Diabetes-specific HLA-DR-restricted proinflammatory T-cell response to wheat polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes.
Diabetes. 2009 Aug;58(8):1789-96. Epub 2009 Apr 28. PMID: 19401421
Majid Mojibian, Habiba Chakir, David E Lefebvre, Jennifer A Crookshank, Brigitte Sonier, Erin Keely, Fraser W Scott
OBJECTIVE: There is evidence of gut barrier and immune system dysfunction in some patients with type 1 diabetes, possibly linked with exposure to dietary wheat polypeptides (WP). However, questions arise regarding the frequency of abnormal immune responses to wheat and their nature, and it remains unclear whether such responses are diabetes specific. RESEARCH DESIGN AND METHODS: In type 1 diabetic patients and healthy control subjects, the immune response of peripheral CD3(+) T-cells to WPs, ovalbumin, gliadin, alpha-gliadin 33-mer peptide, tetanus toxoid, and phytohemagglutinin was measured using a carboxyfluorescein diacetate succinimidyl ester (CFSE) proliferation assay. T-helper cell type 1 (Th1), Th2, and Th17 cytokines were analyzed in WP-stimulated peripheral blood mononuclear cell (PBMNC) supernatants, and HLA was analyzed by PCR. RESULTS: Of 42 patients, 20 displayed increased CD3(+) T-cell proliferation to WPs and were classified as responders; proliferative responses to other dietary antigens were less pronounced. WP-stimulated PBMNCs from patients showed a mixed proinflammatory cytokine response with large amounts of IFN-gamma, IL-17A, and increased TNF. HLA-DQ2, the major celiac disease risk gene, was not significantly different. Nearly all responders carried the diabetes risk gene HLA-DR4. Anti-DR antibodies blocked the WP response and inhibited secretion of Th1 and Th17 cytokines. High amounts of WP-stimulated IL-6 were not blocked. CONCLUSIONS: T-cell reactivity to WPs was frequently present in type 1 diabetic patients and associated with HLA-DR4 but not HLA-DQ2. The presence of an HLA-DR-restricted Th1 and Th17 response to WPs in a subset of patients indicates a diabetes-related inflammatory state in the gut immune tissues associated with defective oral tolerance and possibly gut barrier dysfunction.
Article Published Date : Aug 01, 2009
The influence of gluten: weaning recommendations for healthy children and children at risk for celiac disease.
Nestle Nutr Workshop Ser Pediatr Program. 2007;60:139-51; discussion 151-5. PMID: 17664902
In most developed countries, gluten is currently most commonly introduced between 4 and 6 months of age, in spite of little evidence to support this practice. As for infants at risk of developing food allergies, there is clear evidence that introducing solid foods before the end of the 3rd month is detrimental and should be avoided. A recent growing body of evidence however challenges the notion that solids (and among them, gluten-containing foods) should be introduced beyond the 6th month of life. Another important aspect of gluten introduction into the diet has to do with its possible role in causing type-1 diabetes (IDDM). Recently, a large epidemiological investigation in a cohort of children at risk for IDDM found that exposure to cereals (rice, wheat, oats, barley, rye) that occurred early (< or = 3 months) as well as late (> or = 7 months) resulted in a significantly higher risk of the appearance of islet cell autoimmunity compared to the introduction between 4 and 6 months. As for celiac disease, the protective role of breastfeeding can be considered ascertained, especially the protection offered by having gluten introduced while breastfeeding is continued. Evidence is emerging that early (< or = 3 months) and perhaps even late (7 months or after) first exposure to gluten may favor the onset of celiac disease in predisposed individuals. Additionally, large amounts of gluten at weaning are associated with an increased risk of developing celiac disease, as documented in studies from Scandinavian countries. In celiac children observed in our center, we could show that breastfeeding at the time of gluten introduction delays the appearance of celiac disease and makes it less likely that its presentation is predominantly gastrointestinal. Based on current evidence, it appears reasonable to recommend that gluten be introduced in small amounts in the diet between 4 and 6 months, while the infant is breastfed, and that breastfeeding is continued for at least a further 2-3 months.
Article Published Date : Jan 01, 2007
Prophylactic nutritional modification of the incidence of diabetes in autoimmune non-obese diabetic (NOD) mice.
