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ObjectiveInterferon induced with helicase C domain 1 (IFIH1) single-nucleotide polymorphisms (SNP) rs1990760, rs3747517, and rs10930046 have been shown to be closely related to the risk of autoimmune diseases. The aim of this study was firstly to examine the association of the rs1990760 with type 1 diabetes (T1D) in a Chinese population. Secondly, to assess the association of SNP rs1990760, rs3747517, and rs10930046 with autoimmune diseases susceptibility.MethodsA total of 1,273 T1D patients and 1,010 healthy control subjects in a Chinese population were enrolled in this case-control study. Subsequently, we performed a meta-analysis on the association of the SNP rs1990760, rs3747517, and rs10930046 in the IFIH1 gene with susceptibility to autoimmune diseases. The random and fixed genetic effects models were used to evaluate the association and the effect sizes, including odds ratios (OR) and 95% confidence intervals (CI). Stratification analyses based on ethnicity and the type of autoimmune diseases were performed.ResultsIFIH1 SNP rs1990760 was not associated with a significant risk of T1D in the Chinese population in the case-control study. A total of 35 studies including 70,966 patients and 124,509 controls were identified and included in the meta-analysis. The results displayed significant associations between IFIH1 rs1990760 A allele and rs3747517 C allele and autoimmune diseases risk (OR=1.09, 95% CI: 1.01~1.17; OR=1.24, 95% CI: 1.15~1.25, respectively). Stratified analysis indicated a significant association rs1990760 and rs3747517 with autoimmune diseases risk in the Caucasian population (OR=1.11, 95% CI: 1.02~1.20, OR=1.29, 95% CI: 1.18~1.41, respectively).ConclusionsThis study revealed no association between IFIH1 SNP rs1990760 and T1D in Chinese. Furthermore, the meta-analysis indicated that rs1990760 and rs3747517 polymorphisms, confer susceptibility to autoimmune diseases, especially in the Caucasian population.

BackgroundType 1 diabetes mellitus (T1DM) is caused by immune cell-mediated β-cell dysfunction. In recent decades, N6-methyladenosine (m6A) has attracted widespread attention in the scientific research field because it plays vital roles in the pathogenesis of immunity-related diseases, including autoimmune diseases. However, neither the m6A modification profile nor the potential role it plays in T1DM pathogenesis has been investigated to date.Materials and MethodsAn m6A mRNA epitranscriptomic microarray analysis was performed to analyze m6A regulator expression patterns and m6A methylation patterns in immune cells of T1DM patients (n=6) and healthy individuals (n=6). A bioinformatics analysis was subsequently performed to explore the potential biological functions and signaling pathways underlying T1DM pathogenesis. Furthermore, mRNA expression and m6A methylation levels were subsequently verified by qRT–PCR and methylated RNA immunoprecipitation–qPCR (MeRIP–qPCR), respectively, in the T1DM and healthy groups (n=6 per group).ResultsAmong the multiple m6A regulators, METTL3 and IGF2BP2 had significantly downregulated expression, and YTHDC1 and HNRNPA2B1 had significantly upregulated expression in the T1DM group relative to the healthy group. The microarray analysis revealed 4247 differentially methylated transcripts, including 932 hypermethylated and 3315 hypomethylated transcripts, and 4264 differentially expressed transcripts, including 1818 upregulated transcripts and 2446 downregulated transcripts in the T1DM group relative to the healthy group. An association analysis between methylation and gene expression demonstrated that the expression of 590 hypermethylated transcripts was upregulated, and that of 1890 hypomethylated transcripts was downregulated. Pearson correlation analysis showed significant correlations between the expression levels of differentially expressed m6A regulators and the methylation levels of differentially methylated transcripts and significant correlations between the expression levels of differentially expressed m6A regulators and that of differentially expressed transcripts. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that differentially methylated transcripts were involved in pathways related to immunity, including some closely associated with T1DM.ConclusionsOur study presents m6A regulator expression patterns and m6A methylation patterns of immune cells in T1DM, showing that the m6A mark and m6A regulators are promising targets for T1DM diagnosis and treatment.

BackgroundExosomes carry various types of transcripts, such as messenger RNAs (mRNAs), and play an important role in mediating cell-to-cell communication, thus influencing multiple physiological and pathological processes. However, the role of exosomal mRNAs in T1DM is largely unknown. Here, we aimed to identify the plasma-derived exosomal mRNA expression profiles in T1DM and to explore their potential biological functions in T1DM.Materials and MethodsPlasma-derived exosomes were isolated from 10 patients with T1DM and 10 age- and sex-matched control subjects by size exclusion chromatography methods. Transmission electron microscopy, nanoparticle tracking analysis, and western blot analysis confirmed the presence of exosomes. The exosomal mRNAs were analyzed using the Illumina HiSeq platform. Six differentially expressed mRNAs (DEMs) were randomly selected to determine the expression level by quantitative real-time PCR (qRT−PCR) in a larger cohort (T1DM subjects N=40; control subjects N=40). The biological functions of DEMs were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Protein−protein interaction networks were constructed to explore the potential associations among DEMs.ResultsIn total, 112 DEMs were identified in T1DM, among which 66 mRNAs were upregulated and 46 mRNAs were downregulated. Four of six candidate exosomal mRNAs were successfully validated by qRT−PCR. Bioinformatics analysis indicated that these mRNAs were most significantly involved in positive regulation by host viral transcription (GO enrichment analysis) and oxidative phosphorylation (KEGG pathway analysis).ConclusionsOur study reported the plasma-derived exosomal mRNA expression profiles of T1DM for the first time. The identified DEMs might be associated with the pathogenesis of T1DM, and some DEMs have the potential to serve as biomarkers and therapeutic targets for T1DM.

