Yunan Tang

University of North Carolina at Chapel Hill, North Carolina, United States

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Publications (4)13.52 Total impact

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    ABSTRACT: IFN-β has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-β in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-β inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4(+) lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-β secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4(+) cells. We identified that the endogenous IFN-β from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-β signaling in the CD4(+) cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-β signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4(+) T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-β suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-β-1a treatment induced IFNAR1 and its downstream signaling molecules' gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-β regulation of the CD4(+) T cells' pathogenic cytokine production in patients with MS.
    Journal of immunology (Baltimore, Md. : 1950). 05/2014;
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    ABSTRACT: IFN-beta, an effective therapy against relapsing-remitting multiple sclerosis, is naturally secreted during the innate immune response against viral pathogens. The objective of this study was to characterize the immunomodulatory mechanisms of IFN-beta targeting innate immune response and their effects on dendritic cell (DC)-mediated regulation of T cell differentiation. We found that IFN-beta1a in vitro treatment of human monocyte-derived DCs induced the expression of TLR7 and the members of its downstream signaling pathway, including MyD88, IL-1R-associated kinase 4, and TNF receptor-associated factor 6, while it inhibited the expression of IL-1R. Using small interfering RNA TLR7 gene silencing, we confirmed that IFN-beta1a-induced changes in MyD88, IL-1R-associated kinase 4, and IL-1R expression were dependent on TLR7. TLR7 expression was also necessary for the IFN-beta1a-induced inhibition of IL-1beta and IL-23 and the induction of IL-27 secretion by DCs. Supernatant transfer experiments confirmed that IFN-beta1a-induced changes in DC cytokine secretion inhibit Th17 cell differentiation as evidenced by the inhibition of retinoic acid-related orphan nuclear hormone receptor C and IL-17A gene expression and IL-17A secretion. Our study has identified a novel therapeutic mechanism of IFN-beta1a that selectively targets the autoimmune response in multiple sclerosis.
    The Journal of Immunology 04/2009; 182(6):3928-36. · 5.52 Impact Factor
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    ABSTRACT: TCR degeneracy may facilitate self-reactive T cell activation and the initiation of an autoimmune response in multiple sclerosis (MS). MHC class II alleles of the DR2 haplotype DR2a (DRB5*0101) and DR2b (DRB1*1501) are associated with an increased risk for MS in Caucasian populations. In order to selectively expand and characterize T cells with a high degree of TCR degeneracy that recognize peptides in the context of disease-associated DR2 alleles, we developed DR2-anchored peptide mixtures (APM). We report here that DR2-APM have a high stimulatory potency and can selectively expand T cells with a degenerate TCR (TCR(deg)). Due to the low concentration of individual peptides in the mixtures, T cell clones' proliferative response to DR2-APM implies that multiple peptides stimulate the TCR, which is a characteristic of TCR(deg). The frequency of DR2-APM-reactive T cells is significantly higher in MS patients than in healthy controls, suggesting that they may play a role in the development of the autoimmune response in MS. DR2-APM-reactive cells have a dual DR2 restriction: they recognize DR2-APM in the context of both DR2a and DR2b molecules. The DR2-APM-reactive cells' IL-17 secretion, together with cross-reactivity against myelin peptides, may contribute to their role in the development of autoimmune response in MS.
    European Journal of Immunology 06/2008; 38(5):1297-309. · 4.97 Impact Factor
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    ABSTRACT: This study characterized immunomodulatory targets of statins in humans and their potential for treatment of relapsing remitting multiple sclerosis (RR MS). Statins inhibited the proliferative response of mononuclear cells. Simvastatin, the statin with the strongest antiproliferative effect, inhibited IFN-gamma-induced expression of MHC class II DR on monocytes and decreased their antigen presenting capacity. As for T lymphocytes, it inhibited their activation and expression of the Th1 lineage differentiation markers. Simvastatin inhibited IFN-gamma, TNF-alpha, and IL-2 secretion, as well as the expression of T-bet, a transcription factor that regulates Th1 cell differentiation.
    Journal of Neuroimmunology 10/2006; 178(1-2):130-9. · 3.03 Impact Factor