[Show abstract][Hide abstract] ABSTRACT: . Recently, several studies suggest that galectin-9 (Gal-9) might play a pivotal role in the pathogenesis of autoimmune diseases. However, the exact role of Gal-9 in atherosclerosis remains to be elucidated.
. Serum Gal-9, high-sensitivity C-reactive protein (hs-CRP), interferon- (IFN-)
, interleukin- (IL-) 4, IL-17, and transforming growth factor- (TGF-)
1 were measured. The effect of Gal-9 on peripheral blood mononuclear cells (PBMC) was investigated in patients with normal coronary artery (NCA).
. The lowest level of Gal-9 was found in the ST-segment elevation myocardial infarction (STEMI) group, followed by the non-ST-segment elevation ACS (NSTEACS), the NCA, and the stable angina pectoris (SAP) groups, respectively. Additionally, Gal-9 was found to be independently associated with hs-CRP, lipoprotein(a), and creatinine. Notably, Gal-9 was also noted to be an independent predictor of the Gensini score. Moreover, Gal-9 suppressed T-helper 17 (Th17) and expanded regulatory T cells (Tregs), resulting in decreased IL-17 production and increased secretion of TGF-
. Serum Gal-9 is associated with not only coronary artery disease (CAD), but also the severity of coronary arteries stenosis. Gal-9 can expand Tregs and suppress Th17 development in activated PBMC, implying that Gal-9 has the potential to dampen the development of atherosclerosis and may be a new therapy for CAD.
Preview · Article · Dec 2015 · Mediators of Inflammation
[Show abstract][Hide abstract] ABSTRACT: Atherosclerosis is an autoimmune-inflammatory disease involving both innate and adaptive immune mechanisms. Immune tolerance induction may have therapeutic potential for the suppression of atherosclerosis. Current interest is directed toward mucosal tolerance induction, especially nasal tolerance. Previous studies have shown that heat shock protein 60 (HSP60) is recognized as an important auto-antigen in atherosclerosis, and nasal or oral HSP60 can induce tolerance and ameliorate atherosclerosis by inducing several subsets of regulatory T cells (Tregs) such as latency-associated peptide (LAP)+ and Foxp3+ Tregs. However, little is known regarding the detailed mechanisms of nasal tolerance. Here, we again investigated the impact of nasal HSP60 on atherosclerosis and the mechanisms underlying the anti-atherosclerosis responses. We found that nasal HSP60 caused a significant 33.6% reduction in plaque size at the aortic root in the early stages of atherosclerosis (p<0.001). Notably, a significant increase in activated CD4+CD25+ glycoprotein A repetitions predominant (GARP)+ Tregs, type 1 Tregs (Tr1 cells), and CD4+CD25+Foxp3+ Tregs, as well as a marked decrease in the numbers of type 1 and 17 T-helper cells was detected in the spleens and cervical lymph nodes of HSP60-treated mice. Moreover, nasal HSP60 increases the production of TGF-β and IL-10 and decreases the secretion of IFN-γ and IL-17. Interestingly, the atheroprotective role of nasal HSP60 treatment was partly abrogated by the neutralization of IL-10. Our findings show that nasal administration of HSP60 can attenuate atherosclerotic formation by inducing GARP+ Tregs, Tr1 cells, and Foxp3+ Tregs, and that these Tregs maintain immune homeostasis by secreting IL-10 and TGF-β. This article is protected by copyright. All rights reserved.
