Plaque Antigens Research Articles

Two Cases of Retroperitoneal Fibrosis During Anti-programmed Cell Death 1 Antibody Treatment

Background. Retroperitoneal fibrosis is characterized by fibrosis around the abdominal aorta and iliac arteries. Two-thirds of reported cases had idiopathic causes. Idiopathic retroperitoneal fibrosis is thought to result from a local inflammatory reaction to antigens in the atherosclerotic plaques of the abdominal aorta. Therefore, it is thought that idiopathic retroperitoneal fibrosis may be a manifestation of a systemic autoimmune or inflammatory disease. In contrast, anti-programmed cell death 1 (anti-PD-1) antibodies may overexpress innate immunity. There have been only two case reports on retroperitoneal fibrosis during anti-PD-1 antibody treatment. We encountered two cases of retroperitoneal fibrosis during anti-PD-1 antibody treatment. Cases. Case 1 involved a 57-year-old man who experienced recurrence of squamous cell lung carcinoma after resection. More than 75% of his cancer cells were positive for programmed cell death ligand 1 (PD-L1). He experienced urinary urgency after one year and six months of nivolumab treatment. Computed tomography revealed a homogeneous plaque that was isodense with muscle surrounding the abdominal aorta and iliac arteries. Positron emission tomography revealed the accumulation of fluorodeoxyglucose at the same site. The serum IgG4 level was normal. Although a biopsy specimen was not obtained, the patient was diagnosed with retroperitoneal fibrosis. The patient was treated with steroids. Case 2 involved a 64-year-old man with pulmonary large cell carcinoma. An analysis of the cancer cells revealed that 50-74% of the cells were positive for PD-L1. Lower back pain appeared after one year and 11 months of pembrolizumab treatment. Computed tomography revealed right hydronephrosis and homogeneous plaque on the right side of the abdominal aorta. Although a biopsy specimen was not obtained, the patient was diagnosed with retroperitoneal fibrosis. The patient improved once with steroids but relapsed. Conclusion. We hypothesized that the administration of anti-PD-1 antibodies may have affected the onset of retroperitoneal fibrosis.

Abstract 9391: Early Biomarkers to Predict a Worse Outcome After Acute Myocardial Infarction: Circulating Infectious Extracellular Vesicles From Archaea and M. Pneumoniae Are Present and Correlated to Cytokines IL-6 and IL-10

Acute myocardial infarction (AMI) is related to rupture of atheroma plaques containing pro-inflammatory cytokines, oxidized low-density lipoprotein (oxLDL) and MMP9, a microenvironment compatible with the presence of a pathogenic microbial community. Recently, infectious extracellular vesicles (iEVs) were discovered to be released in co-infections. Previously, we found iEVs positive for archaea DNA and Mycoplasma pneumoniae (Mp) antigens in vulnerable plaques. Now, looking for serum particles biomarkers to differentiate atherosclerotic clinical outcomes we studied 168 patients (pts) from groups: Atherosclerotic (ATR), AMI, AMI with major severity (sAMI) and healthy (CTL) Methods: We quantified and characterized serum iEVs ( 0.79-1.34 μm) through their content using the Flow Cytometry technique and for cytokines using CBA kit, for exosomes (<100nm) we used Nanosight equipment and for correlations we used Spearman 's test. Results: sAMI pts sera presented increased no. of iEVs positive for archaea DNA and Mp, MMP9, IL6 and IL10 cytokine antigens. TNFα was increased in CTL and ATR compared to both AMI groups. TNFα correlated with archaeal IEVs in sIAM group. There was a significant positive correlation between Mp and MMP9 in the AMI, CTL and ATR groups. A significant positive correlation was present between Mp and IL6 in AMI and sAMI groups. ATR and CTL groups had higher no. of exosomes than the sAMI group. Conclusion: Increased numbers of serum IEVs positive for archaea, Mp and MMP9 elements in association with increased levels of IL6, decreased numbers of protective exosomes and correlation between TNF-α vs archaea, are present in sAMI clinical outcome, which suggests that serum IEVs and cytokines levels may constitute new biomarkers to differentiate atherosclerotic clinical outcomes.

