Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors. Similar to the majority of autoimmune diseases, T1DM usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens, which precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies in the serum of T1DM patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects, (i.e. HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from T1DM in multiple populations.A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development. Viral infections may play a role in the chain of events leading to disease, albeit conclusive evidence linking infections with T1DM remains to be firmly established. Two syndromes have been described in which an immunemediated form of diabetes occurs as the result of a single gene defect. These syndromes are termed autoimmune polyglandular syndrome type I (APS-I) or autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), and X-linked poyendocrinopathy, immune dysfunction and diarrhea (XPID). These two syndromes are unique models to understand the mechanisms involved in the loss of tolerance to self-antigens in autoimmune diabetes and its associated organ-specific autoimmune disorders. A growing number of animal models of these diseases have greatly helped elucidate the immunologic mechanisms leading to autoimmune diabetes.

The increasing prevalence of worldwide obesity has emerged as a major risk factor for type 2 diabetes (T2D), hepatosteatosis, and cardiovascular disease. Accumulating evidence indicates that obesity has strong inflammatory underpinnings tightly linked to the development of metabolic diseases. However, the molecular mechanisms by which obesity induces aberrant inflammation associated with metabolic diseases are not yet clearly defined. Recently, RNAs have emerged as important regulators of stress responses and metabolism. RNAs are subject to changes in modification status, higher-order structure, and cellular localization; all of which could affect the affinity for RNA-binding proteins (RBPs) and thereby modify the RNA-RBP networks. Proper regulation and management of RNA characteristics are fundamental to cellular and organismal homeostasis, as well as paramount to health. Identification of multiple single nucleotide polymorphisms (SNPs) within loci of fat mass- and obesity-associated protein (FTO) gene, an RNA demethylase, through genome-wide association studies (GWAS) of T2D, and functional assessments of FTO in mice, support the concept that disruption in RNA modifications leads to the development of human diseases including obesity and metabolic disorder. In obesity, dynamic alterations in modification and localization of RNAs appear to modulate the RNA-RBP networks and activate proinflammatory RBPs, such as double-stranded RNA (dsRNA)-dependent protein kinase (PKR), Toll-like receptor (TLR) 3 and TLR7, and RNA silencing machinery. These changes induce aberrant inflammation and the development of metabolic diseases. This review will describe the current understanding of the underlying causes of these common and altered characteristics of RNA-RBP networks which will pave the way for developing novel approaches to tackle the pandemic issue of obesity.

In addition to autoantigens implicated in thyroid autoimmunity, fibrocytes and derivative fibroblasts express multiple autoantigens associated with T1DM. This expression results from active gene promoters and abundant steady-state mRNA encoding ICA69 and IA-2. These latest findings demonstrate that fibrocytes express antigens relevant to multiple forms of endocrine autoimmunity. They suggest the potential for these cells playing a direct role in immune reactivity directed at the thyroid and pancreatic islets.

We identified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys 27 , Gly 608 , and Pro 671) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (T1D) probands from the TrialNet Pathway to Prevention Study. The presence of IA-2varspecific AAb in relatives was associated with accelerated progression to T1D in those positive for AAb to GAD65 and/or insulin but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1*04-DQB1*03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alters the three amino acids induces changes in the threedimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb to IA-2var would identify high-risk subjects who would benefit from participation in prevention trials who have one islet antibody by traditional testing and otherwise would be misclassified as "low risk" relatives. Type 1 diabetes (T1D) is an autoimmune disease that results from the targeted destruction of pancreatic b-cells by autoreactive T cells (1,2). The development of T1D is associated with the occurrence of autoantibodies (AAb) to pancreatic islet antigens that can be used as predictive biomarkers of disease progression (3). AAb associated with T1D are mainly directed against proteins that are involved in the secretory pathway of insulin, including insulin, glutamic acid decarboxylase (GAD65), islet tyrosine phosphatase-like protein (IA-2), and zinc transporter 8 SLC30A8 (ZnT8). The presence of AAb to IA-2 is associated with a high risk of T1D development (4-7). Screening for T1D-associated AAb allows for identification of asymptomatic, high-risk individuals (8) and for natural history studies of disease in cadaveric donors (9). The neuroendocrine molecule IA-2 is a transmembrane glycoprotein of the tyrosine phosphatase-like protein family that is localized to the insulin-secretory granules of the pancreatic b-cell (10). IA-2 (PTPRN) encodes a 979-amino acid protein containing three domains: the N-terminal extracellular (or luminal) domain (amino acids 1-556), the transmembrane domain (amino acids 557-600), and the COOH-terminal intracellular (or cytoplasmic) domain (amino acids 601-979) containing a juxtamembrane (JM) domain (amino acids 601-686) and a protein tyrosine phosphatase

changes in the functions of regulatory B cells over time and a potentially novel mechanism for inducing the suppressive capabilities of regulatory B cells using IL-5-induced IL-10 production. Results Diabetes is significantly delayed in an adoptive transfer model following injections of MHC-compatible CD19 + cells from young donor NOD mice. Splenocytes isolated from MHC-compatible diabetic female NOD mice were i.v. injected into 6-week-old NOD.scid recipient female mice. NOD.scid recipients receiving single transfers of diabetic splenocytes started to develop T1D at day 20 after transfer (Figure 1A). Cotransfer experiments were performed on day 6 and day 12 using CD19 + cells purified from 6-week-old prediabetic female NOD mice to create a boosted B cell pool mimicking the young prediabetes phase of the NOD donor. We observed a strikingly significant delay in progression to autoimmune diabetes in NOD.scid recipients when purified splenic CD19 + cells from 6-week-old NOD mice were cotransferred (Figure 1A; P < 0.0001). By day 40 after transfer, 100% of the NOD.scid recipients receiving diabetic splenocytes alone had progressed to overt diabetes, while 100% of NOD.scid CD19 + cotransfer recipients were still normoglycemic (Figure 1A). CD4 + and CD8 + T cell populations (gated initially on CD3 + CD19-) were not significantly different after the reconstitution process in NOD.scid recipients receiving either NOD splenocytes alone or CD19 + cotransfers (Figure 1B). Further analysis of the B cells from 6-week-old NOD female mice and matching C57BL/6 and Balb/c controls found that NOD mice have an increased number of CD19 + IgM + CD5 hi CD1d lo traditionally described as Bregs in NOD mice as compared with control strains (Figure 1C) (34-37). Analysis of the CD3 + CD4 + Th repertoire within the spleen revealed a normal distribution of Th1 (IFN-γ-secreting) and Th17 (IL-17A-secreting) T cells, with most of the T cells in the spleen of both NOD.scid recipient populations containing a majority of Th1 pool (Figure 1D), as established in the literature (38, 39). To investigate the possible effect of age, cotransfer experiments were executed by using splenocytes from diabetic NOD donors combined with CD19 + B cells from either 6-week-or >15-week-old nondiabetic female NOD mice (15). While a similar delay in onset as the previous experiment was observed when CD19 + cells from young donors were cotransferred, NOD.scid recipients of CD19 + cells from >15-week-old nondiabetic NOD donors had a similar rate of diabetes progression compared with recipients of splenocytes alone obtained from NOD diabetic donors (Figure 2A). These are the first observations to our knowledge demonstrating that >15-week-old NOD female donors can transfer diabetes within the same amount of time as an already-diabetic NOD female donor. Further analysis of the CD19 + B cell pool taken from the spleen (Figure 2B) found an increased number of antigen-presenting capable marginal zone (MZ) B cells (48.4%) and MZ precursors (16.7%) as a percentage of the total CD...