No preview · Article · Oct 2015 · Clinical & Experimental Immunology
[Show abstract][Hide abstract] ABSTRACT: Increasing studies have demonstrated that atherosclerosis is a chronic immunoinflammatory disease, and that oxidized low-density lipoprotein (oxLDL)-specific T cells contribute to the autoimmune process in atherosclerosis. Oral administration of oxLDL, which was identified as a candidate autoantigen in atherosclerosis, was shown to induce tolerance and suppress atherogenesis. However, the precise mechanisms of mucosal tolerance induction, in particular nasal tolerance, remain unknown. In this study, we explored the effect of nasal oxLDL on atherosclerosis as well as the cellular and molecular mechanisms leading to atheroprotective responses, and then found that nasal oxLDL drastically ameliorate the initiation (47.6 %, p < 0.001) and progression (21.1 %, p = 0.001) of atherosclerosis. Most importantly, a significant 35.8 % reduction of the progression of atherosclerosis was observed in the enhanced immunization group (p < 0.001). These effects were accompanied by a significant increase in CD4+ latency-associated peptide (LAP)+ regulatory T cells (Tregs) and CD4+CD25+Foxp3+ Tregs in spleens and cervical lymph nodes, together with increased transforming growth factor (TGF)-β production and suppressed T-helper cells type 1, 2, and 17 immune responses. Surprisingly, neutralization of TGF-β in vivo partially counteracted the protective effect of nasal oxLDL treatment, indicating that the presence of TGF-β was indispensable to CD4+LAP+ Tregs and CD4+CD25+Foxp3+ Tregs to acquire regulatory properties. Our studies suggest that CD4+LAP+ Tregs and CD4+CD25+Foxp3+ Tregs induced by nasal delivery of oxLDL can inhibit oxLDL-specific T cells response and ameliorate atherosclerosis process.
No preview · Article · Oct 2012 · Journal of Clinical Immunology
[Show abstract][Hide abstract] ABSTRACT: Introduction.
Numerous studies suggest that total cholesterol content of erythrocyte membranes (CEM) might play a critical role in atherosclerotic plaque progression and instability. However, the exact role of CEM in atherosclerosis remains obscure. Our study was designed to investigate the association between CEM and the severity of coronary artery disease (CAD), and to assess the effect of rosuvastatin on CEM levels.
CEM levels were assessed in 136 participants, including acute coronary syndrome (ACS) (non-ST-segment elevation ACS (NSTEACS) and ST-segment elevation myocardial infarction (STEMI)), stable angina pectoris (SAP), and controls. The Gensini score was used to estimate the severity of CAD. Additionally, 54 patients with CAD were medicated with rosuvastatin, 5 or 10 mg once daily, and then checked at 6 months.
The highest level of CEM was found in the STEMI group, followed by the NSTEACS, the SAP, and the control groups. Gensini score in group IV (CEM > 141.6 μg/mg) was markedly higher compared with group I (CEM ≤77.6 μg/mg). Gensini scores in group II (77.6 < CEM ≤111.1 μg/mg) and group III (111.1 < CEM ≤141.6 μg/mg) were also higher than in group I (all P < 0.001). Furthermore, a positive correlation was found between CEM levels and Gensini score (r = 0.714, P < 0.001). CEM levels were dose-dependently reduced by rosuvastatin therapy.
CEM levels are positively associated with the severity of CAD, meaning that CEM might contribute to the development of CAD. Importantly, rosuvastatin could decrease CEM levels in patients with CAD and might effectively help to attenuate the progression of CAD.
Preview · Article · Sep 2012 · Upsala journal of medical sciences
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of dilated cardiomyopathy (DCM) is closely connected with dysfunction of the autoimmune system, and CD4(+)CD25(high)CD127(low/-) regulatory T (Treg) cells have a vital role in maintaining self-tolerance. In this study, we compared the frequency and regulatory function of Treg cells between DCM patients and normal controls.
The frequencies of CD4(+)CD25(+) T cells in DCM patients were statistically decreased compared with normal controls (p<0.05) by flow cytometry, and the levels of FOXP3 mRNA and protein expression in PBMCs (peripheral blood mononuclear cells) of DCM patients were lower than those of normal controls (p<0.01), using real-time RT-PCR assay and western blot. Notably, the suppressive capacity of CD4(+)CD25(high)CD127(low/-) regulatory T cells of DCM patients acting on autologous CD4(+)CD25(-) responder T (Tresp) cells seemed to be partially impaired (43.83+/-3.19% suppression versus 63.17+/-3.66% in normal controls, p=0.01). Surprisingly, Treg cells from DCM patients efficiently suppressed the proliferation of Tresp cells from normal subjects to the similar level as Treg cells from normal subjects on autologous Tresp cells (p=0.286), whereas Treg cells of normal subjects poorly inhibited the proliferation of Tresp cells from DCM patients.
The defective capacity of Treg cells suppressing autologous Tresp cells is attributed to the increasing resistance of Tresp cells to inhibition of Treg cells in DCM patients. Therefore, strategies to improve the susceptibility of Tresp cells to Treg cell-mediated suppression might benefit DCM patients.