Detection of Antigens of Cardiotropic Viruses in Atherosclerotic Plaques in Patients with Fatal Myocardial Infarction

To assess the frequency of detection of cardiotropic virus antigens in coronary artery atherosclerotic plaques in patients with fatal myocardial infarction (MI). We examined fragments of coronary plaques of 12 patients with fatal type 1 MI. Immunohistochemistry (IHC) of plaques was performed with the paraffin blocks using antibodies to Herpes simplex virus (HSV)-1, HSV-2, HSV-6, cytomegalovirus (CMV), parvovirus B19, adenovirus, Epstein-Barr virus and enteroviruses. According to the IHC all patients had virus antigens. The most common virus agents in fragments of coronary plaques were HSV-6 (10 patients) and enteroviruses (5 patients). Antigens of CMV, parvovirus B19, adenovirus, Epstein-Barr virus were not detected in any case. In this study viral antigens in coronary artery atherosclerotic plaques were found in all victims of fatal MI. There was no difference in the frequency of detection and type of viral agents between plaques in culprit arteries and uncomplicated atherosclerotic plaques.

The aorta can act as a site of naïve CD4+ T-cell priming.

Aortic adaptive immunity plays a role in atherosclerosis; however, the precise mechanisms leading to T-cell activation in the arterial wall remain poorly understood. Here, we have identified naïve T cells in the aorta of wild-type and T-cell receptor transgenic mice and we demonstrate that naïve T cells can be primed directly in the vessel wall with both kinetics and frequency of T-cell activation found to be similar to splenic and lymphoid T cells. Aortic homing of naïve T cells is regulated at least in part by the P-selectin glycosylated ligand-1 receptor. In experimental atherosclerosis the aorta supports CD4+ T-cell activation selectively driving Th1 polarization. By contrast, secondary lymphoid organs display Treg expansion. Our results demonstrate that the aorta can support T-cell priming and that naïve T cells traffic between the circulation and vessel wall. These data underpin the paradigm that local priming of T cells specific for plaque antigens contributes to atherosclerosis progression.

MHC class II tetramers identify apolipoprotein B-specific CD4 T cells in mice and humans

Abstract Immunization with atherosclerotic plaque antigens including MHC-II-restricted peptides from apolipoprotein B (ApoB, core protein of low density lipoprotein, LDL) is known to be atheroprotective in animal models. Herein we report a human ApoB peptide whose sequence is identical to mouse ApoB and which binds to both mouse (I-Ab) and human MHC class II. Immunization with this peptide reduced atherosclerotic plaque in the aortas of Apoe−/− mice fed with a Western diet and induced IL-10 producing CD25+FoxP3+ regulatory T cells (Tregs). After peptide restimulation in vivo, responding CD4+ T cells (by Nur77-GFP) were highly enriched in CD25+FoxP3+ Tregs. Using a novel I-Ab tetramer reagent, we further showed that peptide-specific CD4+ T cells expand upon vaccination, ~50% express FoxP3, and were 10-fold enriched for IL-10 producers. In human peripheral blood mononuclear cells (PBMCs) from individuals assessed for subclinical cardiovascular disease, ApoB-specific CD4+ T cells were detected using novel HLA-DR1/ApoB peptide tetramers. Peptide-specific CD4+ T cells from donors with carotid artery plaques showed more RORγt expression and less FoxP3 expression compared to those without. This is the first demonstration of ApoB-specific CD4+ T cells by tetramer in humans and the first animal model evidence of atheroprotective vaccination with a human ApoB peptide.

The Ratio of Regulatory (FOXP3 +) to Total (CD3 +) T Cells Determined by Epigenetic Cell Counting and Cardiovascular Disease Risk: A Prospective Case-cohort Study in Non-diabetics

BackgroundExperimental and clinical evidence indicate that inflammatory processes in atherogenesis and the development of cardiovascular complications are promoted by a loss of regulatory T cell (Treg)-mediated immunological tolerance to plaque antigens. Yet, the association between alterations of systemic Treg frequency and cardiovascular disease incidence remains uncertain. MethodsA nested case-cohort study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg, comprising a random subcohort (n=778) and primary cases of myocardial infarction (MI, n=276) and ischemic stroke (n=151). Pre-diagnostic FOXP3+ Treg and total CD3+ T-lymphocyte (tTL) frequencies in blood were measured by epigenetic-based, quantitative real-time PCR-assisted cell counting. ResultsMultivariate, Prentice-weighted Cox regression analyses revealed that lower Treg/tTL ratios were not associated with the risk of either MI (lowest vs. highest sex-specific quartile; hazard ratio: 0.72, 95% confidence interval: 0.46 to 1.13; Ptrend=0.51) or stroke (HR: 0.90, 95% CI: 0.51 to 1.60; Ptrend=0.78). There were no correlations of Treg/tTL ratios with C-reactive protein, HbA1c, and various lipid parameters. ConclusionsAmong middle-aged adults from the general population, imbalances in the relative frequency of Tregs within the total T cell compartment do not confer an increased risk of MI or stroke.

