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Abstract: Co-inhibitory signals from the B7 superfamily have been demonstrated to induce T cell dysfunction in chronic HBV infection (CHB). However, the expression and function of Z39Ig, a new inhibitor of the B7 superfamily, is still unclear in CHB. Here immunohistochemical staining showed that Z39Ig was restricted to macrophages and that its level was decreased significantly in CHB patients compared to healthy controls. Moreover, reduced Z39Ig expression was positively correlated with plasma HBV load but was inversely related to serum alanine aminotransaminase levels. Further, Z39Ig mRNA had a negative relation to IFN-γ in vivo, and IFN-γ also down-regulated Z39Ig expression on monocyte-derived macrophages (MDMs) in a time- and dose-dependent manner in vitro. Interestingly, Z39Ig expression on MDMs was restored when IFN-γ neutralizing antibodies were added to the T cell/MDM co-culture system, indicating that the IFN-γ derived from activated-T cells may contribute to the reduction of Z39Ig in the CHB environment. Our results suggest that T cells can opposite T cell hyporesponsiveness through dampening Z39Ig inhibitory signals from macrophages and thus maintain their anti-viral function in CHB. Therefore, decreasing Z39Ig signals from macrophages could contribute to CHB clinical therapy. [Copyright &y& Elsevier]

Abstract: Increased lymphocyte apoptosis has been suggested to contribute to the development of systemic lupus erythematosus (SLE), but the critical factors involved in the apoptotic pathways are still unknown. By long serial analysis of gene expression (LongSAGE) profiles and microarray analyses, a novel apoptosis-related gene BclGL expression was found significantly increased in peripheral blood CD4+ T cells of SLE patients, which was correlated with the enhanced CD4+ T cells apoptosis, anti-nuclear antibody (ANA) titer and proteinuria. In vitro, BclGL expression could be specially upregulated by SLE serum stimulation and positively correlated with induced CD4+ T cell apoptosis. Enforcing BclGL overexpression by lentivirus could directly enhance CD4+ T cell apoptosis, but these apoptosis-inducing effects could be partially inhibited by knockdown of BclGL expression. Collectively, these results indicate that increased BclGL expression may contribute to the aberrant CD4+ T cell apoptosis which causes an inappropriate immune response and impaired homeostasis in SLE. [Copyright &y& Elsevier]

Abstract: The co-inhibitory molecule B7-H1 has been broadly detectable on human inflammatory renal tubular epithelial cells (TECs) and is proposed to limit tubular damage through down-regulation of tubulointerstitial infiltration T cell activation. Nevertheless, factors that initiate B7-H1 expression on TECs remain unclarified. The terminal complement complex C5b-9, which deposits diffusely on tubules and glomerules of diseased kidneys, is now recognized as a mediator that triggers cellular activation rather than inducing cell death. Whether the up-regulation of B7-H1 on tubules is also induced by C5b-9 is uncertain. Here, after assembling functional sublytic C5b-9 on the membranes of TECs based on purified complement components, we found that B7-H1 gene transcription and protein synthesis was enhanced by C5b-9. Promoter constructs in a luciferase assay, site-directed mutagenesis and laser scanning confocal microscopy assay (LSCM) revealed that the transcription factor NF-κB is primarily responsible for C5b-9-mediated B7-H1 expression. To further detect the physiologic function of B7-H1, triggering B7-H1 with its agonist mAb (clone 5H1) profoundly enhanced Fas expression on C5b-9-treated TECs and thus induced TEC apoptosis. Interestingly, pretreatment of TECs with Fas blocking antibodies prevented this effect. Our results propose that C5b-9 regulates tubular pathogenesis in glomerulonephritis or other renal autoimmune diseases, possibly through enhances cell apoptosis mediated by B7-H1 signals, in addition to it directly promotes tubular damage. [Copyright &y& Elsevier]