Genetic Variation in Toll-Interacting Protein Is Associated With Leprosy Susceptibility and Cutaneous Expression of Interleukin 1 Receptor Antagonist.
Genetic Variation in Toll-Interacting Protein Is Associated With Leprosy Susceptibility and Cutaneous Expression of Interleukin 1 Receptor Antagonist.
复制标题
DOI：
10.1093/infdis/jiv570
复制
发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Javeed A. Shah;W. Berrington;J. Vary;Richard D. Wells;G. Peterson;C. Kunwar;S. Khadge;D. Hagge
中科院分区：
文献类型：
--
作者：
Javeed A. Shah;W. Berrington;J. Vary;Richard D. Wells;G. Peterson;C. Kunwar;S. Khadge;D. Hagge
麻风病是一种慢性疾病，其特征是皮肤和外周神经病理和免疫反应未能控制麻风分枝杆菌。Toll相互作用蛋白（TOLLIP）调节Toll样受体（TLR）和白细胞介素1受体（IL-1 R）信号传导对抗分枝杆菌。我们分析了85例麻风患者皮肤活检标本中候选免疫基因的信使RNA（mRNA）表达。TOLLIP mRNA与IL-1 R拮抗剂（IL-1 Ra）高度特异相关。在尼泊尔对477例病例和1021例对照进行的病例对照基因关联研究中，TOLLIP单核苷酸多态性rs3793964 TT基因型与麻风易感性增加（隐性，P = 1.4 × 10（-3））以及TOLLIP和IL-1 Ra皮肤表达增加相关。用M.与对照组相比，麻风患者产生的IL-1 Ra显著减少（P <0.001）。这些数据表明M.麻风通过TOLLIP依赖性机制上调IL-1 Ra。抑制TOLLIP可以降低个体对麻风病的易感性，并为IL-1依赖性疾病提供新的治疗靶点。
Leprosy is a chronic disease characterized by skin and peripheral nerve pathology and immune responses that fail to control Mycobacterium leprae. Toll-interacting protein (TOLLIP) regulates Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling against mycobacteria. We analyzed messenger RNA (mRNA) expression of candidate immune genes in skin biopsy specimens from 85 individuals with leprosy. TOLLIP mRNA was highly and specifically correlated with IL-1R antagonist (IL-1Ra). In a case-control gene-association study with 477 cases and 1021 controls in Nepal, TOLLIP single-nucleotide polymorphism rs3793964 TT genotype was associated with increased susceptibility to leprosy (recessive, P = 1.4 × 10(-3)) and with increased skin expression of TOLLIP and IL-1Ra. Stimulation of TOLLIP-deficient monocytes with M. leprae produced significantly less IL-1Ra (P < .001), compared with control. These data suggest that M. leprae upregulates IL-1Ra by a TOLLIP-dependent mechanism. Inhibition of TOLLIP may decrease an individual's susceptibility to leprosy and offer a novel therapeutic target for IL-1-dependent diseases.