Polymorphism in the chemokine receptor 7 gene (CCR7) is associated with previous myocardial infarction in patients undergoing elective coronary angiography.

Coronary artery disease (CAD) remains a major cause of death in developed countries. Both environmental and, less known, genetic factors contribute to progression of CAD to myocardial infarction (MI). Immune system is activated in patients with CAD through dendritic cells (DCs), which present plaque antigens to T lymphocytes. Production of proinflammatory cytokines by activated T cells contributes to plaque rupture in MI. Chemokine receptor 7 (CCR7) on DCs is required for their chemotaxis from plaque to lymph nodes. This makes possible an interaction of DCs with T lymphocytes and initiation of specific immune response. We hypothesized that single nucleotide polymorphisms (SNPs) in CCR7 gene locus are associated with previous MI in patients with CAD. To test this hypothesis, we genotyped six SNPs from the CCR7 gene locus in 300 consecutive patients, admitted for elective coronary angiography. We performed univariate-, multivariate- (including potential confounders) and haplotype-based tests of association of SNPs with previous MI and results of angiography. Allele A of rs17708087 SNP was associated with previous MI. This association remained significant after adjustment for age, sex, smoking, hypercholesterolaemia and drugs used by patients (odds ratio 2.13, 95% confidence interval: 1.13-3.86). Therefore, we conclude that CCR7 gene locus harbours a polymorphism that modifies risk of MI in patients with CAD. Replication of this association could be sought in a prospective cohort of initially healthy individuals.

Idiopathic Retroperitoneal Fibrosis Involving a Unilateral Renal Sinus: A Case Report and Literature Review

Retroperitoneal fibrosis (RPF) is an uncommon fibrotic reaction in the retroperitoneum. There is an idiopathic form and a secondary form associated with IgG4-related disease, drugs (methysergide, pergolide, bromocriptine, ergotamine, methyldopa, hydralazine), infections (tuberculosis, histoplasmosis, actinomycosis), malignancies (carcinoid tumor, Hodgkin’s and non-Hodgkin’s lymphomas, sarcomas, carcinomas of the colon, prostate, breast, and stomach), prior surgeries, and radiation therapy. The idiopathic form accounts for more than two-thirds of cases and it was thought to result from a local inflammatory response to antigens in the atherosclerotic plaques in the abdominal aorta, combined with auto-immunologic factors. Thus, the fibroinflammatory tissue usually encases the infrarenal portion of the abdominal aorta, inferior vena cava, and ureters (1-3). Here, we report two rare cases of idiopathic RPF involving only a unilateral renal pelvis and sinus; thus mimicking renal pelvic cancer.

Atheroprotective immunity and cardiovascular disease: therapeutic opportunities and challenges.

Emerging knowledge of the role of atheroprotective immune responses in modulating inflammation and tissue repair in atherosclerotic lesions has provided promising opportunities to develop novel therapies directly targeting the disease process in the artery wall. Regulatory T (Treg) cells have a protective role through release of anti-inflammatory cytokines and suppression of autoreactive effector T cells. Studies in experimental animals have shown that blocking the generation or action of Treg cells is associated with more aggressive development of atherosclerosis. Conversely, cell transfer and other approaches to expand Treg cell populations invivo result in reduced atherosclerosis. There have been relatively few clinical studies of Treg cells and cardiovascular disease, but the available evidence also supports a protective function. These observations have raised hope that it may be possible to develop therapies that act by enforcing the suppressive activities of Treg cells in atherosclerotic lesions. One approach to achieve this goal has been through development of vaccines that stimulate immunological tolerance for plaque antigens. Several pilot vaccines based on LDL-derived antigens have demonstrated promising results in preclinical testing. If such therapies can be shown to be effective also in clinical trials, this could have an important impact on cardiovascular prevention and treatment. Here, we review the current knowledge of the mode of action of atheroprotective immunity and of the ways to stimulate such pathways in experimental settings. The challenges in translating this knowledge into the clinical setting are also discussed within the perspective of the experience of introducing immune-based therapies for other chronic noninfectious diseases.

