Genome-wide analysis of atypical NK cell subset in mouse model of Systemic Lupus Erythematosus (SLE)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Silvia Bolland
PROVIDER: E-GEOD-63829 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:TLR7/8 and TLR9 signaling pathways have been extensively studied in systemic lupus erythematosus (SLE) as possible mediators of disease. Monocytes are a major source of pro-inflammatory cytokines and are understudied in SLE. In the current project, we investigated sex differences in monocyte activation and its implications in SLE disease pathogenesis.Human blood samples from 27 healthy male controls, 32 healthy female controls, and 25 female patients with SLE matched for age and race were studied. Monocyte activation was tested by flow cytometry and ELISA, including subset proportions, CD14, CD80 and CD86 expression, the percentage of IL-6-producing monocytes, plasma levels of sCD14 and IL-6, and urine levels of creatinine.Monocytes were significantly more activated in women compared to men and in patients with SLE compared to controls in vivo. We observed increased proportions of non-classic monocytes, decreased proportions of classic monocytes, elevated levels of plasma sCD14 as well as reduced surface expression of CD14 on monocytes comparing women to men and lupus patients to controls. Plasma levels of IL-6 were positively related to sCD14 and serum creatinine.Monocyte activation and TLR4 responsiveness are altered in women compared to men and in patients with SLE compared to controls. These sex differences may allow persistent systemic inflammation and resultant enhanced SLE susceptibility.
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Project description:The indicated thymic progenitor population was sorted via FACS and then loaded into a Fluidigm C1 small cell capture chip for single-cell capture, lysis, reverse transcription, and preamplification. Preamplified products were analyzed on a BioMark HD with EvaGreen chemistry. The genes analyzed were selected based on bulk RNA sequencing data and/or prior publications, including genes relevant for gamma/delta T cells and T cell progenitors. B6=C57BL/6J, Rag=B6.Rag1-/-, Tcrd=B6.Tcrd-/-, DN1d=Live/TCRd-/Lin-/CD44+/CD25-/CD24+/cKit-, DN2=Live/TCRd-/Lin-/CD44+/CD25+/cKit+, cKit-=Live/TCRd-/Lin-/CD44+/CD25-/cKit-. Lin=CD3/CD8/CD11b/CD11c/CD19/Gr-1/NK1.1/TCRb/Ter-119 Sample naming nomenclature is as follows: MouseLine_CellPopoulation_DateCaptured_CaptureChamber_CellNumberInChamber
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Project description:We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta?=?1.92?×?10-13, OR?=?1.14), ATG16L2 (rs11235604, Pmeta?=?8.87?×?10?-12, OR?=?0.78), CCL22 (rs223881, Pmeta?=?5.87?×?10-16, OR?=?0.87), ANKS1A (rs2762340, Pmeta?=?4.93?×?10-15, OR?=?0.87) and RNASEH2C (rs1308020, Pmeta?=?2.96?×?10-19, OR?=?0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2?>?0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81?×?10-198?<?P?<?5?×?10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P?<?0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.
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