Background
Patients with type 1 diabetes have shown an increase in circulating cytokines, altered lipoprotein metabolism and signs of vascular dysfunction in response to high‐fat meals. Intestinal ...alkaline phosphatase (IAP) regulates lipid transport and inflammatory responses in the gastrointestinal tract. We therefore hypothesized that changes in IAP activity could have profound effects on gut metabolic homeostasis in patients with type 1 diabetes.
Methods
Faecal samples of 41 nondiabetic controls and 46 patients with type 1 diabetes were analysed for IAP activity, calprotectin, immunoglobulins and short‐chain fatty acids (SCFAs). The impact of oral IAP supplementation on intestinal immunoglobulin levels was evaluated in C57BL/6 mice exposed to high‐fat diet for 11 weeks.
Results
Patients with type 1 diabetes exhibited signs of intestinal inflammation. Compared to controls, patients with diabetes had higher faecal calprotectin levels, lower faecal IAP activities accompanied by lower propionate and butyrate concentrations. Moreover, the amount of faecal IgA and the level of antibodies binding to oxidized LDL were decreased in patients with type 1 diabetes. In mice, oral IAP supplementation increased intestinal IgA levels markedly.
Conclusion
Deprivation of protective intestinal factors may increase the risk of inflammation in the gut – a phenomenon that seems to be present already in patients with uncomplicated type 1 diabetes. Low levels of intestinal IgA and antibodies to oxidized lipid epitopes may predispose such patients to inflammation‐driven complications such as cardiovascular disease and diabetic nephropathy. Importantly, oral IAP supplementation could have beneficial therapeutic effects on gut metabolic homeostasis, possibly through stimulation of intestinal IgA secretion.
:To assess antibodies to malondialdehyde-acetaldehyde-modified low-density lipoprotein (MAA-LDL) in patients with newly diagnosed inflammatory joint disease.
: Patients with rheumatoid arthritis ...(RA), spondyloarthritis (SpA), and undifferentiated arthritis (UA), participating in the Northern Savo 2010 Study, were evaluated for metabolic syndrome (MetS), metabolic and inflammatory markers, antibodies to MAA-LDL,
, and
.
: Among 135 newly diagnosed untreated patients, of whom 53 (39%) were diagnosed to have RA, 44 (33%) SpA, and 38 (28%) UA, 49%, 30%, and 47%, respectively, had MetS. After adjusting for age and gender, anti-MAA-LDL immunoglobulin (Ig)A (p = 0.009), IgG (p = 0.031), and IgM (p = 0.001) levels differed between the diagnostic categories, but not in patients with MetS present or absent. All antibody classes to MAA-LDL correlated with erythrocyte sedimentation rate (ESR), and IgA and IgG antibodies with high-sensitivity C-reactive protein (hs-CRP). IgA antibodies to MAA-LDL correlated with rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs), fasting plasma glucose, IgA antibodies to
, and in IgA and IgG antibodies to
: Among various arthritis groups, antibodies to MAA-LDL were most common in RA. Antibodies to modified lipoproteins were associated with inflammation measured by ESR and hs-CRP. IgA antibodies to MAA-LDL correlated with age, antibodies to periodontal bacteria, RF, ACPA, and fasting glucose. Associations between antibodies to MAA-LDL and antibodies to periodontal bacteria, RA-associated antibodies, inflammatory parameters, and plasma glucose already reflect cardiovascular burden in inflammatory joint diseases at diagnosis.
