Associations of dietary patterns between age 9 and 24 months with risk of celiac disease autoimmunity and celiac disease among children at increased risk.

BACKGROUND: Higher gluten intake in childhood is associated with increased incidence of celiac disease autoimmunity (CDA) and celiac disease. It remains to be studied whether different dietary patterns independent of gluten intake contribute to the incidence. OBJECTIVES: This study aimed to explore associations of dietary patterns by age 2 y with risk of CDA and celiac disease in genetically susceptible children. METHODS: Data was used from 6726 participants at genetic risk of type 1 diabetes and celiac disease enrolled in the observational cohort, The Environmental Determinants of Diabetes in the Young (TEDDY) study. Children were annually screened for tissue transglutaminase autoantibodies (tTGAs) from age 2 y. Principal component analysis extracted dietary patterns, based on intake of 27 food groups assessed by 3-d food records at age 9 to 24 mo. The primary outcome was CDA (i.e., persistently tTGA-positive in at least 2 consecutive samples), and the secondary outcome was celiac disease. During follow-up to mean age 11.0 (standard deviation 3.6) y, 1296 (19.3%) children developed CDA, and 529 (7.9%) were diagnosed with celiac disease. Associations of adherence to dietary patterns (per 5-unit increase) with the study outcomes were estimated by Cox regression models adjusted for risk factors including gluten intake. RESULTS: At age 9 mo, a dietary pattern higher in the food groups vegetable fats and milk was associated with reduced risk of CDA (hazard ratio [HR]: 0.88; 95% confidence interval [CI]: 0.79, 0.98; P = 0.02). At 24 mo, a dietary pattern higher in the food groups wheat, vegetable fats, and juices, and lower in milk, meat, and oats at age 24 mo was associated with increased risk of CDA (HR: 1.18; 95% CI: 1.05, 1.33; P < 0.001) and celiac disease (HR: 1.24; 95% CI: 1.03, 1.50; P = 0.03). CONCLUSIONS: Dietary patterns in early childhood are associated with risk of CDA and celiac disease in genetically predisposed children, independent of gluten intake.

Cytotoxicity-Related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells That Mark Progression to Type 1 Diabetes.

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4+ T cells, in five genetically at risk children with islet autoantibodies who progressed to diabetes over a median of 3 years ("progressors") compared with five children matched for sex, age, and HLA-DR who had not progressed ("nonprogressors"). In progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 progressors and 11 nonprogressors. Flow cytometry confirmed that progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.

Children's erythrocyte fatty acids are associated with the risk of islet autoimmunity.

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in the Young Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case-control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n - 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n - 3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity.

Pharmacokinetics and antibody responses to the CD3 antibody otelixizumab used in the treatment of type 1 diabetes.

Otelixizumab is a chimeric CD3 antibody that has been genetically engineered to remove the glycosylation site in the Fc domain. This limits its ability to bind to complement or Fc receptors and reduces the risk of adverse clinical reactions due to cytokine release. In a trial for treatment of type 1 diabetes, a short treatment with otelixizumab resulted in a reduced requirement for insulin lasting at least 18 months. In the course of this trial, the blood concentrations of the antibody were measured by flow cytometry to determine its pharmacokinetic profile. Dose-dependent accumulation of otelixizumab was demonstrated and modeling of the data indicated that the terminal half-life was approximately 1.5 days. Antibody responses to otelixizumab were measured by 2 methods: a bridging enzyme-linked immunosorbent assay and surface plasmon resonance. The surface plasmon resonance method had a greater sensitivity and was able to detect responses in all patients, starting at 8 days after the commencement of therapy. Neutralizing antibodies were detected in a significant proportion of patients by days 22 to 29. Although no adverse clinical effects were associated with these antibody responses and they did not appear to affect the clearance of the drug, they might have important implications for possible retreatment of the patients.