CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.
CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.
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DOI：
10.1056/nejmoa1615887
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发表时间：
2017-07-06
期刊：
影响因子：
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通讯作者：
Lenardo MJ
中科院分区：
文献类型：
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作者：
Ozen A;Comrie WA;Ardy RC;Domínguez Conde C;Dalgic B;Beser ÖF;Morawski AR;Karakoc-Aydiner E;Tutar E;Baris S;Ozcay F;Serwas NK;Zhang Y;Matthews HF;Pittaluga S;Folio LR;Unlusoy Aksu A;McElwee JJ;Krolo A;Kiykim A;Baris Z;Gulsan M;Ogulur I;Snapper SB;Houwen RHJ;Leavis HL;Ertem D;Kain R;Sari S;Erkan T;Su HC;Boztug K;Lenardo MJ
对单基因胃肠道疾病的研究揭示了对肠道稳态至关重要的分子途径，并使靶向治疗得以发展。我们研究了11例由早发性蛋白丢失性肠病引起的腹痛和腹泻患者，伴有原发性肠淋巴管扩张、低蛋白血症引起的水肿、吸收不良，以及较少发生的常染色体隐性遗传模式后的肠道炎症、复发性感染和血管病性血栓栓塞性疾病。进行全外显子组测序以鉴定基因变体。我们评估了患者细胞中CD55的功能，我们通过外源诱导的CD55表达证实了这一点。我们鉴定了编码CD55/衰变加速因子的基因中的纯合功能丧失突变，导致蛋白表达丧失。患者的T淋巴细胞显示补体活化增加，引起补体表面沉积和可溶性C5a的产生。CD55的共刺激功能和细胞因子调节是有缺陷的。CD55基因重建或补体抑制性治疗性抗体治疗可逆转异常补体激活。CD55缺陷伴补体过度激活、血管病性血栓形成和蛋白丢失性肠病（CHAPLE）疾病是由CD55中的双等位基因功能丧失突变引起的异常补体激活引起的。
Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and, less frequently, bowel inflammation, recurrent infections and angiopathic thromboembolic disease following an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patient cells, which we confirmed through exogenously-induced expression of CD55. We identified homozygous loss-of-function mutations in the gene encoding CD55/Decay accelerating factor, leading to loss of protein expression. Patients’ T lymphocytes displayed increased complement activation causing complement surface deposition and the generation of soluble C5a. Co-stimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) disease is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55.