Role of nucleic acid sensing in the pathogenesis of type 1 diabetes

During infections,nucleic acids of pathogens are also engaged in recognition via several exogenous and cytosolic pattern recognition receptors,such as the toll-like receptors,retinoic acid inducible gene-I-like receptors,and nucleotide-binding and oligomerization domain-like receptors.The binding of the pathogen-derived nucleic acids to their corresponding sensors initiates certain downstream signaling cascades culminating in the release of type-I interferons(IFNs),especially IFN-αand other cytokines to induce proinflammatory responses towards invading pathogens leading to their clearance from the host.Although these sensors are hardwired to recognize pathogen associated molecular patterns,like viral and bacterial nucleic acids,under unusual physiological conditions,such as excessive cellular stress and increased apoptosis,endogenous self-nucleic acids like DNA,RNA,and mitochondrial DNA are also released.The presence of these self-nucleic acids in extranuclear compartments or extracellular spaces or their association with certain proteins sometimes leads to the failure of discriminating mechanisms of nucleic acid sensors leading to proinflammatory responses as seen in autoimmune disorders,like systemic lupus erythematosus,psoriasis and to some extent in type 1 diabetes(T1D).This review discusses the involvement of various nucleic acid sensors in autoimmunity and discusses how aberrant recognition of self-nucleic acids by their sensors activates the innate immune responses during the pathogenesis of T1D.

Th1/Th2 type cytokines in hepatitis B patients treated with interferon-α

Objective To investigate the relationship between the expression of Th1/Th2 type cytokines and the effect of interferon-α therapy. Methods Th1/Th2 type cytokines were assayed by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR) on 23 patients with chronic hepatitis B who were treated with interferon-α.Results Levels of IFN-γ in the supernatant of peripheral blood mononuclear cells (PBMC) cultures from the patients with hepatitis B were slightly lower than those of controls (P=0.07). However, the levels of IL-4 were higher than those of controls (P=0.01). Cytokines measurements during IFN-α treatment showed a trend to decreaseing levels of IL-4 at 4, 12, and 24 weeks. Levels of IFN-γ were slightly increased following IFN-α treatment (P=0.09). In patients with a complete response to IFN-α, the levels of IFN-γ were higher at 24 weeks following IFN-α treatment than that of pre-treatment (P=0.04), and the levels of IL-4 decreased markedly at 12 and 24 weeks (P=0.02, 0.03, respectively). mRNA expression positively correlated with the level of Th1/Th2 type cytokines in the supernatant. Conclusion The expression of Th2 type cytokines is predominant in patients with chronic hepatitis B. Interferon-α therapy can modulate the balance of Th1/Th2 type cytokines, and this is related to its clinical effect. Levels of Th1/Th2 type cytokines could be a predictor of clinical response during Interferon -α treatment.

DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury

Liver damage upon exposure to ionizing radiation(IR),whether accidental or therapeutic,can contribute to liver dysfunction.Currently,radiotherapy(RT)is used for various cancers including hepatocellular carcinoma(HCC);however,the treatment dose is limited by radiation-induced liver disease(RILD)with a high mortality rate.Furthermore,the precise molecular mechanisms of RILD remain poorly understood.Here,we investigated RILD pathogenesis using various knockout mouse strains subjected to whole-liver irradiation.We found that hepatocytes released a large quantity of double-stranded DNA(dsDNA)after irradiation.The cGAS-STING pathway in non-parenchymal cells(NPCs)was promptly activated by this dsDNA,causing interferon(IFN)-I production and release and concomitant hepatocyte damage.Genetic and pharmacological ablation of the IFN-I signaling pathway protected against RILD.Moreover,clinically irradiated human peri-HCC liver tissues exhibited substantially higher STING and IFNβexpression than non-irradiated tissues.Increased serum IFNβconcentrations post-radiation were associated with RILD development in patients.These results delineate cGAS-STING induced type 1 interferon release in NPCs as a key mediator of IR-induced liver damage and described a mechanism of innate-immunity-driven pathology,linking cGAS-STING activation with amplification of initial radiation-induced liver injury.

Type 1 interferon-induced IL-7 maintains CD8＋ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

Type 1 interferon （IFN-I） promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by I FN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus （Ad） in IFN-a receptor knockout （IFNAR-/-） and control mice. To disrupt signaling, monoclonal antibodies （mAbs） against IL-7 receptor alpha （IL-7Re） or PD-L1 were i.p. injected. We found that CD8＋ T cells in IFNAR-/- mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-7 production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell （DCs） and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR-/- and control mice. Injection of PD-Ll-specific mAb in IFNAR-/- mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR-/- mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8＋ T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8＋ T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8＋ T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.