A large body of literature has established the link between periodontal disease and cardiovascular disease. Oxidized low-density lipoproteins (OxLDLs) have a crucial role in atherosclerosis ...progression through initiation of immunological response. Monoclonal IgM antibodies to malondialdehyde-modified low-density lipoprotein (MDA-LDL) and to malondialdehyde acetaldehyde–modified low-density lipoprotein (MAA-LDL) have been shown to cross-react with the key virulence factors of periodontal pathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. We have previously shown that salivary IgA antibodies to MAA-LDL cross-react with P. gingivalis in healthy humans. In this study, we aim to assess whether oral mucosal immune response represented by salivary IgA to MAA-LDL and oral pathogens is associated with coronary artery disease (CAD). Also, the molecular mimicry through antibody cross-reaction between salivary IgA to MAA-LDL and oral pathogens was evaluated. The study subjects consisted of 451 patients who underwent a coronary angiography with no CAD (n = 133), stable CAD (n = 169), and acute coronary syndrome (ACS, n = 149). Elevated salivary IgA antibody levels to MAA-LDL, Rgp44 (gingipain A hemagglutinin domain of P. gingivalis), and Aa-HSP60 (heat shock protein 60 of A. actinomycetemcomitans) were discovered in stable-CAD and ACS patients when compared to no-CAD patients. In a multinomial regression model adjusted for known cardiovascular risk factors, stable CAD and ACS were associated with IgA to MAA-LDL (P = 0.016, P = 0.043), Rgp44 (P = 0.012, P = 0.004), Aa-HSP60 (P = 0.032, P = 0.030), Tannerella forsythia (P = 0.002, P = 0.004), Porphyromonas endodontalis (P = 0.016, P = 0.020), Prevotella intermedia (P = 0.038, P = 0.005), and with total IgA antibody concentration (P = 0.002, P = 0.016). Salivary IgA to MAA-LDL showed cross-reactivity with the oral pathogens tested in the study patients. The study highlights an association between salivary IgA to MAA-LDL and atherosclerosis. However, whether salivary IgA to MAA-LDL and the related oral humoral responses play a causal role in the development in the CAD should be elucidated in the future.
: Oxidized LDL (OxLDL) competes with oxidatively damaged and apoptotic cells for binding to mouse peritoneal macrophages, implying the presence of one or more common domains. However, the nature of ...the ligands involved has not been determined. Studies in this laboratory over the last several years provide evidence that oxidized phospholipids, present in OxLDL and also in the membrane of apoptotic cells, represent one such ligand. These oxidized phospholipids, either in the lipid phase of OxLDL or becoming attached covalently to apoprotein B during LDL oxidation, have been shown to play a major role in the binding of OxLDL to CD36 and to SR‐B1 expressed in transfected cells. The lipid and protein moieties compete with each other to some extent, indicating that they are binding to at least one common site. A monoclonal antibody selected because of its reactivity with OxLDL proved to be an antibody against oxidized phospholipids (but not native phospholipids). This antibody (EO6) blocked the uptake of OxLDL by CD36 and by SR‐B1 in transfected cells by as much as 80%; it also inhibited macrophage phagocytosis of apoptotic cells by about 40%. Thus, the persistence of receptors for OxLDL during evolution is probably accounted for by their role in recognition of ligands on the surfaces of oxidatively damaged or apoptotic cells. This has important implications in biology generally and specifically in atherogenesis, because apoptosis is a prominent feature of late lesions.
.
Background. Ghrelin, a peptide hormone from stomach, stimulates food intake and decreases fat utilization. Ghrelin binds to growth hormone secretagogue receptor (GHSR). GHSR density has been shown ...to be upregulated in atherosclerotic lesions, but the relationship between ghrelin concentration and atherosclerosis has not yet been studied. We, therefore, characterized the association between ghrelin concentration and carotid artery intima‐media thickness (IMT) in a population‐based cohort of 1024 middle‐aged (40–60 years) men and women.
Methods. Intima‐media thickness and the number of atherosclerotic plaques were determined ultrasonographically. Fasting plasma ghrelin concentrations were analysed using RIA‐kit (PhoenixPeptide).
Results. There was a positive association between mean IMT and ghrelin concentration in the analysis of males before and after adjustments for the traditional risk factors of atherosclerosis age, systolic blood pressure, LDL cholesterol, body mass index (BMI), and smoking (ancova, P = 0.004 and P = 0.007, respectively). However, no such association was found in females (P = 0.985 and P = 0.915). There was no correlation between ghrelin and CRP concentrations or ghrelin and smoking.
Conclusion. Ghrelin concentrations and carotid artery atherosclerosis are positively associated in males even after adjustment for the commonly recognized risk factors of atherosclerosis. Experimental and prospective studies are warranted to elucidate the role of ghrelin in atherosclerosis.
Aim
To study the prevalence of carotid artery calcification (CAC) in relation to apical and marginal periodontitis, subgingival dysbiotic bacterial species and serum and saliva immune responses ...against them. In addition, the aim was to analyse the association of CAC with angiographically verified coronary artery disease (CAD) and mortality.
