Characterization of H+,K+-ATPase T cell epitopes in human autoimmune gastritis.

Human autoimmune gastritis (AIG) is an organ-specific inflammatory disorder leading to gastric atrophy and pernicious anemia. Gastric H+,K(+)-ATPase was identified as the autoantigen in both human disease and experimental murine AIG (EAIG). Studies of EAIG significantly contributed to current knowledge of human AIG, but to what extent EAIG mimics AIG is still debated, and the autoantigenic epitopes in AIG are yet unknown.

Immunopotentiating heat shock proteins: negotiators between innate danger and control of autoimmunity.

Heat shock proteins (hsps) are known to be immunodominant antigens of bacteria. Hsps are evolutionarily strongly conserved proteins present in all eukaryotic and prokaryotic cellular organisms and upregulated by several forms of stress. Despite (the paradigm of) self-tolerance, hsp-epitopes homologous to endogenous host hsp sequences have been implicated as T cell epitopes to endow crossreactive, hsp-specific T cells with the capacity to regulate inflammation, such as in experimentally induced autoimmune diseases.

Different heat shock protein 60 species share pro-inflammatory activity but not binding sites on macrophages.

In a study of seven different hsp60 species, we found that all mammalian and microbial proteins shared the property of eliciting an inflammatory response in mouse macrophages. In all cases, TNFalpha production was induced by 0.1 microM concentrations of hsp60.

Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease.

Selective skewing of autoreactive interferon-gamma (IFN-gamma)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%.

Marked enhancement of the antigen-specific immune response by combining plasmid DNA-based immunization with a Schiff base-forming drug.

Although plasmid DNA (pDNA)-based immunization has proven efficacy, the level of immune responses that is achieved by this route of vaccination is often lower than that induced by traditional vaccines, especially for primates and humans. We report here a simple and potent method to enhance pDNA-based vaccination by using two different plasmids encoding viral or bacterial antigens. This method is based on coadministration of low concentrations of a recently described immunopotentiating, Schiff base-forming drug called tucaresol which has led to significant augmentation of antigen-specific humoral and cellular immune responses.

The beta 2-adrenergic agonist salbutamol potentiates oral induction of tolerance, suppressing adjuvant arthritis and antigen-specific immunity.

Therapeutic protocols for treating autoimmune diseases by feeding autoantigens during the disease process have not been very successful to date. In vitro it has been shown that beta-adrenergic agonists inhibit pro-inflammatory cytokine production and up-regulate anti-inflammatory cytokine production. We hypothesized that the protective effect of oral administration of Ag would be enhanced by oral coadministration of the beta(2)-adrenergic agonist salbutamol.

Dynamics of mycobacterial HSP65-induced T-cell cytokine expression during oral tolerance induction in adjuvant arthritis.

Objective: To investigate whether oral administration of mycobacterial heat-shock protein 65 (HSP65) during adjuvant arthritis (AA) induces regulatory cells and cytokines.

Methods: AA was induced in Lewis rats and from the time of disease onset HSP65 in the presence of soya bean trypsin inhibitor (STI) was administered orally every other day. The number of splenic CD4+CD25+ T cells and antigen-induced cytokine mRNA expression were determined.

Multi-locus interactions predict risk for post-PTCA restenosis: an approach to the genetic analysis of common complex disease.

The complexity of recognizing the potential contribution of a number of possible predictors of complex disorders is increasingly challenging with the application of large-scale single nucleotide polymorphism (SNP) typing. In the search for putative genetic factors predisposing to coronary artery restenosis following balloon angioplasty, we determined genotypes for 94 SNPs representing 62 candidate genes, in a prospectively assembled cohort of 342 cases and 437 controls. Using a customized coupled-logistic regression procedure accounting for both additive and interactive effects, we identified seven SNPs in seven genes that, together, showed a statistically significant association with restenosis incidence (P <0.

