The Influence of Type 2 Diabetes-Associated Factors on Type 1 Diabetes.

Current efforts to prevent progression from islet autoimmunity to type 1 diabetes largely focus on immunomodulatory approaches. However, emerging data suggest that the development of diabetes in islet autoantibody-positive individuals may also involve factors such as obesity and genetic variants associated with type 2 diabetes, and the influence of these factors increases with age at diagnosis. Although these factors have been linked with metabolic outcomes, particularly through their impact on ß-cell function and insulin sensitivity, growing evidence suggests that they might also interact with the immune system to amplify the autoimmune response. The presence of factors shared by both forms of diabetes contributes to disease heterogeneity and thus has important implications. Characteristics that are typically considered to be nonimmune should be incorporated into predictive algorithms that seek to identify at-risk individuals and into the designs of trials for disease prevention. The heterogeneity of diabetes also poses a challenge in diagnostic classification. Finally, after clinically diagnosing type 1 diabetes, addressing nonimmune elements may help to prevent further deterioration of ß-cell function and thus improve clinical outcomes. This Perspectives in Care article highlights the role of type 2 diabetes-associated genetic factors (e.g., gene variants at transcription factor 7-like 2 [TCF7L2]) and obesity (via insulin resistance, inflammation, ß-cell stress, or all three) in the pathogenesis of type 1 diabetes and their impacts on age at diagnosis. Recognizing that type 1 diabetes might result from the sum of effects from islet autoimmunity and type 2 diabetes-associated factors, their interactions, or both affects disease prediction, prevention, diagnosis, and treatment.

T-cell factor-4 and MHC upregulation in pigs receiving a live attenuated classical swine fever virus (CSFV) vaccine strain with interferon-gamma adjuvant.

The effect of co-administration of interferon (IFN)-γ in pigs undergoing vaccination with an attenuated strain (LPC) of classical swine fever virus (CSFV) was investigated. Unvaccinated pigs demonstrated pyrexia and died 7-9 days after challenge with virulent CSFV. Pigs receiving the attenuated vaccine remained healthy after virus challenge, except for mild, transient pyrexia, whereas pigs receiving IFN-γ simultaneously with the vaccine demonstrated normal body temperatures after virus challenge. Examination by nested RT-PCR revealed greater viral load in the spleens of the pigs vaccinated with the attenuated CSFV, compared with those that had additionally received IFN-γ. Expression of major histocompatibility complex (MHC) class I and MHC class II molecules was upregulated in the spleens of the IFN-γ treated vaccinated pigs, demonstrated by immunohistochemistry. Based on Western blot analysis, anti-CSFV IgG2 antibodies were elevated in vaccinated pigs by co-administration of IFN-γ (IFN-γ(Hi): P < 0.01; IFN-γ(Lo): P <0.05). By employing the suppression subtractive hybridization technique, RT-PCR, in situ hybridization, and immunohistochemistry, T-cell factor-4 (Tcf-4) mRNA and protein expression were found to be upregulated in the spleens of vaccinated pigs that had received IFN-γ. This study suggests involvement of Tcf-4 in IFN-γ-mediated immune regulation following CSFV vaccination.

Hedgehog inhibits ß-catenin activity in synovial joint development and osteoarthritis.

