Polymorphisms in the Innate Immune IFIH1 Gene, Frequency of Enterovirus in Monthly Fecal Samples during Infancy, and Islet Autoimmunity

Interferon induced with helicase C domain 1 (IFIH1) senses and initiates antiviral activity against enteroviruses. Genetic variants of IFIH1, one common and four rare SNPs have been associated with lower risk for type 1 diabetes. Our aim was to test whether these type 1 diabetes-associated IFIH1 polymorphisms are associated with the occurrence of enterovirus infection in the gut of healthy children, or influence the lack of association between gut enterovirus infection and islet autoimmunity

High levels of immunoglobulin E and a continuous increase in immunoglobulin G and immunoglobulin M by age in children with newly diagnosed type 1 diabetes

The incidence of type 1 diabetes (T1D) is increasing, either because of environmental factors accelerating onset of the disease or because of inducement of autoimmune diabetes in children who previously were at lower risk. High levels of immunoglobulin (Ig), specifically, IgM and IgA, and a low level of IgG were reported in adult patients; however no studies have analyzed the increasing incidence in relation to Ig levels. Our aim was to describe Ig in children newly diagnosed with diabetes and in their healthy siblings. Children with T1D expressed significantly lower IgG (p 0.5) levels were found. Age-specific levels were unchanged over a 9-year period. In patients and siblings IgG. IgA and IgE increased by age (p 0.05). The continued increase in IgG levels by age indicates that adult levels are reached later than in previously studied cohorts, thereby indicating a slower maturation of the immune system. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved

Skap2, a candidate gene for type 1 diabetes, regulates b-cell apoptosis and glycemic control in newly diagnosed patients

The single nucleotide polymorphism rs7804356 located in the Src kinase-associated phosphoprotein 2 (SKAP2) gene is associated with type 1 diabetes (T1D), suggesting SKAP2 as a causal candidate gene. The objective of the study was to investigate if SKAP2 has a functional role in the b-cells in relation to T1D. In a cohort of children with newly diagnosed T1D, rs7804356 predicted glycemic control and residual b-cell function during the 1st year after diagnosis. In INS-1E cells and rat and human islets, proinflammatory cytokines reduced the content of SKAP2. Functional studies revealed that knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat b-cells, suggesting an antiapoptotic function of SKAP2. In support of this, overexpression of SKAP2 afforded protection against cytokine-induced ap-optosis, which correlated with reduced nuclear content of S536-phosphorylated nuclear factor-kB (NF-kB) subunit p65, lower nitric oxide production, and diminished CHOP expression indicative of decreased endoplasmic reticu-lum stress. Knockdown of CHOP partially counteracted the increase in cytokine-induced apoptosis caused by SKAP2 knockdown. In conclusion, our results suggest that SKAP2 controls b-cell sensitivity to cytokines possibly by affecting the NF-kB–inducible nitric oxide synthase– endoplasmic reticulum stress pathway.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Few differences in cytokines between patients newly diagnosed with type 1 diabetes and their healthy siblings

The cause of the worldwide increase in type 1 diabetes (T1D) is largely unknown. T cells are thought to play a role in disease progression. In contemporary research over the last decade, age- and gender-specific serum levels as well as changes of Th1 and Th2-related cytokines are not well described. From a population-based register of children diagnosed from 1997 to 2005 this study explores eight different cytokines at time of diagnosis. Only TGF-beta and IL-18 showed higher levels in patients compared to siblings in an adjusted model (p < 0.01): whereas the other seven cytokines were not significantly different. IL-1 beta, IL-18, IL-12, IL-10 and IL-4 were significantly higher among the youngest children and males had significantly lower levels of IL-10 and IL-12 but higher levels of TNF-alpha. During the nine-year study all of the cytokines increased except TGF-beta, which showed a slight decrease over time. The cytokine levels tended to be highest during summer and were most pronounced for IL-1 beta and TNF-alpha. In conclusion, serum levels of known beta-cell cytotoxic cytokines were indifferent in patients and siblings, while gender, age and season appear to exert some influence on the serum level and need to be explored further. The influence of time on systemic levels cannot be ignored and may reflect decay or environmental impact on the immune system. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved

A possible association between a dysfunctional skin barrier (filaggrin null-mutation status) and diabetes: a cross-sectional study

BACKGROUND: Filaggrin proteins are located in the skin and prevent epidermal water loss and impede the entry of micro-organisms, allergens and chemicals. Filaggrin null mutations are strongly associated with ichthyosis vulgaris and atopic dermatitis. OBJECTIVE: The authors aimed to investigate the association between filaggrin null mutations, atopic dermatitis and diabetes. DESIGN: A random sample of 3335 adults from the general population in Denmark was filaggrin-genotyped for R501X and 2282del4 null-mutations and questioned about atopic dermatitis and diabetes. Furthermore, two independent study populations of patients with type 1 (n=104) or 2 (n=774) diabetes were genotyped. RESULTS: In a crude data analysis, a positive association was detected between the filaggrin null genotype and, respectively, subjects from the general population who reported diabetes (p=0.04) and patients with established type 2 diabetes (p=0.073). Adjustment for age and gender resulted in significant associations for patients with type 2 diabetes (p=0.048) and subjects with self-reported diabetes (p=0.032). CONCLUSIONS: Adult Danes with a filaggrin null genotype had a significantly increased prevalence of self-reported diabetes. This finding was replicated when an independent sample of Danish patients with established type 2 diabetes was compared with control subjects from the general population