Human cytomegalovirus induces upregulation of arginase II: possible implications for vasculopathies

Both human cytomegalovirus (HCMV) and arginase II (ARG II) have been implicated in the pathogenesis of cardiovascular diseases. The effects of HCMV on ARG II are unknown. The aim of this study was to investigate the effects of HCMV on ARG II expression in endothelial and vascular smooth muscle cells (SMC) both in vitro and ex vivo. Endothelial and SMC were infected with either HCMV or UV-irradiated HCMV. Expression of ARG II, endothelial or inducible nitric oxide synthase (eNOS and iNOS, respectively) and viral immediate early (IE) was quantified using quantitative PCR. Ganciclovir and short interfering RNA were used to determine the viral gene mediating the effects on ARG II. Detection of viral antigens and ARG II expression was performed by immunofluorescence or immunohistochemistry. HCMV infection increased both ARG II mRNA and protein levels in the examined cells; this effect was mediated by the HCMV IE2-p86 protein. The upregulation of ARG II was accompanied by a downregulation of eNOS but an induction of iNOS in HCMV-infected endothelial cells. Both eNOS and iNOS expressions were induced in HCMV-infected SMC. ARG II was abundantly expressed in endothelial cells, foam cells and SMC and was importantly significantly upregulated in HCMV-immunoreactive human carotid atherosclerotic plaques. HCMV IE2-p86 mediates ARG II upregulation in vitro and ARG II is co-expressed with HCMV antigens in human carotid atherosclerotic plaques. We speculate that HCMV may contribute to endothelial dysfunction via ARG II induction and reduced eNOS production.

High prevalence of human cytomegalovirus in carotid atherosclerotic plaques obtained from Russian patients undergoing carotid endarterectomy

BackgroundHuman cytomegalovirus (HCMV) infection is associated with cardiovascular disease (CVD) but the role of this virus in CVD progression remains unclear. We aimed to examine the HCMV serostatus in Russian patients (n = 90) who had undergone carotid endarterectomy (CEA) and controls (n = 82) as well as to determine the prevalence of HCMV immediate early (IE) and late (LA) antigens in carotid atherosclerotic plaques obtained from 89 patients. In addition, we sought to determine whether HCMV infection was associated with inflammatory activity in the plaque by quantifying infiltrating CD3 and CD68 positive cells and 5-LO immunoreactivity.MethodsHCMV serology was assessed with ELISA and immunohistochemistry staining was performed to detect HCMV antigens, CD3, CD68 and 5-LO reactivity. The Fisher’s exact test was used to compare i) seroprevalence of HCMV IgG between patients and controls and ii) HCMV-positive or –negative to that of CD3, CD68 and 5-LO immunoreactive cells in plaque samples. The student-t test was performed to connote the significance level of mean optical density between patients and controls.ResultsThe seroprevalence for HCMV IgG was high in both patients and controls (99% and 98%, respectively). Controls had significantly higher IgG titers for HCMV compared with patients (p = 0.0148). Strikingly, we found a high prevalence of HCMV antigens in atherosclerotic plaques; 57/89 (64%) and 47/87 (54%) were HCMV IE and LA positive, respectively. Most plaques had rather low HCMV reactivity with distinct areas of HCMV-positive cells mainly detected in shoulder regions of the plaques, but also in the area adjacent to the necrotic core and fibrous cap. In plaques, the cellular targets for HCMV infection appeared to be mainly macrophages/foam cells and smooth muscle cells. HCMV-positive plaques trended to be associated with increased numbers of CD68 positive macrophages and CD3 positive T cells, while 5-LO reactivity was high in both HCMV-positive and HCMV-negative plaques.ConclusionsIn Russian patients undergoing CEA, HCMV proteins are abundantly expressed in carotid plaques and may contribute to the inflammatory response in plaques via enhanced infiltration of CD68 and CD3 cells.

Chronic Periaortitis

Chronic Periaortitis

Autoimmunity in atherosclerosis: a protective response losing control?

