Apolipoprotein B100 autoimmunity and atherosclerosis - disease mechanisms and therapeutic potential.

PURPOSE OF REVIEW: Adaptive immune responses have been shown to play an important role in the atherosclerotic disease process and both pathogenic and protective immunity has been identified. Apolipoprotein (apo) B100 appears to be a key antigen and novel therapies modulating immune responses against apo B100 have shown promising results in experimental models. This review will discuss recent developments in the mechanistic understanding of apo B100 autoimmunity and approaches taken to use this knowledge for development of novel therapies. RECENT FINDINGS: It has recently been shown that not only apo B100 modified by oxidation but also nonmodified apo B100 is targeted by autoimmune responses. This implies that a corresponding set of regulatory T cells with the same antigen specificity must exist and that these cells under normal circumstances are able to prevent autoimmunity against LDL. Recent studies also suggest that the atheroprotective effect of apo B100 peptide immunization acts by re-enforcing the activity of such cells. SUMMARY: These novel findings suggest that aggravation of plaque inflammation may occur as a result of a local loss of tolerance against LDL in the plaque due to insufficient activity of regulatory T cells. Restoration of lost tolerance represents an interesting novel approach for treatment of cardiovascular disease

Emerging biomarkers and intervention targets for immune-modulation of atherosclerosis - A review of the experimental evidence.

The role of inflammation in atherosclerosis and plaque vulnerability is well recognized. However, it is only during recent years it has become evident that this inflammation is modulated by immune responses against plaque antigens such as oxidized LDL. Interestingly, both protective and pathogenic immune responses exist and experimental data from animal studies suggest that modulation of these immune responses represents a promising new target for treatment of cardiovascular disease. It has been proposed that during early stages of the disease, autoimmune responses against plaque antigens are controlled by regulatory T cells that inhibit the activity of auto-reactive Th1 effector T cells by release of anti-inflammatory cytokines such as IL-10 and TGF-β. As the disease progresses this control is gradually lost and immune responses towards plaque antigens switch towards activation of Th1 effector T cells and release of pro-inflammatory cytokines such as interferon-γ, TNF-α and IL-1β. Several novel immune-modulatory therapies that promote or mimic tolerogenic immune responses against plaque antigens have demonstrated athero-protective effects in experimental models and a first generation of such immune-modulatory therapies are now in early or about to enter into clinical testing. A challenge in the clinical development of these therapies is that our knowledge of the role of the immune system in atherosclerosis largely rests on data from animal models of the disease. It is therefore critical that more attention is given to the characterization and evaluation of immune biomarkers for cardiovascular risk

Plasma oxidized LDL: a predictor for acute myocardial infarction?

Objectives. Oxidized LDL has been attributed a key role in the development of atherosclerosis. Previous studies have demonstrated increased plasma levels of oxidized LDL in patients with established coronary artery disease. The aim of the present study was to investigate if plasma oxidized LDL also predicts risk for development of coronary heart disease (CHD). Design. We used a nested case-control design to study the association between plasma levels of oxidized LDL and risk for development of acute myocardial infarction (AMI) and/or death by CHD. Subjects. Oxidized LDL was analysed by ELISA in cases (n = 26), controls (n = 26) and controls with LDL cholesterol >5.0 mmol L-1 (n = 26). Results. Oxidized LDL correlated with total plasma and LDL cholesterol in both cases (r = 0.72, P < 0.01, r = 0.69, P < 0.01, respectively) and controls (r = 0.71, P < 0.01, r = 0.77, P < 0.01, respectively). The oxidized LDL/plasma cholesterol ratio was higher amongst cases (13.5, range 10.7-19.8) than in controls (12.6, range 9.5-15.8, P < 0.05) and hypercholesterolaemic controls (12.2, range 8.0-16.0, P < 0.01). Conclusions. These findings identify high plasma oxidized LDL/total cholesterol ratio as a possible indicator of increased risk for AMI

Antibodies against gonadotropin-releasing hormone (GnRH) in patients with diabetes mellitus is associated with lower body weight and autonomic neuropathy.

Esophageal dysmotility and gastroparesis are common secondary complications in patients with diabetes mellitus. Patients with dysmotility express antibodies against gonadotropin-releasing hormone (GnRH) in serum. The aim of the present study was to scrutinize patients with diabetes mellitus with regard to the presence of GnRH antibodies, and to examine associations between antibodies and clinical findings

Depletion of enteric gonadotropin-releasing hormone is found in a few patients suffering from severe gastrointestinal dysmotility.

Objective: Many patients, especially women, suffer from severe gastrointestinal pain and dysmotility for several years without being diagnosed. Depletion of gonadotropin-releasing hormone (GnRH) in the enteric nervous system (ENS) has been described in some patients. The aim of this study was to examine the expression of GnRH in ENS and antibodies against GnRH in serum, in a dysmotility patient cohort of southern Sweden. Materials and methods: All consecutive patients (n = 35) referred for laparoscopic full-thickness biopsy because of symptoms or signs of severe dysmotility between 1998 and 2009, or patients with a severe dysmotility disorder having had a bowel resection within the time frame, were considered for inclusion. In 22 cases, representative biopsy material containing ganglia was available, and these patients were included. Medical records were scrutinized. The expression of GnRH was determined by immunohistochemistry in bowel biopsies from these patients and in patients with carcinoma or diverticulosis without ENS histopathology. Antibodies against GnRH in serum were determined by ELISA in patients and controls. Results: 14 patients were diagnosed with enteric dysmotility (ED) and 8 with chronic intestinal pseudo-obstruction due to varying etiology. Immunostained biopsies showed expression of GnRH in the ENS. A reduced expression of GnRH-containing neurons was found in 5 patients, as well as antibodies against GnRH in serum. 3 of these patients had a history of in vitro fertilization (IVF) using GnRH analogs. Conclusions: A subgroup of patients with severe dysmotility had a reduced expression of GnRH-containing neurons in the ENS and expressed antibodies against GnRH in serum

CD8+ T cell activation predominate early immune responses to hypercholesterolemia in Apoe-/- mice

<p>Abstract</p> <p>Background</p> <p>It 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 <it>Apoe^-/-</it>mice a high-fat diet for 4 or 8 weeks.</p> <p>Results</p> <p>The 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.</p> <p>Conclusion</p> <p>Hypercholesterolemia 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.</p

Decreased levels of stem cell factor in subjects with incident coronary events.

It has been proposed that vascular progenitor cells play an important role in vascular repair, but their possible clinical importance in cardiovascular disease has not been fully characterized. Vascular endothelial growth factor A, placental growth factor and stem cell factor (SCF) are three growth factors that are important in recruiting vascular progenitor cells. In this study, we investigated the association between the plasma levels of these growth factors and incident coronary events (CEs)

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

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

IL-22 affects smooth muscle cell phenotype and plaque formation in apolipoprotein E knockout mice.

IL-22 is a recently discovered cytokine that belongs to the family of IL-10 related cytokines. It is produced by activated T-cells and innate lymphoid cells and has been suggested to be involved in tissue repair. As both inflammation and repair play important roles in atherosclerosis we investigated if IL-22 deficiency influences the disease process in Apoe(-/-) mice