An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
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DOI：
10.1056/nejmoa0807865
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发表时间：
2009-06-04
期刊：
影响因子：
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通讯作者：
Goldbach-Mansky R
中科院分区：
文献类型：
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作者：
Aksentijevich I;Masters SL;Ferguson PJ;Dancey P;Frenkel J;van Royen-Kerkhoff A;Laxer R;Tedgård U;Cowen EW;Pham TH;Booty M;Estes JD;Sandler NG;Plass N;Stone DL;Turner ML;Hill S;Butman JA;Schneider R;Babyn P;El-Shanti HI;Pope E;Barron K;Bing X;Laurence A;Lee CC;Chapelle D;Clarke GI;Ohson K;Nicholson M;Gadina M;Yang B;Korman BD;Gregersen PK;van Hagen PM;Hak AE;Huizing M;Rahman P;Douek DC;Remmers EF;Kastner DL;Goldbach-Mansky R
自身炎性疾病表现为炎症，但没有感染、高滴度自身抗体或自身反应性T细胞的证据。我们报告了一种由IL 1 RN突变引起的疾病，IL 1 RN编码白细胞介素-1受体拮抗剂，主要累及皮肤和骨骼。我们研究了来自6个家庭的9名儿童，他们患有新生儿无菌性多灶性骨髓炎、骨膜炎和脓疱病。在第一例患者中，对重组白细胞介素-1受体拮抗剂阿那白滞素经验性治疗的反应促使我们检测白细胞介素-1途径基因（包括IL 1 RN）中蛋白质突变和变化及其功能的存在。我们在9名受影响的儿童中发现了IL 1 RN的纯合突变，其中一个来自加拿大纽芬兰的家庭，三个来自荷兰的家庭，一个来自黎巴嫩的近亲家庭。一名来自波多黎各的非血亲患者为基因组缺失纯合子，包括IL 1 RN和其他5个白细胞介素-1家族成员。至少有三个突变是创始突变;杂合子携带者无症状，体外无细胞因子异常。IL 1 RN突变导致不分泌的截短蛋白，从而使细胞对白细胞介素-1 β刺激反应过度。接受阿那白滞素治疗的患者反应迅速。我们提出白细胞介素-1受体拮抗剂缺乏症（DIRA）一词来表示这种由影响IL 1 RN的突变引起的常染色体隐性自身炎性疾病。白细胞介素-1受体拮抗剂的缺乏允许白细胞介素-1的无对抗作用，导致危及生命的全身性炎症，累及皮肤和骨骼。（ClinicalTrials.gov编号，NCT 00059748。）
Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1–receptor antagonist, with prominent involvement of skin and bone. We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1–receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1–pathway genes including IL1RN. We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1–family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1β stimulation. Patients treated with anakinra responded rapidly. We propose the term deficiency of the interleukin-1–receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1–receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)