Objectives. Autoimmune responses against oxidized low-density lipoprotein are considered to play an important pro-inflammatory role in atherosclerosis and to promote disease progression. T-regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self-tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs.Design. Six-week-old Apoe ) ⁄ ) mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age.Results. At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)-induced interferon-c, interleukin (IL)-4, and IL-10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con Ainduced splenic T-cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210-induced Treg activation as well as the reduction of atherosclerosis. Conclusions. The present findings demonstrate that immunization of Apoe) ⁄ ) mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis-related autoimmunity by antigenspecific activation of Tregs represents a novel approach for treatment of atherosclerosis.

BackgroundIt is well established that adaptive immune responses induced by hypercholesterolemia play an important role in the development of atherosclerosis, but the pathways involved remain to be fully characterized. In the present study we assessed immune responses to hypercholesterolemia induced by feeding Apoe-/- mice a high-fat diet for 4 or 8 weeks.ResultsThe primary immune response in lymph nodes draining the aortic root was an increased expression of interferon (IFN)-γ in CD8+CD28+ T cells, while an activation of IFN-γ expression in CD4+ T cells was observed only after 8 weeks of high-fat diet. Contrarily, spleen CD4+ T cells responded with a higher expression of IL-10. Spleen CD8+ T cells expressed both IFN-γ and IL-10 and showed enhanced proliferation when exposed to Concanavalin A. Plasma levels of IgG and IgM against oxidized LDL did not change, but the level of apolipoprotein B/IgM immune complexes was increased.ConclusionHypercholesterolemia leads to unopposed activation of Th1 immune responses in lymph nodes draining atherosclerotic lesions, whereas Th1 activation in the spleen is balanced by a concomitant activation of Th2 cells. The activation of CD8+ T cells implies that hypercholesterolemia is associated with formation of cell autoantigens.

C-Tb, a novel Mycobacterium tuberculosis and 6-kDa early secretory antigenic target/10-kDa culture filtrate protein (ESAT-6/CFP-10)-specific skin test, has high specificity in bacille Calmette-Guerinvaccinated healthy controls. However, the sensitivity of C-Tb has hitherto not been determined. The objective was to determine the sensitivity of C-Tb in patients with active tuberculosis (TB) in comparison with the tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube (QFT-GIT).C-Tb and TST were randomly administered in a double-blinded fashion to one or the other forearm in 253 patients with active TB with or without HIV co-infection. QFT-GIT testing was performed prior to skin testing.Using a receiver operating characteristic curve-derived cut-point of 5 mm, C-Tb sensitivity was similar to QFT-GIT (73.9 (95% CI 67.8-79.3) versus 75.1 (95% CI 69.3-80.2)), and similar in HIV-infected and HIV-uninfected patients (76.7 (95% CI 69.0-83.3) versus 69.5 (95% CI 59.2-78.5)). However, sensitivity was significantly diminished in HIV-infected patients with CD4 counts <100 cells·mm -3 . C-Tb and QFT-GIT combined had significantly higher sensitivity than C-Tb alone ( p<0.0001). C-Tb was safe with no significant adverse events. The 5 mm cut-point corresponded to that found in the previously published specificity study (TESEC-04).C-Tb has similar sensitivity compared with QFT-GIT for the diagnosis of M. tuberculosis infection. Sensitivity was reduced only in HIV-infected patients with severe immunosuppression. Further studies in different settings are required to validate the proposed 5 mm cut-point. @ERSpublications C-Tb has similar sensitivity compared with QFT-GIT for the diagnosis of M. tuberculosis infection

The immune processes associated with atherogenesis have received considerable attention during recent years. IgG FcRs (FcγR) are involved in activating the immune system and in maintaining peripheral tolerance. However, the role of the inhibitory IgG receptor FcγRIIB in atherosclerosis has not been defined. Bone marrow cells from FcγRIIB-deficient mice and C57BL/6 control mice were transplanted to low-density lipoprotein receptor-deficient mice. Atherosclerosis was induced by feeding the recipient mice a high-fat diet for 8 wk and evaluated using Oil Red O staining of the descending aorta at sacrifice. The molecular mechanisms triggering atherosclerosis was studied by examining splenic B and T cells, as well as Th1 and Th2 immune responses using flow cytometry and ELISA. The atherosclerotic lesion area in the descending aorta was ~5-fold larger in mice lacking FcγRIIB than in control mice (2.75 ± 2.57 versus 0.44 ± 0.42%; p &lt; 0.01). Moreover, the FcγRIIB deficiency resulted in an amplified splenocyte proliferative response to Con A stimulation (proliferation index 30.26 ± 8.81 versus 2.96 ± 0.81%, p &lt; 0.0001) and an enhanced expression of MHC class II on the B cells (6.65 ± 0.64 versus 2.33 ± 0.25%; p &lt; 0.001). In accordance, an enlarged amount of CD25-positive CD4 T cells was found in the spleen (42.74 ± 4.05 versus 2.45 ± 0.31%; p &lt; 0.0001). The plasma Ab and cytokine pattern suggested increased Th1 and Th2 immune responses, respectively. These results show that FcγRIIB inhibits the development of atherosclerosis in mice. In addition, they indicate that absence of the inhibiting IgG receptor cause disease, depending on an imbalance of activating and inhibiting immune cells.

