IntroductionPrevalence of insulin resistance and the metabolic syndrome has been reported to be high in rheumatoid arthritis (RA) patients. Tumor necrosis factor (TNF), a pro-inflammatory cytokine with a major pathogenetic role in RA, may promote insulin resistance by inducing Ser312 phosphorylation (p-Ser312) of insulin receptor substrate (IRS)-1 and downregulating phosphorylated (p-)AKT. We examined whether anti-TNF therapy improves insulin resistance in RA patients and assessed changes in the insulin signaling cascade.MethodsProspective study of RA patients receiving anti-TNF agents (infliximab, n = 49, adalimumab, n = 11, or etanercept, n = 1) due to high disease activity score in 28 joints (DAS28 > 5.1). A complete biochemical profile was obtained at weeks 0 and 12 of treatment. Insulin resistance, insulin sensitivity and pancreatic beta cell function were measured by the Homeostasis Model Assessment (HOMA-IR), the Quantitative Insulin Sensitivity Check Index (QUICKI) and the HOMA-B respectively. Protein extracts from peripheral blood mononuclear cells were assayed by western blot for p-Ser312 IRS-1 and p-AKT. RA patients treated with abatacept (CTLA4.Ig) were used as a control group for insulin signaling studies.ResultsAt study entry, RA patients with high insulin resistance (HOMA-IR above median) had significantly higher mean DAS28 (P = 0.011), serum triglycerides (P = 0.015), and systolic blood pressure levels (P = 0.024) than patients with low insulin resistance. After 12 weeks of anti-TNF therapy, patients with high insulin resistance demonstrated significant reduction in HOMA-IR (P < 0.001), HOMA-B (P = 0.001), serum triglycerides (P = 0.039), and increase in QUICKI (P < 0.001) and serum HDL-C (P = 0.022). Western blot analysis in seven active RA patients with high insulin resistance showed reduction in p-Ser312 IRS-1 (P = 0.043) and increase in p-AKT (P = 0.001) over the study period. In contrast, the effect of CTLA4.Ig on p-Ser312 IRS-1 and p-AKT levels was variable.ConclusionsAnti-TNF therapy improved insulin sensitivity and reversed defects in the insulin signaling cascade in RA patients with active disease and high insulin resistance. The impact of these biochemical changes in modifying cardiovascular disease burden in active RA patients remains to be seen.

Conclusion. These results demonstrate, for the first time, that human plasmacytoid DCs may be educated within the rheumatoid microenvironment to acquire a tolerogenic phenotype. Modulation of the immune response by plasmacytoid DCs might provide novel immune-based therapies in autoimmunity and transplantation.

Obesity and adherence to the Mediterranean diet patterns are factors related independently to indices of AS even in 12-year-old children.

Disruption of the programmed death-1 (PD-1) pathway leads to breakdown of peripheral tolerance and initiation of autoimmunity. The molecular pathways that mediate this effect remain largely unknown. We report here that PD-1 knockout (PD-1 À/À ) mice develop more severe and sustained Ag-induced arthritis (AIA) than WT animals, which is associated with increased T-cell proliferation and elevated levels of IFN-c and IL-17 secretion. MicroRNA analysis of Ag-specific CD4 1 T cells revealed a significant upregulation of microRNA 21 (miR-21) in PD-1 À/À T cells compared with WT controls. In addition, PD-1 inhibition, via siRNA, upregulated miR-21 expression and enhanced STAT5 binding in the miR-21 promoter area. Computational analysis confirmed that miR-21 targets directly the expression of programmed cell death 4 (PDCD4) and overexpression of miR-21 in cells harboring the 3 0 UTR of PDCD4 resulted in reduced transcription and PDCD4 protein expression. Importantly, in vitro delivery of antisense-miR-21 suppressed the Ag-specific proliferation and cytokine secretion by PD-1 À/À T cells, whereas adoptive transfer of Ag-specific T cells, overexpressing miR-21, induced severe AIA. Collectively, our data demonstrate that breakdown of tolerance in PD-1 À/À mice activates a signaling cascade mediated by STAT5, miR-21, and PDCD4 and establish their role in maintaining the balance between immune activation and tolerance.Keywords: Autoimmunity . MicroRNA . Programmed death-1 . Tolerance IntroductionInhibitory signals delivered to activated T cells are essential for the maintenance of immune homeostasis and self-tolerance. Programmed death-1 (PD-1) is a novel negative regulatory molecule that is expressed on activated CD4 1 and CD8 1 T cells and binds to two known ligands, PD-L1 and PD-L2, found on APCs [1][2]. Deficiency of PD-1 (PD-1 À/À ) causes different types of autoimmune diseases such as lupus-like syndrome [3] and autoimmune cardiomyopathy [4] on C57BL/6 and BALB/c genetic backgrounds respectively, whereas PD-1 À/À NOD mice develop accelerated diabetes [5]. In humans, polymorphisms in the PD-1 gene have been associated with susceptibility to systemic lupus erythematosus [6], type I diabetes [7], multiple sclerosis [8], and rheumatoid arthritis [9]. The development of autoimmunity in PD-1 À/À mice resembles that of the cytotoxic T lymphocyte-associated Ag 4 (CTLA-4)-deficient mice [10], though less severe suggesting that the PD-1 pathway may have a crucial role in the maintenance of peripheral tolerance [11]. Delineating the precise molecular pathways that are involved 1754during breakdown of tolerance in the absence of the PD-1 signaling pathway may provide novel insights into our understanding of the pathogenesis of autoimmune diseases.MicroRNAs (miRNAs) represent a novel class of noncoding small RNAs (19-23 nucleotide long) which regulate the expression of more than 30% of protein-coding genes at the post-transcriptional and translational level [12]. Control of expression of their gene targets is mediated by translatio...