Atherosclerosis is a chronic inflammatory disease characterized by accumulation of oxidized lipoproteins, increased cell death and hypertrophic degeneration of the arterial intima. The disease process is associated with local formation of modified self antigens that are targeted by both innate and adaptive immune responses. Although it remains to be firmly established it is likely that these autoimmune responses initially have a beneficial effect facilitating the removal of potentially harmful rest products from oxidized LDL and dying cells. However, studies performed on hypercholesterolaemic mice deficient in different components of the immune system uniformly suggest that the net effect of immune activation is pro-atherogenic and that atherosclerosis, at least to some extent, should be regarded as an autoimmune disease. These observations point to the possibility of developing new treatments for atherosclerosis based on modulation of immune responses against plaque antigens, an approach presently tested clinically for several other chronic inflammatory diseases with autoimmune components. Pilot studies in animals have provided promising results for both parental and oral vaccines based on oxidized LDL antigens. The time when this concept is ready for clinical testing is rapidly approaching but it will be important not to underestimate the difficulties that will be encountered in transferring the promising results from experimental animals into humans.

The Influence of the Regulatory T Lymphocytes on Atherosclerosis

Atherosclerosis is complex inflammatory disease of the arterial wall, in which T lymphocytes play a significant role.1 Since the recognition that T lymphocytes are present in human atherosclerotic plaque nearly 2 decades ago,2 research has focused on the functional importance of these cells in the atherosclerotic process. The majority of T lymphocytes in atherosclerotic lesions are CD4+ T-helper cells with a phenotype characteristic of the proinflammatory T-helper 1 (Th1) subset. These cells recognize specifically antigens that are produced in relative abundance in hypercholesterolemic individuals or in plaques including oxidatively modified LDL (Ox-LDL) and HSP60/65. The T cells are activated when macrophage or dendritic cells present these antigens to the T cells in plaques or lymphoid tissues. The Th1 cells produce inflammatory cytokines IFN-γ, tumor necrosis factor (TNF)-α, and membrane CD40-ligand, which amplify the immune response through activation of macrophages, vascular smooth muscle cells, and endothelial cells.1 See page 2691 Many mechanisms have evolved to maintain immunologic self-tolerance and to limit responses to foreign antigens. One of these mechanisms involves regulatory T cells (Treg) that actively suppress responses of effector T cells. The best- characterized Treg are the natural CD4+CD25+ Treg that mature in the thymus and comprise 5% to 10% of peripheral CD4+ T cells.3 Other surface markers expressed by Treg include CTLA-4 and GITR. FoxP3, a forkhead family transcription factor, is a lineage specification factor for Treg and plays a crucial role in their suppressive function.4 Natural Treg are generated during thymic development, but Treg are also induced in peripheral tissues during immune responses. Treg express antigen receptors typical of effector T cells and are presumably activated by peptide antigens presented by APCs. They also require interleukin (IL)-2 for development and survival. Once activated, Treg may suppress other T …

Investigation of Chlamydia pneumoniae DNA, chlamydial lipopolisaccharide antigens, and Helicobacter pylori DNA in atherosclerotic plaques of patients with aortoiliac occlusive disease

Background and Introduction It has been suggested that chronic infections may have a role in both the initiation and progression of atherosclerosis. While the majority of available data are focused on coronary artery disease, our aim was to investigate the presence of Chlamydia pneumoniae and Helicobacter pylori in samples from aortoiliac occlusive disease. Methods Aorta-iliac atherectomy specimens were collected under sterile conditions from 21 patients (19 male, 2 female) undergoing surgery for aortoiliac occlusive disease. Seventeen macroscopically healthy vessels (12 internal mammary arteries, 3 radial arteries, prepared for coronary artery bypass graft, and 2 traumatic artery specimens, one of which was a superficial femoral artery and the other was a radial artery) were used as control. Blood samples for serological assays were obtained immediately before surgery. The polymerase chain reaction (PCR) was employed to search for H. pylori and C. pneumoniae DNA in atherosclerotic plaques and healthy vessel samples. Group-specific chlamydial lipopolysaccharide (LPS) antigens in atherosclerotic plaques and in healthy vessel samples and serum IgG antibodies to chlamydial LPS were determined by using a commercially available enzyme-linked immunosorbent assay (ELISA). Antibodies to H. pylori were also tested in all cases by means of an in-house ELISA. Results Chlamydial LPS and DNA were detected in 6 of 21 (28.57%) atherosclerotic lesions using ELISA or PCR, respectively. There was no evidence of H. pylori DNA in any plaque specimens. All cases in which C. pneumoniae DNA was positive were also seropositive for antichlamydial LPS. Neither C. pneumoniae DNA nor antigen nor H. pylori DNA was found in the macroscopically healthy samples. Conclusion Our results suggest that C. pneumoniae but not, as proposed, H. pylori may be involved in the pathogenesis of aortoiliac atherosclerosis.

