床与分子特征。方法分析1例在重庆医科大学附属儿童医院就诊的MHCⅡ类分子缺陷病患儿的临床资料、实验室检查,Sanger测序分析患儿CIITA基因序列、PCR法检测T细胞受体长度多样性,流式细胞术检测HLA-DR蛋白表达。结果患儿,男,2岁2月,3月起病,表现为反复腹泻、呼吸道感染、持续CMV感染、卡介苗病、重度营养不良,IgG、IgA下降、IgM升高,CD4~+T细胞比例下降但数量正常、CD4/CD8比例倒置。CIITA基因复合杂合突变,c.3223C>T来源于父亲;c.1240delC来源于母亲,为未报道新发突变。患儿B细胞和单核细胞表面的HLA-DR表达明显降低,T细胞功能轻度受损。确诊后患儿行单倍体造血干细胞移植,因发生严重的移植物抗宿主病死亡。结论经临床、免疫学筛查、基因及流式细胞术检测,确诊MHCⅡ类分子缺陷患儿1例,其母源突变c.1240delC既往未见报道。反复多病原感染伴有CD4+细胞比例和(或)数量下降需警惕该病可能,综合临床与实验室检查行MHC-Ⅱ蛋白表达及基因测序可确诊该病,造血干细胞移植是目前根治的唯一办法,但成功率较其他联合免疫缺陷病低。
MHC class Ⅱ deficiency is a rare primary immunodeficiency disease caused by CIITA or FRX family monogenic mutation. Herein, we investigated the clinical features, genetic variation of CIITA gene and the HLA-DR expression in a 2 year-old male patient with recurrent diarrhea, respiratory infection, persistent CMV infection, BCG disease and severe malnutrition. Immunological analysis revealed a reduce of CD4~+T cells frequency in the periphery with inverted CD4/CD8 ratio and hypogammaglobulinemia. Compound heterozygous mutations in CIITA were detected by Sanger sequencing, showing a paternal mutation c.3223 C>T and a novel maternal mutation c.1240 delC resulting in absence of HLA-DR expression in CD19+B cells and CD14+ monocytes. And the function of T cells were slightly impaired. In conclusion, a Chinese patient with a novel maternal mutation in CIITA has diagnosed by analysis of clinical and immunological features, gene sequencing and protein analysis. Hematopoietic stem cell transplantation is still the only radical method but with a lower success rate comparing with other combine immunodeficiency.
MHC class Ⅱ deficiency is a rare primary immunodeficiency disease caused by CIITA or FRX family monogenic mutation. Herein, we investigated the clinical features, genetic variation of CIITA gene and the HLA-DR expression in a 2 year-old male patient with recurrent diarrhea, respiratory infection, persistent CMV infection, BCG disease and severe malnutrition. Immunological analysis revealed a reduce of CD4~+T cells frequency in the periphery with inverted CD4/CD8 ratio and hypogammaglobulinemia. Compound heterozygous mutations in CIITA were detected by Sanger sequencing, showing a paternal mutation c.3223 C>T and a novel maternal mutation c.1240 delC resulting in absence of HLA-DR expression in CD19+B cells and CD14+ monocytes. And the function of T cells were slightly impaired. In conclusion, a Chinese patient with a novel maternal mutation in CIITA has diagnosed by analysis of clinical and immunological features, gene sequencing and protein analysis. Hematopoietic stem cell transplantation is still the only radical method but with a lower success rate comparing with other combine immunodeficiency.
引文
[1]Hanna S,Etzioni A.MHC class I and II deficiencies[J].JAllergy Clin Immunol,2014,134(2):269-275.
[2]Picard C,Fischer A.Hematopoietic stem cell transplantation and other management strategies for MHCclassⅡdeficiency[J].Immunol Allergy Clin North Am,2010,30(2):173-178.
[3]周丽娜,丁媛,李黎,等.全血淋巴细胞流式细胞术精细免疫分型方法的建立[J].免疫学杂志,2015,31(6):523-527.
[4]张素倩,唐文静,吴俊峰,等.1例CD3ε缺陷致重症联合免疫缺陷病的临床及免疫学特征分析[J].免疫学杂志,2016,31(5):421-425.
[5]Farrokhi S,Shabani M,Aryan Z,et al.MHC classⅡdeficiency:Report of a novel mutation and special review[J].Allergol Immunopathol(Madr),2018,46(3):263-275.
[6]Small TN,Qasim W,Friedrich W,et al.Alternative donor SCT for the treatment of MHC classⅡdeficiency[J].Bone Marrow Transplant,2013,48(2):226-232.
[7]Renella R,Picard C,Neven B,et al.Human leucocyte antigen-identical haematopoietic stem cell transplantation in major histocompatiblity complex classⅡimmunodeficiency:reduced survival correlates with an increased incidence of acute graft-versus-host disease and pre-existing viral infections[J].Br J Haematol,2006,134(5):510-516.