It is well established that atherosclerosis is caused by an inflammatory process in the arterial intima. However, it is only

Background The findings of experimental studies suggest that the immune system plays a key role in atherosclerosis, but the clinical importance of different immune cells in cardiovascular disease remains poorly characterized. In this study we investigated the association between CD8+ T cells and carotid disease as well as development of cardiovascular disease events. Methods The study cohort comprised 700 subjects from the cardiovascular arm of the Malmö Diet and Cancer Study. Peripheral blood mononuclear cells, obtained at the 1991–1994 baseline investigation and stored at −140 °C, were thawed and the different CD8+ T‐cell populations analysed by flow cytometry. Baseline carotid intima–media thickness and stenosis were assessed by ultrasonography and clinical events were monitored through validated national registers. Results Subjects with a high fraction of CD8+ T cells were characterized by decreased cytokine release from activated leucocytes, metabolic signs of insulin resistance and increased incidence of coronary events; hazard ratios (95% confidence intervals) for the second and third tertiles of CD8+ T cells were 2.57 (1.16, 5.67) and 2.61 (1.19, 5,71), respectively, in a Cox proportional hazards regression model. Correlations were found between the fraction of CD8+CD25+ T cells and the degree of carotid stenosis (r = 0.11, P < 0.01), and between the CD8+CD56−IFN‐γ+ T‐cell fraction and the degree of stenosis (r = −0.18, P < 0.005). The association between CD8+CD56−IFN‐γ+ T cells and carotid stenosis remained significant after controlling for major cardiovascular disease risk factors. Conclusion This study provides prospective clinical evidence for a role of CD8+ T cells in cardiovascular disease and suggests the existence of CD8+ T‐cell subsets with different pathological functions.

Antigen presenting cells (APC) have the ability to present both extra-cellular and intra-cellular antigens via MHC class I molecules to CD8+ T cells. The cross presentation of extra-cellular antigens is reduced in mice with deficient Antigen Peptide Transporter 1 (TAP1)-dependent MHC class I antigen presentation, and these mice are characterized by a diminished CD8+ T cell population. We have recently reported an increased activation of CD8+ T cells in hypercholesterolemic Apoe−/− mice. Therefore, this study included TAP1-deficient Apoe−/− mice (Apoe−/−Tap1−/−) to test the atherogenicity of CD8+ T cells and TAP1-dependent cross presentation in a hypercholesterolemic environment. As expected the CD8+ T cell numbers were low in Apoe−/−Tap1−/− mice in comparison to Apoe−/− mice, constituting ∼1% of the lymphocyte population. In spite of this there were no differences in the extent of atherosclerosis as assessed by en face Oil Red O staining of the aorta and cross-sections of the aortic root between Apoe−/−Tap1−/− and Apoe−/− mice. Moreover, no differences were detected in lesion infiltration of macrophages or CD3+ T cells in Apoe−/−Tap1−/− compared to Apoe−/− mice. The CD3+CD4+ T cell fraction was increased in Apoe−/−Tap1−/− mice, suggesting a compensation for the decreased CD8+ T cell population. Interestingly, the fraction of CD8+ effector memory T cells was increased but this appeared to have little impact on the atherosclerosis development.In conclusion, Apoe−/−Tap1−/− mice develop atherosclerosis equal to Apoe−/− mice, indicating a minor role for CD8+ T cells and TAP1-dependent antigen presentation in the disease process.

Immune responses against modified self-antigens generated by hypercholesterolemia play an important role in atherosclerosis identifying the immune system as a possible novel target for prevention and treatment of cardiovascular disease. It has recently been shown that these immune responses can be modulated by subcutaneous injection of adjuvant. In the present study we