Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy.
Dipartimento di Scienze Cardiovascolari e Pneumologiche, Università Cattolica del Sacro Cuore, Rome, Italy.
Front Immunol. 2022 Jul 8;13:845526. doi: 10.3389/fimmu.2022.845526. eCollection 2022.
Human epicardial adipose tissue, a dynamic source of multiple bioactive factors, holds a close functional and anatomic relationship with the epicardial coronary arteries and communicates with the coronary artery wall through paracrine and vasocrine secretions. We explored the hypothesis that T-cell recruitment into epicardial adipose tissue (EAT) in patients with non-ST segment elevation myocardial infarction (NSTEMI) could be part of a specific antigen-driven response implicated in acute coronary syndrome onset and progression.
We enrolled 32 NSTEMI patients and 34 chronic coronary syndrome (CCS) patients undergoing coronary artery bypass grafting (CABG) and 12 mitral valve disease (MVD) patients undergoing surgery. We performed EAT proteome profiling on pooled specimens from three NSTEMI and three CCS patients. We performed T-cell receptor (TCR) spectratyping and CDR3 sequencing in EAT and peripheral blood mononuclear cells of 29 NSTEMI, 31 CCS, and 12 MVD patients. We then used computational modeling studies to predict interactions of the TCR beta chain variable region (TRBV) and explore sequence alignments. The EAT proteome profiling displayed a higher content of pro-inflammatory molecules (CD31, CHI3L1, CRP, EMPRINN, ENG, IL-17, IL-33, MMP-9, MPO, NGAL, RBP-4, RETN, VDB) in NSTEMI as compared to CCS ( < 0.0001). CDR3-beta spectratyping showed a TRBV21 enrichment in EAT of NSTEMI (12/29 patients; 41%) as compared with CCS (1/31 patients; 3%) and MVD (none) (ANOVA for trend < 0.001). Of note, 11/12 (92%) NSTEMI patients with TRBV21 perturbation were at their first manifestation of ACS. Four patients with the first event shared a distinctive TRBV21-CDR3 sequence of 178 bp length and 2/4 were carriers of the human leukocyte antigen (HLA)-A03:01 allele. A 3D analysis predicted the most likely epitope able to bind HLA-A301 and interact with the TRBV21-CDR3 sequence of 178 bp length, while the alignment results were consistent with microbial DNA sequences.
Our study revealed a unique immune signature of the epicardial adipose tissue, which led to a 3D modeling of the TCRBV/peptide/HLA-A3 complex, in acute coronary syndrome patients at their first event, paving the way for epitope-driven therapeutic strategies.
人类的心外膜脂肪组织是多种生物活性因子的动态来源，与心外膜冠状动脉具有密切的功能和解剖关系，并通过旁分泌和血管分泌的方式与冠状动脉壁进行交流。我们提出假说，即非 ST 段抬高型心肌梗死（NSTEMI）患者的 T 细胞募集到心外膜脂肪组织（EAT）中，可能是急性冠脉综合征发病和进展中涉及特定抗原驱动反应的一部分。
我们纳入了 32 名 NSTEMI 患者和 34 名慢性冠脉综合征（CCS）患者（行冠状动脉旁路移植术，CABG），以及 12 名二尖瓣疾病（MVD）患者（行手术治疗）。我们对来自 3 名 NSTEMI 和 3 名 CCS 患者的 pooled 样本进行了 EAT 蛋白质组分析。我们对 29 名 NSTEMI、31 名 CCS 和 12 名 MVD 患者的 EAT 和外周血单核细胞进行了 T 细胞受体（TCR）谱型分析和 CDR3 测序。然后，我们使用计算模型研究来预测 TCRβ链可变区（TRBV）的相互作用，并探索序列比对。EAT 蛋白质组分析显示，与 CCS 相比，NSTEMI 中促炎分子（CD31、CHI3L1、CRP、EMPRINN、ENG、IL-17、IL-33、MMP-9、MPO、NGAL、RBP-4、RETN、VDB）的含量更高（<0.0001）。EAT 中 CDR3-β谱型分析显示，与 CCS（31 名患者中 1 名；3%）和 MVD（无）相比，NSTEMI 中 TRBV21 富集（29 名患者中 12 名；41%）（方差分析趋势检验<0.001）。值得注意的是，12 名 NSTEMI 患者中有 11 名（92%）在首次出现 ACS 时出现了 TRBV21 改变。4 名首次出现该改变的患者具有独特的 178bp 长的 TRBV21-CDR3 序列，其中 2 名是人类白细胞抗原（HLA）-A03：01 等位基因的携带者。3D 分析预测了最有可能与 HLA-A301 结合并与 178bp 长的 TRBV21-CDR3 序列相互作用的表位，而序列比对结果与微生物 DNA 序列一致。
我们的研究揭示了心外膜脂肪组织的独特免疫特征，这导致了 TCRBV/肽/HLA-A3 复合物的 3D 建模，在急性冠脉综合征患者首次发病时，为表位驱动的治疗策略铺平了道路。