A prospective evaluation of the heat shock protein 70 gene polymorphisms and the risk of stroke.

Genetic polymorphisms of heat shock protein 70-kD (HSP70) gene family have recently been hypothesized to be risk factors for cerebral ischemia. However, no prospective epidemiological data evaluating this gene family are available. The present investigation was conducted to examine the possible associations between the HSP70-1 nucleotide 190.

Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis.

The 65 kD heat shock protein (HSP) has been implicated in the aetiology of recurrent aphthous stomatitis (RAS). We have previously demonstrated that peptide 91-105 derived from the sequence of mycobacterial 65 kD HSP stimulates specifically lymphocytes from patients with RAS. In this investigation, we show that both CD4+ and CD8+ T cells were significantly stimulated with mycobacterial peptide 91-105.

Non-random chromosomal distribution of SSLPs: systematic assessment using a novel genetic linkage map between two closely related rat strains.

Simple sequence length polymorphisms (SSLPs) are a widely used tool for genetic studies in humans and model animals. Experimental crosses among closely related strains that differ primarily in the trait that is to be mapped carry the advantage of avoiding co-segregation of potentially confounding traits. However, their realization is encumbered by the limited availability of newly arisen informative SSLPs among such strains.

Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis.

While increased concentrations of C-reactive protein (CRP) are associated with increased vascular risk, little information is available describing genetic determinants of this effect. In a large prospective cohort of apparently healthy men, we found plasma CRP concentrations to be significantly reduced among carriers of a 1059G/C polymorphism in the human CRP gene (GC or CC) as compared with non-carriers (GG). However, the polymorphism examined was not significantly associated with risk of arterial thrombosis despite the fact that CRP concentrations are a potent independent predictor of future vascular events in this cohort.

A prospective evaluation of the CD14 and CD18 gene polymorphisms and risk of stroke.

Background And Purpose: Genetic polymorphisms of the CD14 lipopolysaccharide receptor gene (CD14) and the CD18 leukocyte adhesion molecule gene (CD18) have recently been hypothesized to be risk factors for atherothrombosis. However, no prospective data on subsequent risk of stroke are available. The present investigation was conducted to examine the possible association between the CD14 C(-260)T and CD18 codon 441 gene polymorphisms and the incidence of stroke in a large, prospective, matched case-control sample from the Physicians' Health Study.

A prospective evaluation of the angiotensin-converting enzyme D/I polymorphism and left ventricular remodeling in the 'Healing and Early Afterload Reducing Therapy' study.

The D/I (deletion, D, insertion, I) polymorphism of the angiotensin-converting enzyme (ACE) gene has been extensively studied for its association with a number of cardiovascular and other disease states. However, its potential association with differential clinical efficacy of ACE inhibitors (ACE-I) administered to patients who had suffered a myocardial infarction (MI), i.e.

Wnt signaling controls the phosphorylation status of beta-catenin.

At the heart of the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. In cells that do not receive Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate beta-catenin, thus marking the latter for proteasomal degradation.

A prospective evaluation of the interleukin-1 receptor antagonist intron 2 gene polymorphism and the risk of myocardial infarction.

While an interleukin-1 receptor antagonist gene polymorphism (IL1RN-VNTR) has recently been hypothesized to be a risk factor for coronary artery disease, no prospective data relating this polymorphism to subsequent risk of coronary events are available. We therefore investigated the association between IL1RN-VNTR genotype and the incidence of myocardial infarction (MI) in a large, prospective cohort of initially healthy men. The IL1RN-VNTR was evaluated among 385 MI case subjects and an equal number of age- and smoking-matched control subjects during a 12-year follow-up.

Induction of IL-10 and inhibition of experimental arthritis are specific features of microbial heat shock proteins that are absent for other evolutionarily conserved immunodominant proteins.

