Project description:Post-translational modifications (PTMs) are considered to be an important factor in the pathogenesis of SLE. Lysine 2-hydroxyisobutyryl (Khib), as an emerging post-translational modification of proteins, is involved in some important biological metabolic activities. We compared the Khib levels of SLE patients and healthy controls based on liquid chromatography-tandem mass spectrometry, and then performed proteomic analysis. The results showed that Khib in SLE patients was up-regulated at 865 sites of 416 proteins and down-regulated at 630 sites of 349 proteins. The site abundance, distribution and function of Khib protein were further analyzed. Bioinformatics analysis showed that complement, coagulation cascade and platelet activation in immune-related pathways were significantly enriched, indicating that the differential modification proteins between them might affect SLE.
Project description:Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that displays a significant gender difference in terms of incidence and severity. However, the underlying mechanisms accounting for sexual dimorphism remain unclear. To reveal the heterogeneity in the pathogenesis of SLE between male and female patients. PBMC were collected from 15 patients with SLE (7 males, 8 females) and 15 age-matched healthy controls (7 males, 8 females) for proteomic analysis. Enrichment analysis of proteomic data revealed that type I interferon signaling and neutrophil activation networks mapped to both male and female SLE, while male SLE has a higher level of neutrophil activation compared with female SLE. Our findings define gender heterogeneity in the pathogenesis of SLE and may facilitate the development of gender-specific treatments.
Project description:To clarify the role of interferon regulatory factor 5 (IRF5) other than inducing type I interferons (IFNs) in the pathogenesis of systemic lupus erythematosus (SLE), we performed transcriptome analysis of peripheral blood from Lyn-deficient mice with concomitant Ifnar1 or Irf5 deficiency. The results of gene set enrichment analysis (GSEA) suggest that IRF5 is involved in the induction of not only IFN-inducible genes (ISGs) but also oxidative phosphorylation (OXPHOS)-related genes in the SLE pathogenesis.
Project description:The aim of the study was to test the hypothesis that SLE patient sera contains IgG reactivity to serum factor antigens concomitant with prototypical autoimmne antigens. We diluted patient sera 1:250 and incubated dilutions on a nitrocellulose-platform array printed with whole protein antigens. In this study, serum from 45 individuals (subsetted into high and low interferon signature as well as healthy control categories) was profiled for IgG autoantibody reactivity to whole protein autoimmune and serum factor antigens. SLE and specifically IFN high patient sera was found using the significance analysis of microarrays (SAM) algorithm to be significantly more reactive with prototypical autoimmune antigens and select serum factor array antigens.
Project description:Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3,073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we constructed a massively parallel reporter assays (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into Epstein-Barr virus-transformed B cell line GM12878 revealed 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Combined with allelic enhancer activity analyses in Jurkat cell line, we identified shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around 51 allelic variants identified one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second, larger class of TFs that also bind allelically but do not have their motifs directly altered by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.