Search

Summary: Children diagnosed with a combination of type 1 diabetes (T1D) and celiac disease (CD) show a dysregulated T helper type 1 (Th1)/Th17 response. Besides the cellular involvement, several soluble immune markers are involved in the autoimmune process of both T1D and CD. Only few studies have examined the peripheral pattern of different cytokines, chemokines and acute‐phase proteins (APP) in children with combined T1D and CD. To our knowledge, no studies have evaluated the serum levels of adipocytokines and matrix metalloproteinases (MMPs) in this context. The purpose of the present study was to acquire more knowledge and to gain deeper understanding regarding the peripheral immunoregulatory milieu in children with both T1D and CD. The study included children diagnosed with both T1D and CD (n = 18), children with T1D (n = 27) or CD (n = 16) and reference children (n = 42). Sera were collected and analysis of 28 immune markers (cytokines, chemokines, APPs, adipocytokines and MMPs) was performed using the Luminex technique. The major findings showed that children with a double diagnosis had lower serum levels of interleukin (IL)‐22, monocyte chemoattractant protein (MIP)‐1α, monocyte chemoattractant protein (MCP)‐1, procalcitonin, fibrinogen, visfatin and matrix metalloproteinase (MMP)‐2. These results indicate a suppressed immune profile in children with combined T1D and CD, including Th17 cytokines, chemokines, APPs, adipocytokines and MMPs. We conclude that, besides cytokines and chemokines, other immune markers, e.g. APPs, adipocytokines and MMPs, are of importance for further investigations to elucidate the heterogeneous immune processes present in patients diagnosed with T1D in combination with CD. [ABSTRACT FROM AUTHOR]

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression when bound to specific DNA sequences. Crosstalk between steroid NR systems has been studied for understanding the development of hormone-driven cancers but not to an extent at a genetic level. This study aimed to investigate crosstalk between steroid NRs in conserved intron and exon sequences, with a focus on steroid NRs involved in prostate cancer etiology. For this purpose, we evaluated conserved intron and exon sequences among all 49 members of the NR Superfamily (NRS) and their relevance as regulatory sequences and NR-binding sequences. Sequence conservation was found to be higher in the first intron (35%), when compared with downstream introns. Seventy-nine percent of the conserved regions in the NRS contained putative transcription factor binding sites (TFBS) and a large fraction of these sequences contained splicing sites (SS). Analysis of transcription factors binding to putative intronic and exonic TFBS revealed that 5 and 16%, respectively, were NRs. The present study suggests crosstalk between steroid NRs, e.g., vitamin D, estrogen, progesterone, and retinoic acid endocrine systems, through cis-regulatory elements in conserved sequences of introns and exons. This investigation gives evidence for crosstalk between steroid hormones and contributes to novel targets for steroid NR regulation.

Type 1 diabetes ( T1D) and coeliac disease are both characterized by an autoimmune feature. As T1D and coeliac disease share the same risk genes, patients risk subsequently developing the other disease. This study aimed to investigate the expression of T helper ( Th), T cytotoxic ( Tc) and regulatory T cells ( Treg) in T1D and/or coeliac disease children in comparison to healthy children. Subgroups of T cells ( Th : CD4+ or Tc : CD8+); naive ( CD27+CD28+CD45RA+CCR7+), central memory ( CD27+CD28+CD45RA− CCR7+), effector memory (early differentiated; CD27+CD28+CD45RA− CCR7− and late differentiated; CD27− CD28− CD45RA− CCR7−), terminally differentiated effector cells ( TEMRA; CD27− CD28− CD45RA+CCR7−) and Treg ( CD4+CD25+FOXP3+CD127−) cells, and their expression of CD39, CD45RA, CD101 and CD129, were studied by flow cytometry in T1D and/or coeliac disease children or without any of these diseases (reference group). Children diagnosed with both T1D and coeliac disease showed a higher percentage of TEMRA CD4+ cells ( P < 0·05), but lower percentages of both early and late effector memory CD8+ cells ( P < 0·05) compared to references. Children with exclusively T1D had lower median fluorescence intensity ( MFI) of forkhead box protein 3 ( FoxP3) ( P < 0·05) and also a lower percentage of CD39+ and CD45RA+ within the Treg population ( CD4+CD25+FOXP3+CD127−) ( P < 0·05). Children with exclusively coeliac disease had a higher MFI of CD101 ( P < 0·01), as well as a higher percentage of CD129+ ( P < 0·05), in the CD4+CD25hi lymphocyte population, compared to references. In conclusion, children with combined T1D and coeliac disease have a higher percentage of differentiated CD4+ cells compared to CD8+ cells. T1D children show signs of low CD39+/CD45RA+ Treg cells that may indicate loss of suppressive function. Conversely, children with coeliac disease show signs of CD101+/CD129+ Treg cells that may indicate suppressor activity. [ABSTRACT FROM AUTHOR]