Methodology
In the present random Parogene cohort, the patients had an indication for coronary angiography. Apical and marginal periodontitis were diagnosed during clinical and radiographic oral examinations, and CAC on panoramic radiographs (n = 492). Presence and severity of CAD were registered from angiography. Subgingival dysbiotic bacterial species were quantitated using checkerboard DNA‐DNA‐hybridization, and serum and saliva antibody levels were determined by immunoassays. The cohort was followed‐up for 10 years or until death (median 9.9, range 0.21–10.4) via linkage to the national death register. The statistical models were adjusted for age, gender, smoking, hypertension, diabetes and dyslipidemia.
Results
A total of 102 (20.7%) patients had detectable CAC, which was moderate in 81 (16.4%) and severe in 21 (4.3%). CAC was associated (OR, 95% CI) with severe apical periodontitis (2.25, 1.15–4.41), root canal fillings (1.15, 1.04–1.26), alveolar bone loss (2.66, 1.21–5.84), severe periodontal inflammation (2.23, 1.11–4.47), high level of gram‐negative subgingival species (2.73, 1.34–5.50), saliva IgG against dysbiotic species (1.05, 1.01–1.10/unit) and severe (2.58, 1.36–4.90) and chronic (2.13, 1.15–3.93) CAD. A total of 105 (20.7%) patients died during the follow‐up and 53 (10.4%) deaths were because of cardiovascular diseases (CVD). Severe CAC predicted worse survival with HRs (95% CI) of 3.08 (1.58–6.06) for all‐cause and 3.43 (1.42–8.25) for CVD death.
Conclusions
CAC on panoramic tomography was associated with (i) apical and marginal periodontitis and dysbiotic bacterial species giving rise to an immunological response, and with (ii) severe, chronic CAD and increased mortality. The results further emphasize the role of oral infections in CAD and the importance of referring a patient with CAC for a cardiovascular evaluation.
Inorganic polyphosphates are evolutionarily conserved bioactive phosphate polymers found as various chain lengths in all living organisms. In mammals, polyphosphates play a vital role in the ...regulation of cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates are found along with endotoxins in pathogenic gram-negative bacteria and can participate in bacterial virulence. We aimed to investigate, whether exogenously administered polyphosphates modulate human leukocyte function in vitro by treating the cells with three different chain lengths of polyphosphates (P14, P100, and P700). The long-chain polyphosphates, P700, had a remarkable capacity to downregulate type I interferon signaling dose dependently in THP1-Dual cells while only a slight elevation could be observed in the NF-κB pathway with the highest dose of P700. P700 treatment decreased LPS-induced IFNβ transcription and secretion, STAT1 phosphorylation, and downregulated subsequent interferon stimulated gene expression in primary human peripheral blood mononuclear cells. P700 also augmented LPS-induced secretion of IL-1α, IL-1β, IL-4, IL-5, IL-10, and IFNγ. Furthermore, P700 has previously been reported to increase the phosphorylation of several intracellular signaling mediators, such as AKT, mTOR, ERK, p38, GSK3α/β, HSP27, and JNK pathway components, which was supported by our findings. Taken together, these observations demonstrate the extensive modulatory effects P700 has on cytokine signaling, and the inhibitory effects specifically targeted to type I interferon signaling in human leukocytes.
The immune response to oxidized LDL (OxLDL) may play an important role in atherogenesis. Working with apoE-deficient mice, we isolated a panel of OxLDL-specific B-cell lines that secrete IgM Abs that ...specifically bind to oxidized phospholipids such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC). These Abs block uptake of OxLDL by macrophages, recognize similar oxidation-specific epitopes on apoptotic cells, and are deposited in atherosclerotic lesions. The Abs were found to be structurally and functionally identical to classic "natural" T15 anti-PC Abs that are of B-1 cell origin and are reported to provide optimal protection from virulent pneumococcal infection. These findings suggest that there has been natural selection for B-1 cells secreting oxidation-specific/T15 antibodies, both for their role in natural immune defense and for housekeeping roles against oxidation-dependent neodeterminants in health and disease.
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