Search

Bone formation is impaired in both type 1 diabetes and type 2 diabetes (T2D), whereas sclerostin, an antagonist of bone formation, is increased in T2D only. No data are available on latent autoimmune diabetes in adults (LADA), an autoimmune type of diabetes that may clinically resemble T2D at diagnosis. We evaluated serum sclerostin and bone turnover markers in LADA compared with those in T2D and whether metabolic syndrome (MetS) affects sclerostin in T2D or LADA.

There is increasing evidence that interindividual epigenetic variation is an etiological factor in common human diseases. Such epigenetic variation could be genetic or non-genetic in origin, and epigenome-wide association studies (EWASs) are underway for a wide variety of diseases/phenotypes. However, performing an EWAS is associated with a range of issues not typically encountered in genome-wide association studies (GWASs), such as the tissue to be analyzed. In many EWASs, it is not possible to analyze the target tissue in large numbers of live humans, and consequently surrogate tissues are employed, most commonly blood. But there is as yet no evidence demonstrating that blood is more informative than buccal cells, the other easily accessible tissue. To assess the potential of buccal cells for use in EWASs, we performed a comprehensive analysis of a buccal cell methylome using whole-genome bisulfite sequencing. Strikingly, a buccal vs. blood comparison reveals > 6X as many hypomethylated regions in buccal. These tissue-specific differentially methylated regions (tDMRs) are strongly enriched for DNaseI hotspots. Almost 75% of these tDMRs are not captured by commonly used DNA methylome profiling platforms such as Reduced Representational Bisulfite Sequencing and the Illumina Infinium HumanMethylation450 BeadChip, and they also display distinct genomic properties. Buccal hypo-tDMRs show a statistically significant enrichment near SNPs associated to disease identified through GWASs. Finally, we find that, compared with blood, buccal hypo-tDMRs show significantly greater overlap with hypomethylated regions in other tissues. We propose that for non-blood based diseases/phenotypes, buccal will be a more informative tissue for EWASs.

Autoimmune diseases affect 10% or more of the UK population. In organ-specific autoimmune diseases a particular tissue is targeted by the aggressive immune response. Type 1 diabetes is due to destruction of insulin-secreting islet cells. Both genetic and environmental factors cause type 1 diabetes and environmental events can operate very early, even in utero. The early induction of diabetes-associated autoantibodies and the long pre-diabetic period means that autoimmune diabetes in children can be predicted by detecting these autoantibodies. The purpose of prediction is prevention and initial studies suggest that it is possible to modify the disease process. However, the impact of such therapy on the disease is as yet extremely modest.

Stiff person syndrome (SPS) is a chronic autoimmune disease associated with humoral and cellular immune responses to glutamic acid decarboxylase (GAD) 65. Another chronic autoimmune disease, type 1 diabetes (T1D), is also associated with autoimmune responses to this antigen, but T1D patients develop SPS only extremely rarely and only a third of SPS patients develop T1D (mostly mild manifestations in adulthood). In a previous study, we described important differences between T1D and SPS in the autoimmune response to GAD 65: (1) T cells of SPS patients recognize epitopes in the middle of GAD 65 (amino residues 81-171 and 313-403), whereas patients with T1D preferentially recognize another middle (161-243) and a C-terminal region (473-555); and (2) GAD antibodies (Abs) were nearly exclusively of the Th1-associated IgG1 type in T1D, whereas SPS patients had both Th1- and Th2-associated IgG4 and IgE GAD Abs. These differences were not simply related to different HLA alleles. Fine epitope mapping revealed further distinct T cell epitopes in both diseases despite similar HLA background. Therefore, a single autoantigen can elicit different immune responses causing distinct chronic autoimmune diseases possibly related to a Th1 or Th2 bias of the disease.

Insulin-dependent diabetes (IDDM) is probably mediated by T lymphocytes recognizing critical β cell autoantigens. Glutamic acid decarboxylase (GAD) 65 is a major antigen in IDDM. T cells in both IDDM patients and controls respond to GAD 65 and certain epitopes of this molecule. To clarify the immune response to GAD 65 we established T cell clones specifically recognizing epitopes of GAD 65. We obtained T cell clones to GAD 65 peptides 161–175 (from a healthy individual), and 505–519 and 521–535 (from two IDDM patients). On extensive screening T cells responsive to peptide 161–175 were found only in controls, while T cells responsive to peptide 521–535 were found only in IDDM patients; T cells from both IDDM patients and controls responded to peptide 505–519. We could exclude simple genetic shaping of these T cell responses since the responses differed between genetically identical twins discordant for IDDM. Reactivity of T cell clones from the control to peptide 161–175 was restricted by HLA DR1 but promiscuous for HLA DR4 as DR4+ EBV transformed B cells and DR4+ mouse L-transfectants could present the peptide. As DR4+ antigen presenting cells of diabetics could present peptide 161–175 to some clones, the lack of response to this epitope in diabetic patients cannot be due to inadequate antigen presentation but is probably due to deletion of these cells either centrally or peripherally. Reactivity of clones to peptide 505–519 was either HLA DR1 or DQ1 restricted. In conclusion, T cell clones to specific epitopes of GAD 65 provide a model to clarify those differences in the immune response to this autoantigen between controls and IDDM patients.

Pancreatic islet cell autoantigens associated with insulin-dependent diabetes mellitus (IDDM) include a recently identified family of protein tyrosine phosphatase-like molecules, notably IA-2 and IA-2β. IA-2 is a 979 amino acid transmembrane protein located on human chromosome 2q35, whereas IA-2β is 986 amino acids long located on human chromosome 7q36. Comparison of human IA-2 and IA-2β showed 74% identity within the intercellular domains, but only 27% indentify within the extracellular domains. These IA-2 molecules are expressed predominantly in cells of neuroendocrine origin, particularly pancreatic islets and brain. Radioimmunoprecipitation with recombinant IA-2 and IA-2β has been used to measure autoantibodies to these molecules and their intracellular fragments. Autoantibodies to IA-2 are detected in the majority (60% to 80%) of newly diagnosed IDDM patients and in less than 2% of controls. The major antigenic determinants of both IA-2 and IA-2β reside within the C-terminus of their intracellular domains. In first-degree relatives of IDDM patients, the presence of autoantibodies to IA-2 is predictive of IDDM and in combination with autoantibodies to glutamic acid decarboxylase (GAD) the positive predictive value is in the 50% range. The role of IA-2 and IA-2β in the pathogenesis of IDDM is still unclear. Identification of these antigens has extended our ability to predict the disease and may be valuable in the search for antigen-specific therapies to prevent IDDM. © 1998 John Wiley & Sons, Ltd.