Genetic Polymorphism at CCL5 Is Associated With Protection in Chagas' Heart Disease: Antagonistic Participation of CCR1(+) and CCR5(+) Cells in Chronic Chagasic Cardiomyopathy.
Genetic Polymorphism at CCL5 Is Associated With Protection in Chagas' Heart Disease: Antagonistic Participation of CCR1(+) and CCR5(+) Cells in Chronic Chagasic Cardiomyopathy.
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DOI：
10.3389/fimmu.2018.00615
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发表时间：
2018
影响因子：
7.3
通讯作者：
Lannes-Vieira J
中科院分区：
文献类型：
--
作者：
Batista AM;Alvarado-Arnez LE;Alves SM;Melo G;Pereira IR;Ruivo LAS;da Silva AA;Gibaldi D;da Silva TDESP;de Lorena VMB;de Melo AS;de Araújo Soares AK;Barros MDS;Costa VMA;Cardoso CC;Pacheco AG;Carrazzone C;Oliveira W Jr;Moraes MO;Lannes-Vieira J
慢性心肌病是查加斯病的主要临床表现，查加斯病是由克氏锥虫感染引起的疾病。慢性心肌病(CCC)的一个特征是以CD8+和CD4+T细胞和巨噬细胞为主的纤维性炎症。CC-趋化因子配体和受体被认为可以推动细胞向CD患者的心脏组织迁移。CC-趋化因子配体和受体基因的单核苷酸多态(SNPs)可能决定蛋白质的表达。在这里，我们评估了CC趋化因子CCL2(Rs1024611)和CCL5(rs2107538，rs2280788)以及CCL5/RANTES受体CCR1(rs3181077，rs1491961，rs3136672)和CCR5(Rs1799987)的SNPs与CCC风险和进展的关系。我们对来自巴西东北部伯南布哥州CD流行区的406名血清阳性患者进行了横断面关联研究。患者分为非心源性(A，n = 110例)和心源性(轻度，B1，n = 163例；重度，C，n = 133例)。CD患者血清CCL5和CCL2/MCP-1水平升高，但与CCC的危险程度和严重程度无关，也与SNP基因型无关。在调整了性别和民族的协变量后进行Logistic回归分析，CCL5−403(Rs2107538)、CT杂合子(OR = 0.5，P值 = 0.04)和T携带者(OR = 0.5，P值 = 0.01)与CCc的保护作用有关。为了深入了解CCL5-CCR5/CCR1轴在CCC中的参与，用哥伦比亚T.ruzi株感染小鼠。心肌组织中CCL5浓度升高。脾组织中CCR1+CD8+T细胞和CD14+巨噬细胞减少，CCR5+细胞增加。重要的是，CCR1+CD14+巨噬细胞主要为IL-10+，而CCR5+细胞主要为肿瘤坏死因子+。CCR5缺陷感染的小鼠表现出肿瘤坏死因子浓度的降低和心脏组织的损伤。在感染CCR5的−/−小鼠中选择性阻断CCR1Met-RANTES治疗支持CCR1ccc的保护作用。此外，寄生虫抗原刺激CD患者外周血中CCR1+CD8+T细胞的频率和CCL5的产生增加。总体而言，我们的数据支持CCL5和CCR1+细胞的基因变体对Chagas心脏病具有保护作用，将CCL5-CCR1轴确定为免疫刺激的目标。
Chronic cardiomyopathy is the main clinical manifestation of Chagas disease (CD), a disease caused by Trypanosoma cruzi infection. A hallmark of chronic chagasic cardiomyopathy (CCC) is a fibrogenic inflammation mainly composed of CD8+ and CD4+ T cells and macrophages. CC-chemokine ligands and receptors have been proposed to drive cell migration toward the heart tissue of CD patients. Single nucleotide polymorphisms (SNPs) in CC-chemokine ligand and receptor genes may determine protein expression. Herein, we evaluated the association of SNPs in the CC-chemokines CCL2 (rs1024611) and CCL5 (rs2107538, rs2280788) and the CCL5/RANTES receptors CCR1 (rs3181077, rs1491961, rs3136672) and CCR5 (rs1799987) with risk and progression toward CCC. We performed a cross-sectional association study of 406 seropositive patients from endemic areas for CD in the State of Pernambuco, Northeast Brazil. The patients were classified as non-cardiopathic (A, n = 110) or cardiopathic (mild, B1, n = 163; severe, C, n = 133). Serum levels of CCL5 and CCL2/MCP-1 were elevated in CD patients but were neither associated with risk/severity of CCC nor with SNP genotypes. After logistic regression analysis with adjustment for the covariates gender and ethnicity, CCL5 −403 (rs2107538) CT heterozygotes (OR = 0.5, P-value = 0.04) and T carriers (OR = 0.5, P-value = 0.01) were associated with protection against CCC. To gain insight into the participation of the CCL5–CCR5/CCR1 axis in CCC, mice were infected with the Colombian T. cruzi strain. Increased CCL5 concentrations were detected in cardiac tissue. In spleen, frequencies of CCR1+ CD8+ T cells and CD14+ macrophages were decreased, while frequencies of CCR5+ cells were increased. Importantly, CCR1+CD14+ macrophages were mainly IL-10+, while CCR5+ cells were mostly TNF+. CCR5-deficient infected mice presented reduced TNF concentrations and injury in heart tissue. Selective blockade of CCR1 (Met-RANTES therapy) in infected Ccr5−/− mice supported a protective role for CCR1 in CCC. Furthermore, parasite antigen stimulation of CD patient blood cells increased the frequency of CCR1+CD8+ T cells and CCL5 production. Collectively, our data support that a genetic variant of CCL5 and CCR1+ cells confer protection against Chagas heart disease, identifying the CCL5-CCR1 axis as a target for immunostimulation.
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影响因子：
3.7
作者：
Frade AF;Pissetti CW;Ianni BM;Saba B;Lin-Wang HT;Nogueira LG;de Melo Borges A;Buck P;Dias F;Baron M;Ferreira LR;Schmidt A;Marin-Neto JA;Hirata M;Sampaio M;Fragata A;Pereira AC;Donadi E;Kalil J;Rodrigues V;Cunha-Neto E;Chevillard C
通讯作者：
Chevillard C
影响因子：
4.4
作者：
Chvatchko, Y;Proudfoot, AEI;Wells, TNC
通讯作者：
Wells, TNC
影响因子：
3.8
作者：
Espinola Carvalho, Cristiano Marcelo;Silverio, Jaline Coutinho;Lannes-Vieira, Joseli
通讯作者：
Lannes-Vieira, Joseli
影响因子：
3.7
作者：
Acevedo, Gonzalo R.;Longhi, Silvia A.;Gomez, Karina A.
通讯作者：
Gomez, Karina A.
影响因子：
9.8
作者：
Hotez PJ
通讯作者：
Hotez PJ