Both the WNT/ß-catenin and hedgehog signaling pathways are important in the regulation of limb development, chondrocyte differentiation, and degeneration of articular cartilage in osteoarthritis (OA). It is not clear how these signaling pathways interact in interzone cell differentiation and synovial joint morphogenesis. Here, we determined that constitutive activation of hedgehog signaling specifically within interzone cells induces joint morphological changes by selectively inhibiting ß-catenin-induced Fgf18 expression. Stabilization of ß-catenin or treatment with FGF18 rescued hedgehog-induced phenotypes. Hedgehog signaling induced expression of a dominant negative isoform of TCF7L2 (dnTCF7L2) in interzone progeny, which may account for the selective regulation of ß-catenin target genes observed. Knockdown of TCF7L2 isoforms in mouse chondrocytes rescued hedgehog signaling-induced Fgf18 downregulation, while overexpression of the human dnTCF7L2 orthologue (dnTCF4) in human chondrocytes promoted the expression of catabolic enzymes associated with OA. Similarly, expression of dnTCF4 in human chondrocytes positively correlated with the aggrecanase ADAMTS4. Consistent with our developmental findings, activation of ß-catenin also attenuated hedgehog-induced or surgically induced articular cartilage degeneration in mouse models of OA. Thus, our results demonstrate that hedgehog inhibits selective ß-catenin target gene expression to direct interzone progeny fates and articular cartilage development and disease. Moreover, agents that increase ß-catenin activity have the potential to therapeutically attenuate articular cartilage degeneration as part of OA.

TLR2-dependent activation of ß-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation.

Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1, which recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. In this study, we show that TLR2 signaling via AKT activates the ß-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of ß-catenin/T cell factor 4 was critical to induce regulatory molecules IL-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress proinflammatory cytokines. Deletion of ß-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the ß-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of ß-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.

Paneth's disease.

In about 70% of patients Crohn's disease (CD) affects the small intestine. This disease location is stable over time and associated with a genetic background different from isolated colonic disease. A characteristic feature of small intestinal host defense is the presence of Paneth cells at the bottom of the crypts of Lieberkühn. These cells produce different broad spectrum antimicrobial peptides (AMPs) most abundantly the α-defensins HD-5 and -6 (DEFA5 und DEFA6). In small intestinal Crohn's disease both these PC products are specifically reduced. As a functional consequence, ileal extracts from Crohn's disease patients are compromised in clearing bacteria and enteroadherent E. coli colonize the mucosa. Mechanisms for defective antimicrobial Paneth cell function are complex and include an association with a NOD2 loss of function mutation, a disturbance of the Wnt pathway transcription factor TCF7L2 (also known as TCF4), the autophagy factor ATG16L1, the endosomal stress protein XBP1, the toll-like receptor TLR9, the calcium mediated potassium channel KCNN4 as well as mutations or inactivation of HD5. Thus we conclude that small intestinal Crohn's disease is most likely a complex disease of the Paneth cell: Paneth's disease.

Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD Study 5).

AIMS: We previously demonstrated the presence of two different populations among adult-onset autoimmune diabetes (latent autoimmume diabetes of adults; LADA) having high or low titre of antibodies to glutamic acid decarboxylase (GADA). The transcription factor 7-like 2 (TCF7L2) gene has been recognized as the major gene associated with Type 2 diabetes. The aim of the present study was to evaluate whether the phenotypic heterogeneity of LADA based on GADA titre is associated with TCF7L2 polymorphisms. METHODS: Two hundred and fifty patients identified as LADA, divided into two subgroups with low (< or = 32 arbitrary units) or high (> 32 units) GADA titre, 620 subjects with Type 2 diabetes [from the Non-Insulin Requiring Autoimmune Diabetes (NIRAD) study cohort of 5330 subjects] in addition to 551 consecutive cases of Type 1 diabetes and 545 normoglycaemic subjects were analysed for the rs12255372 and rs7903146 polymorphisms of the TCF7L2 gene using Taqman. RESULTS: The genotype and allele distributions of the two polymorphisms revealed similar frequencies in subjects with low GADA titre and Type 2 diabetes. High GADA titre, Type 1 diabetes and controls also showed comparable frequencies. A significant increase of GT/TT genotypes of the rs12255372 single-nucleotide polymorphism (SNP) and CT/TT genotypes of the rs7903146 SNP was observed in low GADA titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and controls (P < or = 0.04 for both comparisons). The risk alleles of both variants were increased in low GADA titre and Type 2 diabetes compared with high GADA titre, Type 1 diabetes and control subjects (P < 0.02 for all comparisons). CONCLUSIONS: TCF7L2 common genetic variants of susceptibility are associated only with low GADA antibody titre in LADA patients.