[8]吴戊辰,王薇,宋红梅,等.主要组织相容性复合物Ⅱ类分子缺陷病一例伴文献复习[J].中华儿科杂志,2016,54(8):614-618.
[9]陈秋瑜,王文婕,孙金峤,等.CIITA基因突变所致MHCⅡ分子缺陷病2例临床分析并文献复习[J].中国实用儿科杂志,2018,33(1):55-59.
[10]Krawczyk M,Reith W.Regulation of MHC classⅡexpression,a unique regulatory system identified by the study of a primary immunodeficiency disease[J].Tissue Antigens,2006,67(3):183-197.
[11]Clarridge K,Leitenberg D,Loechelt B,et al.Major histocompatibility complex class II deficiency due to a novel mutation in RFXANK in a child of mexican descent[J].J Clin Immunol,2016,36(1):4-5.
[12]Reith W,Math B.The bare lymphocyte syndrome and the regulation of MHC expression[J].Annu Rev Immunol,2001,19:331-373.
[13]Dziembowska M,Fondaneche MC,Vedrenne J,et al.Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency[J].Immunogenetics,2002,53(10/11):821-829.
[14]Lev A,Simon AJ,Broides A,et al.Thymic function in MHCclass II-deficient patients[J].J Allergy Clin Immunol,2013,131(3):831-839.
[15]Kuo CY,Chase J,Garcia Lloret M,et al.Newborn screening for severe combined immunodeficiency does not identify bare lymphocyte syndrome[J].J Allergy Clin Immunol,2013,131(6):1693-1695.
[16]Marcus N,Stauber T,Lev A,et al.MHC II deficient infant identified by newborn screening program for SCID[J].Immunol Res,2018,66(4):537-542.
[2]Picard C,Fischer A.Hematopoietic stem cell transplantation and other management strategies for MHCclassⅡdeficiency[J].Immunol Allergy Clin North Am,2010,30(2):173-178.
[3]周丽娜,丁媛,李黎,等.全血淋巴细胞流式细胞术精细免疫分型方法的建立[J].免疫学杂志,2015,31(6):523-527.
[4]张素倩,唐文静,吴俊峰,等.1例CD3ε缺陷致重症联合免疫缺陷病的临床及免疫学特征分析[J].免疫学杂志,2016,31(5):421-425.
[5]Farrokhi S,Shabani M,Aryan Z,et al.MHC classⅡdeficiency:Report of a novel mutation and special review[J].Allergol Immunopathol(Madr),2018,46(3):263-275.
[6]Small TN,Qasim W,Friedrich W,et al.Alternative donor SCT for the treatment of MHC classⅡdeficiency[J].Bone Marrow Transplant,2013,48(2):226-232.
[7]Renella R,Picard C,Neven B,et al.Human leucocyte antigen-identical haematopoietic stem cell transplantation in major histocompatiblity complex classⅡimmunodeficiency:reduced survival correlates with an increased incidence of acute graft-versus-host disease and pre-existing viral infections[J].Br J Haematol,2006,134(5):510-516.
[8]吴戊辰,王薇,宋红梅,等.主要组织相容性复合物Ⅱ类分子缺陷病一例伴文献复习[J].中华儿科杂志,2016,54(8):614-618.
[9]陈秋瑜,王文婕,孙金峤,等.CIITA基因突变所致MHCⅡ分子缺陷病2例临床分析并文献复习[J].中国实用儿科杂志,2018,33(1):55-59.
[10]Krawczyk M,Reith W.Regulation of MHC classⅡexpression,a unique regulatory system identified by the study of a primary immunodeficiency disease[J].Tissue Antigens,2006,67(3):183-197.
[11]Clarridge K,Leitenberg D,Loechelt B,et al.Major histocompatibility complex class II deficiency due to a novel mutation in RFXANK in a child of mexican descent[J].J Clin Immunol,2016,36(1):4-5.
[12]Reith W,Math B.The bare lymphocyte syndrome and the regulation of MHC expression[J].Annu Rev Immunol,2001,19:331-373.
[13]Dziembowska M,Fondaneche MC,Vedrenne J,et al.Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency[J].Immunogenetics,2002,53(10/11):821-829.
[14]Lev A,Simon AJ,Broides A,et al.Thymic function in MHCclass II-deficient patients[J].J Allergy Clin Immunol,2013,131(3):831-839.
[15]Kuo CY,Chase J,Garcia Lloret M,et al.Newborn screening for severe combined immunodeficiency does not identify bare lymphocyte syndrome[J].J Allergy Clin Immunol,2013,131(6):1693-1695.
[16]Marcus N,Stauber T,Lev A,et al.MHC II deficient infant identified by newborn screening program for SCID[J].Immunol Res,2018,66(4):537-542.
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