Expression of functional T-cell markers and T-cell receptor Vbeta repertoire in endomyocardial biopsies from patients presenting with acute myocarditis and dilated cardiomyopathy

Abstract

Aims To quantify and functionally characterize the intramyocardial T‐cells in endomyocardial biopsies (EMBs) from patients presenting with acute myocarditis (AMC) and dilated cardiomyopathy (DCM). Methods and results Expression of genes characterizing Th1 [interferon (IFN)γ, Tbet‐1, Eomesodermin, interleukin (IL)‐27], Th2 (IL‐4, IL‐5, GATA3), Th17 (IL‐17), regulatory [regulatory T‐cells (Treg); FoxP3, TGFβ, IL‐10], anergic (GRAIL), and cytotoxic T‐cells (CTLs: Perforin, Granulysin, Granzyme A), as well as of functional T‐cell receptor Vbeta (TRBV) families were investigated in EMBs from AMC patients (n= 58) and DCM patients (n= 34) by pre‐amplified real‐time reverse transcription‐polymerase chain reaction. These data were compared with EMBs from n= 19 controls. Expression of CD3d, CD3z, and TRBC (T‐cell receptor beta constant region) were associated with the immunohistological diagnosis of inflammatory cardiomyopathy (DCMi). In EMBs from DCM patients with increased CD3d expression, significantly increased markers of Th1 (IFNγ, T‐bet, Eomesodermin), regulatory T‐cells (Treg; FoxP3, TGFβ), and cytotoxic T‐cells (CTLs: Perforin, Granulysin, Granzyme A) were present, while no differential polarization of T‐cells was found in EMBs form AMC patients. A differential dominance of distinct functional TRBV families was associated with different cardiotropic viruses: TRBV 11 and 24 with Parvovirus B19; TRBV4, 10 and 28 with human herpes virus type 6; and TRBV14 for Coxsackie virus, respectively. Conclusions The T‐cell infiltrates in human DCMi are characterized by differential expression of functional T‐cell markers indicating Th1, Treg, and CTLs, while no major role could be confirmed for Th17. The virus‐associated differential TRBV dominance suggests an antiviral specificity of virus‐induced T‐cell responses in human DCMi.

Differential Cardiac MicroRNA Expression Predicts the Clinical Course in Human Enterovirus Cardiomyopathy

“…Several technical advances [6][7][8][9] made it then technically feasible to conduct EMB-based microarray studies 6 , and more recently also the additional comprehensive measurement of cardiac miR profiles (with comprehensive coverage of Sanger miRBase v14) from the same samples. Based on this technological progress we decided to investigate the transcriptomes of cardiomyopathy patients, as determined in their initial diagnostic biopsies, not only for diagnostic purposes, but also to identify marker patterns allowing prognostic conclusions regarding an individual patient's clinical course (morbidity, mortality, capacity for virus elimination in those infected, influence of cardiac inflammation, etc.).…”

“…We and others have recently demonstrated therapeutic potential of organ-targeted RNAi, [3][4][5] and others investigated therapeutic strategies based on modulation of microRNA (miR) functions. [6][7][8] About disease pathogenesis, it has become evident that confinement on the analysis of protein-coding regions of the human genome is incomplete because many noncoding variants are associated with important human diseases. 9,10 Inclusion of the noncoding genomic elements in pathogenetic studies seems mandatory, and one of the approaches is comprehensive transcriptome mapping encompassing protein-coding genes, as well as small and large noncoding RNAs.…”

Defective Circulating Regulatory B Cells in Patients with Dilated Cardiomyopathy

“…Additionally, auto-antibodies directed against heart specific-antigens were detected in their serum [7, 8]. However, regulatory T cells (Tregs) have a beneficial role in DCM by suppressing TH1-dominant CD4 + T-cell responses [9-11]. …”

Down-regulation of microRNA-451a facilitates the activation and proliferation of CD4+ T cells by targeting Myc in patients with dilated cardiomyopathy

“…The plasma concentration of miR-423-5p was elevated and was positively correlated with the level of N-terminal brain natriuretic peptide, thus serving as a diagnostic biomarker for heart failure caused by DCM (20). The immune inflammation mediated by CD4 ϩ T cells is implicated in the development of DCM (21). However, the role of miRNAs in the aberrant activation of CD4 ϩ T cells associated with DCM remains poorly understood.…”