Bacterial heat shock proteins (hsp) are evolutionary conserved immunodominant proteins that manifest amino acid homologies with hsp present in mammalian cells. Preimmunization with mycobacterial hsp65 has been found to protect against various forms of experimental arthritis. As these protective effects have previously been attributed to induction of self homologue cross-reactive T cell responses, the question was raised as to whether this protective effect could be extended to other highly conserved and immunodominant microbial Ags with mammalian homologues.

Angiotensin gene polymorphism as a determinant of posttransplantation renal dysfunction and hypertension.

Background: Polymorphism of the genes associated with angiotensin, including angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and the type 1 (AT1) and type 2 (AT2) angiotensin II receptors, has been implicated in the pathophysiology of hypertension, ischemic heart disease, and progression of chronic renal disease.

Methods: We investigated the impact of the ACE, AGT, AT1, and AT2 genotypes on renal allograft function in 148 patients (77 men, 71 women) who underwent transplantation over a 5-year period. Patients were genotyped using polymerase chain reaction sequence-specific primers and polymerase chain reaction followed by restriction fragment length polymorphism analysis.

The human internal thoracic artery releases more nitric oxide in response to vascular endothelial growth factor than the human saphenous vein.

Objective: Endothelial nitric oxide inhibits smooth muscle cell proliferation, reducing the chance of vascular intimal thickening. In this study we investigated whether the superior long-term patency of the internal thoracic artery in human coronary bypass grafting compared with that of the saphenous vein could be explained by different levels of nitric oxide production.

Methods: The baseline endogenous nitric oxide production appeared to be 50% higher in the internal thoracic artery than in the saphenous vein.

Cardiac remodeling after myocardial infarction is impaired in IGF-1 deficient mice.

Objective: To obtain more insight in the role of IGF-1 in cardiac remodeling and function after experimental myocardial infarction. We hypothesized that cardiac remodeling is altered in IGF-1 deficient mice, which may affect cardiac function.

Methods: A myocardial infarction was induced by surgical coronary artery ligation in heterozygous IGF-1 deficient mice.

Absence of linkage for bone mineral density to chromosome 12q12-14 in the region of the vitamin D receptor gene.

Polymorphisms in the region of the gene for the vitamin D receptor (VDR) (chromosome 12q12-14) have been associated with differences in bone mineral density (BMD) in some studies but not in others. Because linkage analysis assesses allele sharing identical-by-descent among relatives instead of the association of a particular allele of an anonymous marker, we have performed a linkage study for bone BMD using microsatellite markers flanking the VDR locus. The present study explores whether or not relatives who share the chromosomal region containing the VDR gene have more similar bone density.

Selecting SNPs in two-stage analysis of disease association data: a model-free approach.

For large numbers of marker loci in a genomic scan for disease loci, we propose a novel 2-stage approach for linkage or association analysis. The two stages are (1) selection of a subset of markers that are 'important' for the trait studied, and (2) modelling interactions among markers and between markers and trait. Here we focus on stage 1 and develop a selection method based on a 2-level nested bootstrap procedure.

A prospective evaluation of the CD14 C(-260)T gene polymorphism and the risk of myocardial infarction.

The T allele at position -260 of the CD14 lipopolysaccharide receptor gene (CD14) has recently been hypothesized to be a risk factor for myocardial infarction (MI). However, no prospective data relating this polymorphism to risk of future MI are available. In the physicians' health study (PHS), 14916 apparently healthy men were followed over a 12-year period for incident MI.

Ace D/I polymorphism and incidence of post-PTCA restenosis: a prospective, angiography-based evaluation.

Early restenosis is the major complication of percutaneous transluminal coronary angioplasty (PTCA), occurring in approximately 30% of all initially successful procedures. The D/I polymorphism of the ACE gene, which has variably been reported to represent a risk factor for manifestations of ischemic heart disease, has recently been implicated in the pathophysiology of restenosis after PTCA by some investigators but not by others. All studies conducted thus far involved relatively small sample sizes.