Hematology and Blood Transfusion Division, Clinical and Experimetnal Oncology Department, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), R Dr. Diogo de Farias, 824, 04037-002 Vila Clementino, São Paulo, SP, Brazil.
Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Sciences/ICB, University of São Paulo/USP, Av. Prof. Lineu Prestes, 1730, 05508-000 Butantã, São Paulo, SP, Brazil.
Cytokine. 2022 Jan;149:155717. doi: 10.1016/j.cyto.2021.155717. Epub 2021 Oct 7.
Sickle cell disease (SCD), one of the most common single-gene disorders, is caused by mutations in the hemoglobin ß-chain gene. Clinical presentation is heterogeneous, and inflammation is a common condition. Thereby, we hypothesized that inflammasome and related cytokine IL-1ß could represent significant SCD pathogenesis contributors.
161 SCD (SS/Sβ) patients were enrolled for the study. Seven single nucleotide polymorphisms (SNPs) in 5 inflammasome genes (NLRP1, NLRP3, NLRC4, CARD8, IL1B) were selected based on minor allele frequency. Total peripheral blood mononuclear cells (PBMC) and monocytes were isolated from 10 out of 161 SCD patients (HbSS) and 10 healthy donors (control group, Ctrl) for inflammasome analysis.
SCD patients presented a functional impairment of inflammasome, with monocytes and peripheral blood mononuclear cells (PBMC) exhibiting a different NLRP3 inflammasome activation rate. Gain-of-function variants in NLRP1 and IL1B genes resulted associated with a mild SCD clinical presentation.
Our results can contribute to the understanding of SCD inflammation. SCD patients showed possible exhaustion of monocytes due to chronic inflammation, moreover others cells in PBMC can contribute to the NLRP3 inflammasome activation. NLRP1 gain-of-function was associated with mild clinical presentation, suggesting that other inflammasome receptors can be involved in SCD. This is the first study reporting a significant contribution of inflammasome SNPs in SCD.
镰状细胞病（SCD）是最常见的单基因疾病之一，由血红蛋白β链基因突变引起。临床表现具有异质性，炎症是常见的病症。因此，我们假设炎症小体和相关细胞因子 IL-1ß 可能是 SCD 发病机制的重要贡献者。
本研究纳入了 161 名 SCD（SS/Sβ）患者。根据次要等位基因频率，选择了 5 个炎症小体基因（NLRP1、NLRP3、NLRC4、CARD8、IL1B）中的 7 个单核苷酸多态性（SNP）。从 161 名 SCD 患者（HbSS）和 10 名健康供体（对照组，Ctrl）中的 10 名中分离出总外周血单核细胞（PBMC）和单核细胞，用于炎症小体分析。
SCD 患者的炎症小体功能受损，单核细胞和外周血单核细胞（PBMC）表现出不同的 NLRP3 炎症小体激活率。NLRP1 和 IL1B 基因的功能获得性变体与轻度 SCD 临床表现相关。
我们的研究结果有助于了解 SCD 炎症。SCD 患者由于慢性炎症可能出现单核细胞功能衰竭，此外 PBMC 中的其他细胞也可能参与 NLRP3 炎症小体的激活。NLRP1 功能获得性与轻度临床表型相关，提示 SCD 中可能涉及其他炎症小体受体。这是第一项报道炎症小体 SNP 在 SCD 中具有重要贡献的研究。
