Valéria de Freitas Dutra1, Vinícius Nunes Cordeiro Leal2, Fernanda Pereira Fernandes3, Cláudia Regina Lustosa Souza4, Maria Stella Figueiredo5, Alessandra Pontillo6. 1. 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. Electronic address: valeriafdutra@yahoo.com. 2. 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. Electronic address: vinicius.nunescl@usp.br. 3. 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. Electronic address: fernanda.pereira.fernandes@usp.br. 4. 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. 5. 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. Electronic address: stella.figueiredo@unifesp.br. 6. 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.
Abstract
BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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. DISCUSSION: 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.
BACKGROUND: 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. MATERIAL AND METHODS: 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. RESULTS: 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. DISCUSSION: 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.