The Role of the T‐cell Inducible Co‐stimulatory Molecule ICOS in the Development of Atherosclerosis

Background T-cell-mediated immune responses to plaque antigens are important in mediating the inflammatory response in atherosclerosis. The inducible co-stimulatory molecule (ICOS) is expressed on activated T cells after antigen stimulation and has important T-cell regulatory functions. Method Bone morrow chimeras were produced by transplanting ICOS-deficient bone marrow into atherosclerosis-prone low-density lipoprotein receptor (LDLR)-deficient mice. Atherosclerosis was analyzed after 8 weeks of high-fat diet. Results ICOS deficiency significantly increased atherosclerosis. Mice transplanted with ICOS deficient cells had an increase in fractional lesion area in the aortic sinuses from 37.4 ± 2.2% to 53.6 ± 2.2% (P<0.0001), a 43% increase in the atherosclerotic burden. Immunohistochemistry of the atherosclerotic lesions demonstrated a 3 to 4 fold increase in CD4(+) T cell infiltration, as well as increased macrophage infiltration. This increase correlated with a significant increase in the in-vitro proliferation of spleen CD4(+) T cell stimulated with anti-CD3 antibodies. Moreover, there was also an increase in the specific proliferation towards Oxidized-LDL (10 mg/ml) in mice transplanted with ICOS deficient cells. This corresponded with an increased pro-inflammatory (IL-2, IFN-γ, TNFα) cytokine profile in these cells by both protein level secretion and RT-PCR analysis and a decrease in the expression of the anti-inflammatory cytokine TGF-β. Serum levels of the pro-inflammatory chemokine MCP-1 was increased in these mice. Conclusion ICOS has a role in the development of atherosclerosis by down regulating the pro-inflammatory immune response.

T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses

The influence of the immune system on atherosclerosis involves both helper T (Th) cell and antibody responses to plaque antigens. These responses may have proatherogenic and protective effects. T-bet is a transcription factor required for Th1 differentiation and regulates the balance between Th1 and Th2 responses in inflammatory diseases. To clarify how helper T cell subset differentiation influences atherosclerosis, we compared lesion development and immune responses to plaque antigens in low-density lipoprotein receptor-deficient (Ldlr-/-) mice with or without functional T-bet genes. Atherosclerosis was significantly reduced in T-bet-deficient Ldlr-/- mice compared with Ldlr-/- controls, and the lesions that did develop in the absence of T-bet had less smooth muscle cell content. Furthermore, T-bet deficiency caused a Th2 switch in the response to the atherosclerosis-associated antigen heat shock protein-60, and a change in T-dependent isotypes of oxidized LDL-specific antibodies. Of particular significance, T-bet deficiency caused a >250% increase in the titer of E06 antibodies, which are known to be atheroprotective and whose production by B-1 B cells is enhanced by IL-5. These findings establish that T cell subset differentiation influences both T cell and antibody responses that modulate atherosclerosis, and validate the therapeutic goal of skewing T responses to atherosclerosis-associated antigens.

B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice.

Several lines of evidence indicate that T-cell responses influence the progression of atherosclerotic disease. Interferon-gamma (IFN-gamma)-producing T cells specific for lesional antigens, including oxidized LDLs and heat shock protein 60 (HSP60), may promote lesion development as well as plaque instability. B7-1 and B7-2 are closely related molecules expressed on antigen-presenting cells that provide costimulatory signals for T-cell activation. This study tested the hypothesis that the ability of T cells to influence atherosclerosis depends on B7-1/B7-2 costimulation. B7-1/B7-2/LDL receptor (LDLR)-deficient mice and LDLR-deficient control mice were fed a 1.25% cholesterol or control diet for 8 and 20 weeks. Total serum cholesterol levels and extent and phenotype of atherosclerosis were analyzed. Splenic and lymph node CD4+ T cells from the animals were cultured with mouse recombinant HSP60 or media and antigen-presenting cells and analyzed for IFN-gamma and interleukin-4 production. The absence of B7-1 and B7-2 significantly reduced early cholesterol diet-induced atherosclerotic lesion development in LDLR-deficient mice compared with B7-1/B7-2-expressing control mice. Furthermore, CD4+ T cells from the cholesterol-fed B7-deficient mice secreted a significantly lower amount of IFN-gamma in response to mouse HSP60 in vitro than did T cells from B7-expressing control mice. The data show that B7-1 and B7-2 regulated the development of atherosclerotic lesions and the priming of lesional antigen-specific T cells. This study highlights the B7-CD28 pathway as a potentially important target for immunomodulation of atherosclerosis.

