Interleukin-36-Receptor Antagonist Deficiency and Generalized Pustular Psoriasis
Interleukin-36-Receptor Antagonist Deficiency and Generalized Pustular Psoriasis
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DOI：
10.1056/nejmoa1013068
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发表时间：
2011-08-18
影响因子：
158.5
通讯作者：
Smahi, Asma
中科院分区：
文献类型：
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作者：
Marrakchi, Slaheddine;Guigue, Philippe;Smahi, Asma
泛发性脓疱性银屑病是一种原因不明的危及生命的疾病。它的特点是突然，反复发作的高热，泛发性皮疹，播散性脓疱，白细胞增多和血清C-反应蛋白水平升高，这可能与斑块型psoriasis. METHODS相关，我们进行了纯合性定位和直接测序在9个突尼斯多发性常染色体隐性遗传性脓疱型银屑病家族。我们评估了突变对蛋白质表达和构象、稳定性和功能的影响。我们确定了与染色体2 q13-q14.1上1.2兆碱基间隔和IL 36 RN中的纯合错义突变的显著连锁，IL 36 RN编码白细胞介素-36受体拮抗剂（白细胞介素-36Ra），一种细胞因子。该突变预测了氨基酸位置27（L27 P）处的脯氨酸残基取代亮氨酸。人白细胞介素-36 Ra的基于同源性的结构建模表明，位置27处的脯氨酸影响白细胞介素-36 Ra的稳定性及其与其受体白细胞介素-1受体样2（白细胞介素-1受体相关蛋白2）的相互作用。生物化学分析表明，L27 P变体表达较差，并且在白细胞介素-8报告基因测定中抑制白细胞介素诱导的应答方面不如非变体白细胞介素-36 Ra有效，导致炎性细胞因子的产生增加（特别是白细胞介素-8）的角质形成细胞。36 Ra的结构和功能导致炎性细胞因子分泌失调和全身性脓疱性银屑病。（由法国国家研究机构和法国皮肤病学会资助）
BACKGROUNDGeneralized pustular psoriasis is a life-threatening disease of unknown cause. It is characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein, which may be associated with plaque-type psoriasis.METHODSWe performed homozygosity mapping and direct sequencing in nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis. We assessed the effect of mutations on protein expression and conformation, stability, and function.RESULTSWe identified significant linkage to an interval of 1.2 megabases on chromosome 2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin-36-receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra suggests that the proline at position 27 affects both the stability of interleukin-36Ra and its interaction with its receptor, interleukin-1 receptor-like 2 (interleukin-1 receptor-related protein 2). Biochemical analyses showed that the L27P variant was poorly expressed and less potent than the nonvariant interleukin-36Ra in inhibiting a cytokine-induced response in an interleukin-8 reporter assay, leading to enhanced production of inflammatory cytokines (interleukin-8 in particular) by keratinocytes from the patients.CONCLUSIONSAberrant interleukin-36Ra structure and function lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. (Funded by Agence Nationale de la Recherche and Societe Francaise de Dermatologie.)