Diabetes mellitus (DM) is an endocrine disorder characterized by a relative or absolute lack of insulin due to the dysfunction or destruction of β-cells. DM is one of the fastest growing challenges to global health in the 21st century and places a tremendous burden on affected individuals and their families and countries. Although insulin and antidiabetic drugs have been used to treat DM, a radical cure for the disease is unavailable. The pathogenesis of DM remains unclear. Emerging roles of circular RNAs (circRNAs) in DM have become a subject of global research. CircRNAs have been verified to participate in the onset and progression of DM, implying their potential roles as novel biomarkers and treatment tools. In the present review, we briefly introduce the characteristics of circRNAs. Next, we focus on specific roles of circRNAs in type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus and diabetes-associated complications.

BackgroundsExosomes contain several types of transcripts, including long non-coding RNAs (lncRNAs), and have been shown to exert important effects in human diseases. However, the roles of exosomal lncRNAs in type 1 diabetes mellitus (T1DM) have not been well investigated. In the present study, we characterized the plasma-derived exosomal lncRNAs expression profiles of T1DM and predict their potential function in the pathogenesis of T1DM.Material and MethodsExosomal lncRNA expression profiles were detected by Illumina Hiseq platform (T1DM subjects N=10; age-, sex- matched Control subjects N=10). Six exosomal lncRNAs were selected to validate their expression level by using quantitative real-time PCR (qRT-PCR) (T1DM subjects N=30; age-, sex- matched Control subjects N=30). Bioinformatics analysis approaches were carried out to explore the potential biological function of differentially expressed lncRNAs.ResultsA total of 162 differentially expressed exosomal lncRNAs were identified in T1DM patients compared with control subjects, among which 77 up-regulated and 85 down-regulated. The expression level of the selected six lncRNAs didn’t show significant difference in the following qRT-PCR analysis. Gene Ontology analysis enriched terms such as activation of phospholipase D activity, neuronal cell body membrane, and calcium sensitive guanylate cyclase activator activity for cis-acting genes of lncRNAs, and metal ion binding for trans-acting genes. The most enriched Kyoto Encyclopedia of Genes and Genomes pathways for the lncRNAs were associated with oxidative phosphorylation and Parkinson’s disease for cis-acting genes, and pathways in cancer as well as focal adhesion for trans-acting genes.ConclusionsThis study characterized the lncRNA profiles of plasma-derived exosomes from T1DM for the first time and these results highlighted the potential role of exosomal lncRNAs in T1DM pathogenesis. A better understanding of exosomal lncRNA profiling will provide novel insights into its molecular mechanisms.

T cell Ig and mucin domain (Tim) protein family members were identified to be important regulators of the immune response. As their name indicates, Tim proteins were originally considered a T cell-specific markers, and they mainly regulate the responses of T helper cells. However, accumulating evidence indicates that Tims are also expressed on antigen-presenting cells (APCs), such as monocytes, macrophages, dendritic cells (DCs) and B cells, and even plays various roles in natural killer cells (NKs) and mast cells. In recent years, the expression and function of Tims on different cells and the identification of new ligands for the Tim family have suggested that the Tim family plays a crucial role in immune regulation. In addition, the relationship between Tim family gene polymorphisms and susceptibility to several autoimmune diseases has expanded our knowledge of the role of Tim proteins in immune regulation. In this review, we discuss how the Tim family affects immunomodulatory function and the potential role of the Tim family in typical autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D). A deeper understanding of the immunoregulatory mechanism of the Tim family might provide new insights into the clinical diagnosis and treatment of autoimmune diseases.

Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.

The NLRP3 (nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a protein complex expressed in cells. It detects danger signals and induces the production of active caspase-1 and the maturation and release of IL (interleukin)-33, IL-18, IL-1β and other cytokines. T1DM (type 1 diabetes mellitus) is defined as a chronic autoimmune disorder characterized by the autoreactive T cell-mediated elimination of insulin-positive pancreatic beta-cells. Although the exact underlying mechanisms are obscure, researchers have proposed that both environmental and genetic factors are involved in the pathogenesis of T1DM. Furthermore, immune responses, including innate and adaptive immunity, play an important role in this process. Recently, the NLRP3 inflammasome, a critical component of innate immunity, was reported to be associated with T1DM. Here, we review the assembly and function of the NLRP3 inflammasome. In addition, the activation and regulatory mechanisms that enhance or attenuate NLRP3 inflammasome activation are discussed. Finally, we focus on the relationship between the NLRP3 inflammasome and T1DM, as well as its potential value for clinical use.

T1DM (type 1 diabetes mellitus), which results from the irreversible elimination of beta-cells mediated by autoreactive T cells, is defined as an autoimmune disease. It is widely accepted that T1DM is caused by a combination of genetic and environmental factors, but the precise underlying molecular mechanisms are still unknown. To date, more than 50 genetic risk regions contributing to the pathogenesis of T1DM have been identified by GWAS (genome-wide association studies). Notably, more than 60% of the identified candidate genes are expressed in islets and beta-cells, which makes it plausible that these genes act at the beta-cell level and play a key role in the pathogenesis of T1DM. In this review, we focus on the current status of candidate genes that act at the beta-cell level by regulating the innate immune response and antiviral activity, affecting susceptibility to proapoptotic stimuli and influencing the pancreatic beta-cell phenotype.