Apolipoprotein L genes are novel mediators of inflammation in beta cells

Aims/hypothesisInflammation induces beta cell dysfunction and demise but underlying molecular mechanisms remain unclear. The apolipoprotein L (APOL) family of genes has been associated with innate immunity and apoptosis in non-pancreatic cell types, but also with metabolic syndrome and type 2 diabetes mellitus. Here, we hypothesised that APOL genes play a role in inflammation-induced beta cell damage.MethodsWe used single-cell transcriptomics datasets of primary human pancreatic islet cells to study the expression of APOL genes upon specific stress conditions. Validation of the findings was carried out in EndoC-βH1 cells and primary human islets. Finally, we performed loss- and gain-of-function experiments to investigate the role of APOL genes in beta cells.ResultsAPOL genes are expressed in primary human beta cells and APOL1, 2 and 6 are strongly upregulated upon inflammation via the Janus kinase (JAK)−signal transducer and activator of transcription (STAT) pathway. APOL1 overexpression increases endoplasmic reticulum stress while APOL1 knockdown prevents cytokine-induced beta cell death and interferon-associated response. Furthermore, we found that APOL genes are upregulated in beta cells from donors with type 2 diabetes compared with donors without diabetes mellitus.Conclusions/interpretationAPOLs are novel regulators of islet inflammation and may contribute to beta cell damage during the development of diabetes.Therapeutic cell differentiatio

Thyroglobulin as an autoantigen: what can we learn about immunopathogenicity from the correlation of antigenic properties with protein structure?

Autoantibodies against human thyroglobulin are a hallmark of autoimmune thyroid disease in humans, and are often found in normal subjects. Their pathogenic significance is debated. Several B-cell epitope-bearing peptides have been identified in thyroglobulin. They are generally located away from the cysteine-rich regions of tandem sequence repetition. It is possible that our current epitopic map is incomplete because of the difficulty that proteolytic and recombinant approaches have in restituting conformational epitopes based upon proper pairing between numerous cysteinyl residues. Furthermore, the homology of cysteine-rich repeats with a motif occurring in several proteins, endowed with antiprotease activity, suggests that these regions may normally escape processing and presentation to the immune system, and brings attention to the mechanisms, such as oxidative cleavage, by which such cryptic epitopes may be exposed. A number of T-cell epitope-bearing peptides, endowed with thyroiditogenic power in susceptible mice, were also identified. None of them was dominant, as none was able to prime in vivo lymph node cells that would proliferate or transfer autoimmune thyroiditis to syngeneic hosts, upon stimulation with intact thyroglobulin in vitro. More than half of them are located within the acetylcholinesterase-homologous domain of thyroglobulin, and overlap B-cell epitopes associated with autoimmune thyroid disease, while the others are located within cysteine-rich repeats. The immunopathogenic, non-dominant character of these epitopes also favours the view that the development of autoimmune thyroid disease may involve the unmasking of cryptic epitopes, whose exposure may cause the breaking of peripheral tolerance to thyroglobulin. Further research in this direction seems warranted

DUOX Defects and Their Roles in Congenital Hypothyroidism.

Extracellular hydrogen peroxide is required for thyroperoxidase-mediated thyroid hormone synthesis in the follicular lumen of the thyroid gland. Among the NADPH oxidases, dual oxidases, DUOX1 and DUOX2, constitute a distinct subfamily initially identified as thyroid oxidases, based on their level of expression in the thyroid. Despite their high sequence similarity, the two isoforms present distinct regulations, tissue expression, and catalytic functions. Inactivating mutations in many of the genes involved in thyroid hormone synthesis cause thyroid dyshormonogenesis associated with iodide organification defect. This chapter provides an overview of the genetic alterations in DUOX2 and its maturation factor, DUOXA2, causing inherited severe hypothyroidism that clearly demonstrate the physiological implication of this oxidase in thyroid hormonogenesis. Mutations in the DUOX2 gene have been described in permanent but also in transient forms of congenital hypothyroidism. Moreover, accumulating evidence demonstrates that the high phenotypic variability associated with altered DUOX2 function is not directly related to the number of inactivated DUOX2 alleles, suggesting the existence of other pathophysiological factors. The presence of two DUOX isoforms and their corresponding maturation factors in the same organ could certainly constitute an efficient redundant mechanism to maintain sufficient H2O2 supply for iodide organification. Many of the reported DUOX2 missense variants have not been functionally characterized, their clinical impact in the observed phenotype remaining unresolved, especially in mild transient congenital hypothyroidism. DUOX2 function should be carefully evaluated using an in vitro assay wherein (1) DUOXA2 is co-expressed, (2) H2O2 production is activated, (3) and DUOX2 membrane expression is precisely analyzed.info:eu-repo/semantics/publishe