Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences University of Sao Paulo, Sao Paulo, Brazil.
Infect Genet Evol. 2013 Oct;19:274-9. doi: 10.1016/j.meegid.2013.06.006. Epub 2013 Jun 13.
Polymorphisms in innate immunity genes are known to be involved in the multifactorial susceptibility to Mycobacterium leprae infection. M. leprae can downregulate IL-1β secretion escaping monocyte digestion. The intracellular receptors NLRPs (NACHT, LRR and PYD domains-containing proteins) sense pathogen associated molecular patterns (PAMPs) activating caspase-1 and IL-1β secretion in the context of inflammasome. Considering the possible role of inflammasome in the immune response against M. leprae, known single nucleotide polymorphisms (SNPs) in two NLRP genes, NLRP1 and NLRP3, were analyzed in Brazilian leprosy patients. Disease-associated SNPs (5 in NLRP1 and 2 in NLRP3), previously associated to infections and to immunologic disorders, were genotyped in 467 leprosy patients (327 multibacillary, MB; 96 paucibacillary, PB) and in 380 healthy controls (HC) from the state of Sao Paulo (Brazil), and in 183 patients (147MB; 64PB) and 186 HC from Mato Grosso (Brazil). Logistic regression analysis was performed considering susceptibility to leprosy di per se (leprosy versus HC) and clinical form (MB versus PB), adjusting for gender and ethnicity. Whereas none of the considered SNPs were statistically associated with leprosy, the NLRP1 combined haplotype rs2137722/G-rs12150220/T-rs2670660/G resulted significantly more frequent in patients than in HC as well as in PB than in MB. While both associations were lost after correction for gender and ethnicity, the NLRP1 combined haplotype rs2137722/G-rs12150220/A-rs2670660/G resulted strongly associated to PB. NLRP1 might be involved in the susceptibility to leprosy with particular emphasis for PB clinical form. Although preliminary, this is the first report linking NLRPs and inflammasome with leprosy: replication studies as well as functional assays are envisaged to deeper investigate the role of NLRP1 in M. leprae infection. Interestingly, NLRP1 SNPs were previously associated to susceptibility to Crohn disease, suggesting that NLRP1 could be a new modifier gene in common between leprosy and Crohn disease.
先天免疫基因的多态性被认为与麻风分枝杆菌感染的多因素易感性有关。麻风分枝杆菌可以下调白细胞介素-1β的分泌，逃避单核细胞的消化。细胞内受体 NLRPs（含有 NACHT、LRR 和 PYD 结构域的蛋白）感知病原体相关分子模式（PAMPs），在炎症小体的情况下激活半胱天冬酶-1 和白细胞介素-1β的分泌。考虑到炎症小体在针对麻风分枝杆菌的免疫反应中的可能作用，分析了巴西麻风病患者中两个 NLRP 基因（NLRP1 和 NLRP3）中已知的单核苷酸多态性（SNP）。先前与感染和免疫紊乱相关的疾病相关 SNP（NLRP1 中的 5 个和 NLRP3 中的 2 个）在来自巴西圣保罗州的 467 例麻风病患者（327 例多菌型，MB；96 例少菌型，PB）和 380 例健康对照者（HC）以及来自马托格罗索州的 183 例患者（147 例 MB；64 例 PB）和 186 例 HC 中进行了基因分型。考虑到麻风病本身的易感性（麻风病与 HC）和临床形式（MB 与 PB），进行了 logistic 回归分析，并对性别和种族进行了调整。尽管没有考虑到的 SNP 与麻风病有统计学关联，但 NLRP1 组合单倍型 rs2137722/G-rs12150220/T-rs2670660/G 在患者中比在 HC 中以及在 PB 中比在 MB 中更为频繁。虽然这两种关联在性别和种族校正后均丢失，但 NLRP1 组合单倍型 rs2137722/G-rs12150220/A-rs2670660/G 与 PB 强烈相关。NLRP1 可能与麻风病的易感性有关，特别是对 PB 临床形式的易感性。尽管这是初步报告，但这是首次将 NLRPs 和炎症小体与麻风病联系起来的报告：预计将进行复制研究和功能测定，以更深入地研究 NLRP1 在麻风分枝杆菌感染中的作用。有趣的是，NLRP1 SNP 先前与克罗恩病的易感性有关，这表明 NLRP1 可能是麻风病和克罗恩病之间的一个新的修饰基因。