In vivo conversion of racemized beta-amyloid ([D-Ser 26]A beta 1-40) to truncated and toxic fragments ([D-Ser 26]A beta 25-35/40) and fragment presence in the brains of Alzheimer's patients.

The lag between beta-amyloid (A beta) deposition and neurodegeneration in Alzheimer's disease (AD) suggests that age-dependent factors are involved in the pathogenesis. Racemization of Ser and Asp in A beta is a typical age-dependent modification in AD. We have shown recently that A beta1-40 racemized at Ser(26) ([D-Ser(26)]A beta 1-40) is soluble and non-toxic to neuronal cells, but is easily converted by brain proteases to truncated toxic fragments, [D-Ser(26)]A beta 25-35/40. Furthermore, [D-Ser(26)]A beta1-40 in vivo, produced a drastic and synergistic neuronal loss by enhancing the excitotoxicity when co-injected into rat hippocampus with ibotenic acid, an excitatory amino acid, suggesting an in vivo conversion of non-toxic [D-Ser(26)]A beta1-40 to toxic fragments including [D-Ser(26)]A beta 25-35/40. In this study, we further investigated the mechanism behind the in vivo neuronal loss by [D-Ser(26)]A beta1-40 and ibotenic acid in rats, and also searched for the presence of [D-Ser(26)]A beta 25-35/40 antigens in AD brains. Quantitative analyses of the damaged area indicate clearly that non-toxic [D-Ser(26)]A beta 1-40 caused as much neurodegeneration as toxic [D-Ser(26)]A beta 25-35/40. MK-801, an NMDA receptor antagonist, completely inhibited the neurodegeneration. The immunohistochemical analyses using anti-[D-Ser(26)]A beta 25-35/40-specific antibodies demonstrated the presence of [D-Ser(26)]A beta 25-35/40 antigens in senile plaques and in degenerating hippocampal CA1 neurons in AD brains, but not in age-matched control brains. These results strengthen our hypothesis that soluble [D-Ser(26)]A beta1-40, possibly produced during aging, is released from plaques and converted by proteolysis to toxic [D-Ser(26)]A beta 25-35/40, which damage hippocampal CA1 neurons by enhancing excitotoxicity in AD. This may account for the lag between A beta deposition and neurodegeneration in AD.

The relationship between oral malodor, gingivitis, and periodontitis. A review.

Volatile sulfur compounds (VSC) are a family of gases which are primarily responsible for halitosis, a condition in which objectionable odors are present in mouth air. Although most patients perceive this condition as primarily a cosmetic problem, an increasing volume of evidence is demonstrating that extremely low concentrations of many of these compounds are highly toxic to tissues. VSC may, therefore, play a role in the pathogenesis of inflammatory conditions such as periodontitis. Since these compounds result from bacterial putrefaction of protein, investigations have been conducted to determine whether specific bacteria are associated with odor production. Two members of this family, hydrogen sulfide (H2S) and methyl mercaptan (CH3SH), are primarily responsible for mouth odor. Although many bacteria produce H2S, the production of CH3SH, especially at high levels, is primarily restricted to periodontal pathogens. Direct exposure to either of these metabolites adversely affects protein synthesis by human gingival fibroblasts in culture. However, methyl mercaptan has the greatest effect. Other in vitro experiments have demonstrated that cells exposed to methyl mercaptan synthesize less collagen, degrade more collagen, and accumulate collagen precursors which are poorly cross-linked and susceptible to proteolysis. CH3SH also increases permeability of intact mucosa and stimulates production of cytokines which have been associated with periodontal disease. VSC, and in particular methyl mercaptan, are therefore capable of inducing deleterious changes in both the extracellular matrix and the local immune response of periodontal tissues to plaque antigens. This article reviews these data and emphasizes the potential importance of VSC in the transition of periodontal tissues from clinical health to gingivitis and then to periodontitis.