Abstract
IntroductionThe aim of the study was to determine whether Olf1/EBF associated zinc finger protein (OAZ), a transcription factor encoded by a positional systemic lupus erythematosus (SLE) candidate gene, plays a functional role in the pathogenesis in SLE.MethodsGene expression levels in peripheral blood cells (PBLs) measured using quantitative real-time polymerase chain reaction (qPCR) were assessed for association with disease activity and the presence of specific autoantibodies. Peripheral blood mononuclear cells (PBMCs) were incubated with specific siRNAs for three days, then cells were harvested for measuring mRNA levels using qPCR, and supernatants for levels of total immunoglobulin (Ig)G and IgM as well as secreted cytokines, chemokine and antinuclear antibodies (ANA) using ELISA. Indirect immunofluorescence was also applied for ANA detection.ResultsOAZ gene expressions in PBLs from 40 ANA-positive SLE patients were significantly increased than those from 30 normal controls (P < 0.0001) and 18 patients with rheumatoid arthritis (P < 0.01). In SLE patients, OAZ transcripts were positively correlated with SLE disease activity index (SLEDAI) score (r = 0.72, P < 0.0001) and higher in those positive for anti-dsDNA or anti-Sm antibodies (both P < 0.05). Co-culturing with OAZ siRNAs reduced mRNA levels of OAZ by 74.6 ± 6.4% as compared to those co-cultured with non-targeting siRNA and OAZ silencing resulted in reduced total IgG, ANA, interferon (IFN)-γ, interleukin (IL)-10, IL-12 and IL-21, but elevated CCL2 levels in culture supernatants (P < 0.05). The declined ANA levels correlated with inhibited OAZ expression (r = 0.88, P = 0.05), reduced IL-21 levels (r = 0.99, P < 0.01), and elevated chemokine (C-C motif) ligand 2 levels (r = -0.98, P < 0.01). Expressions of ID1-3 were significantly down-regulated by 68.7%, 70.2% and 67.7% respectively after OAZ silence, while ID3 was also highly expressed in SLE PBLs (P < 0.0001) and associated with disease activity (r = 0.76, P < 0.0001) as well as anti-dsDNA or anti-Sm antibodies (both P < 0.05).ConclusionsElevated expression of OAZ transcripts in SLE PBLs were strongly correlated with disease activity. Suppression of OAZ expression inhibited downstream ID levels, and secretion of ANA and IL-21, implicating a role of OAZ pathway in the pathogenesis of SLE.
Highlights
The aim of the study was to determine whether Olf1/early B cell (EBF) associated zinc finger protein (OAZ), a transcription factor encoded by a positional systemic lupus erythematosus (SLE) candidate gene, plays a functional role in the pathogenesis in SLE
Our studies showed that Olf1/EBF associated zinc finger protein (OAZ) mRNA levels in peripheral blood cells were elevated in SLE patients as compared to those in either normal or disease controls (RA patients)
OAZ expressions were negatively correlated with methylprednisolone doses, implying that there should be an even greater elevation of OAZ expression in those patients with high SLE disease activity index (SLEDAI) scores because they were treated with high dose of steroids
Summary
The aim of the study was to determine whether Olf1/EBF associated zinc finger protein (OAZ), a transcription factor encoded by a positional systemic lupus erythematosus (SLE) candidate gene, plays a functional role in the pathogenesis in SLE. Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with relatively strong genetic components that genome wide linkage scans performed in the past decade have identified chromosome 16p12.3 to q12.2 to be the second-strongest locus linked to SLE after HLA (6p22.3 to 6p21.1) [1,2,3,4,5,6,7,8]. Fine mapping experiments of the chromosome 16p locus have shown multiple association signals clustering in several regions [8,12], suggesting more than one gene may be involved in the increased risk of SLE. Genotyping of five SNPs within intron 4 and intron 5 of OAZ reveals preferential transmission of haplotypes containing SNPs and/or the SLEassociated D16S517 allele [14], suggesting OAZ may be a positional candidate gene within the 16q interval
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