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Han X.,CAS Shanghai Institutes for Biological Sciences | Wang Y.,CAS Shanghai Institutes for Biological Sciences | Zhang X.,Shanghai JiaoTong University | Qin Y.,Shanghai JiaoTong University | And 12 more authors.
Arthritis and Rheumatology | Year: 2016

Objective: Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA-130b (miR-130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN. Methods: Kidney tissues from patients and (NZB × NZW)F1 lupus-prone mice were collected for detecting miR-130b levels. Primary renal mesangial cells (RMCs) were used to determine the role of miR-130b in the IFN pathway. We overexpressed miR-130b by administering miR-130b agomir in a mouse model of IFNα-accelerated LN to test its therapeutic efficacy. Results: Down-regulated miR-130b expression was observed in kidney tissues from patients and lupus-prone mice. Further analysis showed that underexpression of miR-130b correlated negatively with abnormal activation of the IFN response in LN patients. In vitro, overexpressing miR-130b suppressed signaling downstream from the type I IFN pathway in RMCs by targeting IFN regulatory factor 1 (IRF-1). The opposite effect was observed when endogenous miR-130b expression was inhibited. The inverse correlation between IRF1 and miR-130b levels was detected in renal biopsy samples from LN patients. More importantly, in vivo administration of miR-130b agomir reduced IFNα-accelerated progression of LN, with decreased proteinuria, lower levels of immune complex deposition, and lack of glomerular lesions. Conclusion: MicroRNA-130b is a novel negative regulator of the type I IFN pathway in renal cells. Overexpression of miR-130b in vivo ameliorates IFNα-accelerated LN, providing potential novel strategies for therapeutic intervention in LN. © 2016, American College of Rheumatology


PubMed | CAS Shanghai Institutes for Biological Sciences, University of Florida, Shanghai JiaoTong University and Cincinnati Childrens Hospital Medical Center and Cincinnati Medical Center
Type: Journal Article | Journal: Arthritis & rheumatology (Hoboken, N.J.) | Year: 2016

Type I interferon (IFN) is a critical pathogenic factor during the progression of lupus nephritis (LN). Although microRNAs (miRNAs) have been shown to control the IFN response in immune cells in LN, the role of miRNAs in resident renal cells remains unclear. We undertook this study to investigate the role of microRNA-130b (miR-130b) in the IFN pathway in renal cells as well as its therapeutic effect in LN.Kidney tissues from patients and (NZB NZW)F1 lupus-prone mice were collected for detecting miR-130b levels. Primary renal mesangial cells (RMCs) were used to determine the role of miR-130b in the IFN pathway. We overexpressed miR-130b by administering miR-130b agomir in a mouse model of IFN-accelerated LN to test its therapeutic efficacy.Down-regulated miR-130b expression was observed in kidney tissues from patients and lupus-prone mice. Further analysis showed that underexpression of miR-130b correlated negatively with abnormal activation of the IFN response in LN patients. In vitro, overexpressing miR-130b suppressed signaling downstream from the type I IFN pathway in RMCs by targeting IFN regulatory factor 1 (IRF-1). The opposite effect was observed when endogenous miR-130b expression was inhibited. The inverse correlation between IRF1 and miR-130b levels was detected in renal biopsy samples from LN patients. More importantly, in vivo administration of miR-130b agomir reduced IFN-accelerated progression of LN, with decreased proteinuria, lower levels of immune complex deposition, and lack of glomerular lesions.MicroRNA-130b is a novel negative regulator of the type I IFN pathway in renal cells. Overexpression of miR-130b in vivo ameliorates IFN-accelerated LN, providing potential novel strategies for therapeutic intervention in LN.


PubMed | Karolinska Institutet, University of South Australia, Sanatorio Parque, University of Strasbourg and 32 more.
Type: Journal Article | Journal: Arthritis & rheumatology (Hoboken, N.J.) | Year: 2016

More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjgrens syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls.All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction.We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P=0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P=0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients.The estimated prevalence of SLE and SS in women with 47,XXX was 2.5 and 2.9 times higher, respectively, than that in women with 46,XX and 25 and 41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.


PubMed | Wake forest University, Cincinnati Childrens Hospital Medical Center and Cincinnati Medical Center, University of Chicago, Mayo Medical School and 5 more.
Type: Journal Article | Journal: Genes and immunity | Year: 2015

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon-alpha (IFN-) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. About 40-50% of patients have high IFN-, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs low IFN- in over 1550 SLE cases, including genome-wide association study and replication cohorts. In meta-analysis, the top associations in European ancestry were protein kinase, cyclic GMP-dependent, type I (PRKG1) rs7897633 (P(Meta) = 2.75 10(-8)) and purine nucleoside phosphorylase (PNP) rs1049564 (P(Meta) = 1.24 10(-7)). We also found evidence for cross-ancestral background associations with the ankyrin repeat domain 44 (ANKRD44) and pleckstrin homology domain containing, family F member 2 gene (PLEKHF2) loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN- production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic sub-phenotypes becomes an attractive strategy for genetic discovery in complex disease.

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