Br J Nutr. 1993 Mar;69(2):597-607. PMID: 8490012
J Hoorfar, K Buschard, F Dagnaes-Hansen
Experiments in rodent models of insulin-dependent diabetes mellitus (IDDM) suggest that destruction of pancreatic beta cells can be both initiated and inhibited by certain environmental factors such as dietary constituents. We studied nutritional impact of certain protein sources of natural-ingredient, non-purified (NP) rodent diet on diabetes incidence and insulitis severity in the spontaneous diabetic, non-obese diabetic (NOD) mouse. Long-term ad lib. feeding of diets containing wheat flour (800 g/kg), and to a lesser extent soya-bean meal (400 g/kg), were associated with relatively high diabetes incidence (65 and 45% respectively), whereas a diet based on hydrolysed casein (HC; 200 g/kg) as the only source of protein significantly (compared with the wheat-flour diet) inhibited expression of diabetes (22%). Feeding a hypo-allergenic soya-bean-protein hydrolysate resulted in diabetes incidence and insulitis severity similar to that of the soya-bean-meal-fed group. This may indicate that protein hydrolysis per se may not be necessary for dietary modification of diabetes in the NOD mouse. The window of vulnerability to diabetogenic diets was found to be between weaning and about 70 d of age. In the diabetic mice insulitis was less frequent in the HC-fed group when compared with those fed NP (P = 0.04), soybean meal (P = 0.03), soya-bean-protein hydrolysate (P = 0.012) or wheat flour (P = 0.0002). In the non-diabetic mice the wheat-flour diet was associated with a high insulitis severity in comparison with the HC group (P = 0.004). Early avoidance of NP diet was associated with lower degree of insulitis in both diabetic (P = 0.00003) and non-diabetic mice (P = 0.001) when compared with the mice fed on the HC diet later in life. These findings are contributing to further clarification of diabetes-promoting dietary constituents, which may have some nutritional implications for IDDM-susceptible children.
Article Published Date : Mar 01, 1993
A Summary of the Biological Processes, Disease-Associated Changes, and Clinical Applications of DNA Methylation.
Methods Mol Biol. 2018;1708:3-30
Authors: Andersen GB, Tost J
DNA methylation at cytosines followed by guanines, CpGs, forms one of the multiple layers of epigenetic mechanisms controlling and modulating gene expression through chromatin structure. It closely interacts with histone modifications and chromatin remodeling complexes to form the local genomic and higher-order chromatin landscape. DNA methylation is essential for proper mammalian development, crucial for imprinting and plays a role in maintaining genomic stability. DNA methylation patterns are susceptible to change in response to environmental stimuli such as diet or toxins, whereby the epigenome seems to be most vulnerable during early life. Changes of DNA methylation levels and patterns have been widely studied in several diseases, especially cancer, where interest has focused on biomarkers for early detection of cancer development, accurate diagnosis, and response to treatment, but have also been shown to occur in many other complex diseases. Recent advances in epigenome engineering technologies allow now for the large-scale assessment of the functional relevance of DNA methylation. As a stable nucleic acid-based modification that is technically easy to handle and which can be analyzed with great reproducibility and accuracy by different laboratories, DNA methylation is a promising biomarker for many applications.
PMID: 29224136 [PubMed - in process]
Renal Resistive Index as a Novel Indicator for Renal Complications in High-Fat Diet-Fed Mice.
Kidney Blood Press Res. 2017 Dec 07;42(6):1128-1140
Authors: Xu H, Ma Z, Lu S, Li R, Lyu L, Ding L, Lu Q
BACKGROUND/AIMS: The renal resistive index (RI) is a novel candidate as a renal injury prognostic indicator, but it remains unclear how renal RI levels correspond to renal injury in diabetic nephropathy.
METHODS: To examine this issue, we compared 8-week-old male C57BL/6 mice fed with high-fat diet (HFD) versus chow diet (CHD) for 16 weeks. At 8 and 12 weeks, the glomerular filtration rate (GFR), urinary albumin-to-creatinine ratio (UACR), and inflammatory factors (IL-1β, IL-6, TNFα, and MCP-1) were measured, along with the increase in renal RI.
RESULTS: Our study suggests RI values positively correlate with GFR for the first 12 weeks of HFD feeding. In contrast, the GFR of 16-week HFD feeding is lower than that of 12-week HFD feeding, whereas RI levels are significantly increased. Additionally, our study suggests RI values accurately indicate the renal fibrosis and renal injury in HFD-fed mice treated with lovastatin.
CONCLUSION: This study seems to confirm the utility of a noninvasive and repeatable ultrasound parameter to rapidly evaluate renal fibrosis in a HFD-induced type 2 diabetic mouse model in vivo. This highly sensitive and comparable renal RI measurement could monitor the whole procedure of disease development in real-time. RI measurement of the renal artery is capable of differentiating responses to standard therapy with lovastatin in HFD-fed mice from the CHD group.
PMID: 29224015 [PubMed - as supplied by publisher]