Activation of immune responses against the basement membrane component collagen type IV does not affect the development of atherosclerosis in ApoE-deficient mice.

Oxidation of low-density lipoprotein (LDL) in the arterial extracellular matrix results in malondialdehyde (MDA)-modifications of surrounding matrix proteins. We have recently demonstrated an association between high levels of autoantibodies against MDA-modified collagen type IV and risk for development of myocardial infarction. Collagen type IV is an important component of the endothelial basement membrane and influences smooth muscle cell function. We hypothesized that immune responses against collagen type IV could contribute to vascular injury affecting the development of atherosclerosis. To investigate this possibility, we induced an antibody-response against collagen type IV in apolipoprotein E (Apo E)-deficient mice. Female ApoE-/- mice on C57BL/6 background were immunized with α1α2 type IV collagen chain peptides linked to the immune-enhancer PADRE, PADRE alone or PBS at 12 weeks of age with three subsequent booster injections before the mice were killed at 23 weeks of age. Immunization of PADRE alone induced autoantibodies against PADRE, increased IL-4 secretion from splenocytes and reduced SMC content in the subvalvular plaques. Immunization with peptides of α1α2 type IV collagen chains induced a strong IgG1antibody response against collagen type IV peptides without affecting the distribution of T cell populations, plasma cytokine or lipid levels. There were no differences in atherosclerotic plaque development between collagen α1α2(IV)-PADRE immunized mice and control mice. Our findings demonstrate that the presence of antibodies against the basement membrane component collagen type IV does not affect atherosclerosis development in ApoE-/- mice. This suggests that the association between autoantibodies against collagen type IV and risk for myocardial infarction found in humans does not reflect a pathogenic role of these autoantibodies.

Anti-ApoA-I IgG antibodies are not associated with carotid artery disease progression and first-time cardiovascular events in middle-aged individuals.

OBJECTIVE: IgG antibodies against apolipoprotein A-I (ApoA-I) have been found to be elevated in subjects from the general population with clinically manifest cardiovascular disease and in myocardial infarction patients with an adverse prognosis. Here, we investigated whether these antibodies are prospectively associated with carotid artery disease progression and with the risk for first-time cardiovascular events in individuals with no previous history of cardiovascular disease. APPROACH AND RESULTS: We selected 383 subjects from the cardiovascular cohort of Malmö Diet and Cancer study who suffered a coronary event during a median follow-up period of 15.4 (10.3-16.4) years and 395 age- and sex-matched controls. None of the study participants had a previous history of coronary artery disease or stroke. Anti-ApoA-I IgG were measured by ELISA in serum samples collected at baseline. Intima-media thickness (IMT) was measured in the common carotid artery and in the carotid bifurcation at baseline and after 15.9 (±1.5) years. We found no associations between anti-ApoA-I IgG and carotid artery IMT at baseline or with IMT progression during follow-up. In Cox proportional hazards analyses adjusted for traditional cardiovascular risk factors, the hazard ratio (HR 95%CI) for the primary outcome, incident coronary events, was 0.97 (0.75-1.25), P = 0.782, in subjects with anti-ApoA-I IgG within the highest tertile compared with the lowest tertile. Similarly, we did not find any associations with the secondary outcome, incident first-time stroke. CONCLUSIONS: Serum autoantibodies against ApoA-I do not correlate with disease progression and adverse events in cardiovascular disease-free individuals from the general population.

CD4+ CD56+ natural killer T-like cells secreting interferon-γ are associated with incident coronary events.

BACKGROUND: CD3(+) CD56(+) natural killer T (NKT)-like cells are a subset of T cells characterized by expression of NK receptors and potent antitumour activity. It has also been suggested that they have a role in autoimmune disease, and levels of NKT-like cells are elevated in patients with coronary disease. OBJECTIVES: To investigate whether high levels of CD3(+) CD56(+) NKT-like cells are associated with an increased incidence of cardiovascular disease and a lower incidence of cancer. METHODS: This was a prospective study including 700 subjects participating in the baseline investigation of the Malmö Diet and Cancer study between 1991 and 1994. Leucocytes obtained at the baseline investigation and stored at -140 °C were thawed and CD3(+) CD56(+) cells analysed by flow cytometry. The incidence rates of cancer and coronary events during a mean follow-up of 15 years were determined through national registers. RESULTS: Subjects in the lowest tertile of interferon (IFN)-γ-expressing CD4(+) CD56(+) cells were found to have an increased risk of incidence of coronary events (log-rank test: P < 0.05). This association remained significant after controlling for age, sex, smoking, body mass index, hypertension, diabetes and the Th1/Th2 and Th1/Treg cell ratios in a Cox proportional hazards regression model (hazard ratio 1.98, 95% confidence interval 1.24-3.16), but not when the LDL/HDL ratio was included in the model. There were no associations between CD3(+) CD56(+) NKT-like cells and incident cancer. CONCLUSIONS: The present results could not confirm the hypothesis that low levels of CD3(+) CD56(+) NKT-like cells are associated with a higher incidence of cancer and a lower incidence of cardiovascular disease. However, we found that low levels of IFN-γ-expressing CD3(+) CD4(+) CD56(+) NKT-like cells were associated with an increased incidence of coronary events and that this association may be dependent on lipoproteins.

High levels of IgM against methylglyoxal-modified apolipoprotein B100 are associated with less coronary artery calcification in patients with type 2 diabetes.

OBJECTIVE: Advanced glycation end products (AGE) have been implicated in diabetic vascular complications through activation of pro-inflammatory genes. AGE-modified proteins are also targeted by the immune system resulting in the generation of AGE-specific autoantibodies, but the association of these immune responses with diabetic vasculopathy remains to be fully elucidated. The aim of this study was to determine whether antibodies against apolipoprotein B100 modified by methylglyoxal (MGO-apoB100) are associated with coronary atherosclerosis in patients with type 2 diabetes. METHODS: We measured antibodies against MGO-apoB100 in plasma from 497 type 2 diabetic patients without clinical signs of cardiovascular disease. Severity of coronary disease was assessed as coronary artery calcium (CAC) imaging. Immunoglobulin (Ig)M and IgG levels recognizing MGO-apoB100 were determined by enzyme-linked immunosorbent assay. RESULTS: Anti-MGO-apoB100 IgM antibody levels were higher in subjects with a low to moderate CAC score (≤400 Agatston units) than in subjects with a high score (>400 Agatston units; 136.8±4.4 vs. 101.6± 7.4 arbitrary units (AU), P<0.0001) and in subjects demonstrating no progression of CAC during 30 months of follow-up (136.4±5.7 vs. 113.9 ± 6.2 AU in subjects with progression, P<0.0001). Subjects with a family history of premature myocardial infarction had lower levels of anti-MGO-apoB100 IgM. Female subjects had higher levels of anti-MGO-apoB100 antibodies and lower CAC than men. Accordingly, high levels of IgM against MGO-apoB100 are associated with less severe and a lower risk of progression of coronary disease in subjects with type 2 diabetes. CONCLUSIONS: Although conclusions regarding causal relationships based on epidemiological observations need to be made with caution, our findings suggest the possibility that anti-MGO-apoB100 IgM may be protective in diabetic vasculopathy.