1例CIITA新发突变致MHC-Ⅱ类分子缺陷病的临床与分子特征

Clinical and molecular features of a Chinese patient with novel mutations in CIITA

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.