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Cross-reacting antibacterial auto-antibodies are produced within coronary atherosclerotic plaques of acute coronary syndrome patients.

ABSTRACT: Coronary atherosclerosis, the main condition predisposing to acute myocardial infarction, has an inflammatory component caused by stimuli that are yet unknown. We molecularly investigated the nature of the immune response within human coronary lesion in four coronary plaques obtained by endoluminal atherectomy from four patients. We constructed phage-display libraries containing the IgG1/kappa antibody fragments produced by B-lymphocytes present in each plaque. By immunoaffinity, we selected from these libraries a monoclonal antibody, arbitrarily named Fab7816, able to react both with coronary and carotid atherosclerotic tissue samples. We also demonstrated by confocal microscopy that this monoclonal antibody recognized human transgelin type 1, a cytoskeleton protein involved in atherogenesis, and that it co-localized with fibrocyte-like cells transgelin+, CD68+, CD45+ in human sections of coronary and carotid plaques. In vitro fibrocytes obtained by differentiating CD14+ cells isolated from peripheral blood mononuclear cells also interacted with Fab7816, thus supporting the hypothesis of a specific recognition of fibrocytes into the atherosclerotic lesions. Interestingly, the same antibody, cross-reacted with the outer membrane proteins of Proteus mirabilis and Klebsiella pneumoniae (and possibly with homologous proteins of other enterobacteriaceae present in the microbiota). From all the other three libraries, we were able to clone, by immunoaffinity selection, human monoclonal antibodies cross-reacting with bacterial outer membrane proteins and with transgelin. These findings demonstrated that in human atherosclerotic plaques a local cross-reactive immune response takes place.

SUBMITTER: Canducci F

PROVIDER: S-EPMC3412836 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Cross-reacting antibacterial auto-antibodies are produced within coronary atherosclerotic plaques of acute coronary syndrome patients.

Canducci Filippo F Saita Diego D Foglieni Chiara C Piscopiello Maria Rosaria MR Chiesa Roberto R Colombo Antonio A Cianflone Domenico D Maseri Attilio A Clementi Massimo M Burioni Roberto R

PloS one 20120806 8

Coronary atherosclerosis, the main condition predisposing to acute myocardial infarction, has an inflammatory component caused by stimuli that are yet unknown. We molecularly investigated the nature of the immune response within human coronary lesion in four coronary plaques obtained by endoluminal atherectomy from four patients. We constructed phage-display libraries containing the IgG1/kappa antibody fragments produced by B-lymphocytes present in each plaque. By immunoaffinity, we selected fro ...[more]

PMID: 22879930

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Project description:This study sought to determine whether the classification of human coronary atherosclerotic plaques with T1, T2, and ultrashort echo time (UTE) cardiac magnetic resonance (CMR) would correlate well with atherosclerotic plaque classification by histology.CMR has been extensively used to classify carotid plaque, but its ability to characterize coronary plaque remains unknown. In addition, the detection of plaque calcification by CMR remains challenging. Here, we used T1, T2, and UTE CMR to evaluate atherosclerotic plaques in fixed post-mortem human coronary arteries. We hypothesized that the combination of T1, T2, and UTE CMR would allow both calcified and lipid-rich coronary plaques to be accurately detected.Twenty-eight plaques from human donor hearts with proven coronary artery disease were imaged at 9.4-T with a T1-weighted 3-dimensional fast low-angle shot (FLASH) sequence (250-?m resolution), a T2-weighted rapid acquisition with refocused echoes (RARE) sequence (in-plane resolution 0.156 mm), and an UTE sequence (300-?m resolution). Plaques showing selective hypointensity on T2-weighted CMR were classified as lipid-rich. Areas of hypointensity on the T1-weighted images, but not the UTE images, were classified as calcified. Hyperintensity on the T1-weighted and UTE images was classified as hemorrhage. Following CMR, histological characterization of the plaques was performed with a pentachrome stain and established American Heart Association criteria.CMR showed high sensitivity and specificity for the detection of calcification (100% and 90%, respectively) and lipid-rich necrotic cores (90% and 75%, respectively). Only 2 lipid-rich foci were missed by CMR, both of which were extremely small. Overall, CMR-based classification of plaque was in complete agreement with the histological classification in 22 of 28 cases (weighted ? = 0.6945, p < 0.0001).The utilization of UTE CMR allows plaque calcification in the coronary arteries to be robustly detected. High-resolution CMR with T1, T2, and UTE contrast enables accurate classification of human coronary atherosclerotic plaque.

Project description:Background: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation‚ notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies. Methods: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity. Results: In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4<CD8), exhibiting clonal expansion of specific TCRs. Interestingly, we found that these plaque T cells had TCRs specific for influenza, coronavirus, and other viral epitopes, which share sequence homologies to proteins found on smooth muscle cells and endothelial cells, suggesting potential autoimmune-mediated T-cell activation in the absence of active infection. To better understand the potential function of these activated plaque T cells, we then interrogated their transcriptome at the single-cell level. Of the 3 T-cell phenotypic clusters with the highest expression of the activation marker HLA-DRA, 2 clusters expressed a proinflammatory and cytolytic signature characteristic of CD8 cells, while the other expressed AREG (amphiregulin), which promotes smooth muscle cell proliferation and fibrosis, and, thus, contributes to plaque progression. Conclusions: Taken together, these findings demonstrate that plaque T cells are clonally expanded potentially by antigen engagement, are potentially reactive to self-epitopes, and may interact with smooth muscle cells and macrophages in the plaque microenvironment.

Dataset Information

Cross-reacting antibacterial auto-antibodies are produced within coronary atherosclerotic plaques of acute coronary syndrome patients.

Publications

Cross-reacting antibacterial auto-antibodies are produced within coronary atherosclerotic plaques of acute coronary syndrome patients.

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