Although the role of the T cell-mediated autoimmune reaction in type 1 diabetes (T1D) is conclusive, studies including data from human circulating CD4+ and CD8+ lymphocytes subsets during the disease onset and posterior development are scarce. Further, chemokines and chemokine receptors are key players in the migration of pathogenic T cells into the islets of non-obese diabetic mice developing T1D, but few studies have investigated these markers in human T1D patients. We studied the expression of T helper 1 (Th1)- and Th2-associated chemokine receptors, and the two isoforms of CD45 leucocyte antigen on CD4+ and CD8+ lymphocytes from T1D and healthy children, as well as the secretion of chemokines in cell supernatants in peripheral blood mononuclear cells. Our results showed increased expression of CCR7 and CD45RA and reduced CD45RO on CD8+ cells among recent-onset T1D patients. The percentages of CD4+ cells expressing CXC chemokine receptor 3 (CXCR3), CXCR6 and CCR5, and the secretion of interferon-γ-induced protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α and MIP-1β was lower among diabetics. Low expression of Th1-associated receptors and secretion of chemokines, together with an increased amount of CD8+ cells expressing CD45RA and CCR7 in T1D patients therefore might represent suboptimal Th function in T1D, leading to impaired T cytotoxic responses or alternatively reflect a selective recruitment of Th1 cells into the pancreas. [ABSTRACT FROM AUTHOR]

BACKGROUND: Imbalance of T-helper (Th)1- and Th2-like cytokines has been associated with type 1 diabetes. We therefore studied the immune deviation in antigen-specific T cells from diagnosis onwards in type 1 diabetic children. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 15 children after 4 days, 3 months and 18 months of being diagnosed with type 1 diabetes, from 15 healthy children matched by age and gender to the type 1 diabetic children and from 14 children with and 35 children without HLA-risk genes. Secretion of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) was detected by ELISPOT after stimulation with glutamic acid decarboxylase (GAD(65), protein and aa 247-279), recombinant tyrosinphosphatase (IA-2), insulin, ovalbumin and phytohaemagglutinin (PHA). RESULTS: Secretion of IFN-gamma in PBMC stimulated with GAD(65) (p < 0.05), the GAD(65)-peptide (p < 0.01), IA-2 (p < 0.01), and insulin (p < 0.01) was lower in diabetic children at diagnosis than in healthy children. Stimulation of PBMC with GAD(65) and IA-2 decreased the secretion of IFN-gamma in children with HLA-risk genotype. Spontaneous and antigen-induced IFN-gamma secretion increased significantly after diagnosis of the disease, but did not exceed the levels observed in healthy children. Fasting C-peptide levels at diagnosis correlated with insulin-induced IFN-gamma (R = 0.52; p = 0.05) and negatively with spontaneous IL-4 secretion (R = -0.62; p < 0.05). CONCLUSION: A diminished IFN-gamma secretion and the association of fasting C-peptide levels with cytokine response in children with type 1 diabetes suggest that factors related to beta-cell function in type 1 diabetes may modify T-cell function. Thus, the T-cell responses detected at or after diagnosis may not reflect the pathogenic process leading to type 1 diabetes. Copyright (c) 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]