Olf1/EBF associated zinc finger protein interfered with antinuclear antibody production in patients with systemic lupus erythematosus

Feng, Xuebing; Rong-liang, LI; Huang, Jing; Zhang, Huayong; Zhu, Li; Hua, Bingzhu; Tsao, Betty P.; Sun, Lingyun

doi:10.1186/ar2972

Cited by 8 publications

(14 citation statements)

References 48 publications

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“…Consistent with ours [11], several studies have also provided evidences that the IL-21 pathway plays an important role in the pathogenesis of SLE [18], [19]. The production of IL-21 is mainly restricted to two subsets of CD4 + T cells, Th17 and Tfh.…”

Section: Discussionsupporting

confidence: 87%

“…Previously we have shown there was a nearly perfect correlation between the extent of IL-21 and ANA production in vitro [11], strongly supporting a role of Tfh cell in the developing of SLE. However, it is still unclear how these cells are modulated in SLE.…”

Section: Introductionsupporting

confidence: 57%

“…Of the 42 SLE patients recruited, 29 was reassessed for ANA values, 24 for IgG antibodies to anti-dsDNA and 37 for anti-extractable nuclear antigen using reagents from Euroimmun AG (Lübeck, Germany). Values for ANA were calculated as described [11] and detection range for IgG anti-dsDNA antibody is 10∼800 IU/ml.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Aberrant Circulating Tfh Cell Proportions by Corticosteroids in Patients with Systemic Lupus Erythematosus

et al. 2012

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ObjectiveTo observe the proportion of peripheral T follicular helper (Tfh) cells in patients with systemic lupus erythematosus (SLE) and to assess the role of steroids on Tfh cells from SLE patients.MethodsPeripheral blood mononuclear cells (PBMCs) from 42 SLE patients and 22 matched healthy subjects were collected to assess proportions of circulating CXCR5+PD1+/CD4+ T cells (Tfh), CD4+CCR6+ T cells (Th17-like) and CD19+CD138+ plasma cells by flow cytometry. 8 of the patients had their blood redrawn within one week after receiving methylprednisolone pulse treatment. Disease activity was evaluated by SLE disease activity index. To test the effect of IL-21 and corticosteroids on Tfh cells in vitro, PBMCs harvested from another 15 SLE patients were cultured with medium, IL-21, or IL-21+ dexamethasone for 24 hours and 72 hours. PBMCs from an independent 23 SLE patients were cultured with different concentrations of dexamethasone for 24 hours.ResultsCompared to normal controls, percentages of circulating Tfh cells, but not Th17 cells, were elevated in SLE patients and correlated with disease activity. Proportions of Tfh cells in SLE patients were positively correlated with those of plasma cells and serum levels of antinuclear antibodies. After methylprednisolone pulse treatment, both percentages and absolute numbers of circulating Tfh cells were significantly decreased. In vitro cultures showed an increase of Tfh cell proportion after IL-21 stimulation that was totally abolished by the addition of dexamethasone. Both 0.5 and 1 µM dexamethasone decreased Tfh cells dose dependently (overall p = 0.013).ConclusionsWe demonstrated that elevated circulating Tfh cell proportions in SLE patients correlated with their disease activities, and circulating levels of plasma cells and ANA. Corticosteroids treatment down-regulated aberrant circulating Tfh cell proportions both in vivo and in vitro, making Tfh cells a new treatment target for SLE patients.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionsupporting

confidence: 57%

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Inhibition of Aberrant Circulating Tfh Cell Proportions by Corticosteroids in Patients with Systemic Lupus Erythematosus

et al. 2012

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“…Accell small interfering RNAs (siRNAs) targeting SMG7 (E-021305), glyceraldehyde 3-phosphate dehydrogenase ( GAPDH , as positive control; D-001930) or with non-targeting sequences (as negative control; D-001910) were synthesised by Dharmacon 12. PBMCs from 13 patients with SLE were isolated by Ficoll-Hypaque, resuspended in Accell delivery media plus 3 μM siRNA, distributed to 96-well plates at 2×10 5 cells/well, and divided into silence groups for SMG7 , GAPDH , non-targeting and medium-only mock controls.…”

Section: Methodsmentioning

confidence: 99%

Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

et al. 2016

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Objectives Following up the SLE GWAS identification of NMNAT2 at rs2022013, we fine-mapped its 150kb flanking regions containing NMNAT2 and SMG7 in a 15,292 case-control multi-ancestry population and tested functions of identified variants. Methods We performed genotyping using custom array, imputation by IMPUTE 2.1.2, and allele specific functions using qRT-PCR and luciferase reporter transfections. SLE PBMCs were cultured with siRNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. Results We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (P=2.4×10−8, OR=1.23 [95%CI=1.14–1.32]). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 SLE patients and 119 controls (P=1.1×10−3 and 6.8×10−8, respectively) and conferred reduced transcription activity in transfected HEK-293 and Raji cells (P=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including RNP and Sm. We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titers of SLE patients (r=−0.31, P=0.01), and SMG7 knockdown increased levels of ANA IgG and CCL19 in SLE PBMCs (P=2.0×10−5 and 2.0×10−4, respectively). Conclusions We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk-allele associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.

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“…The underlying causes of diffuse B cell overreactivity in this disease are still unclear. We previously showed that a lupus candidate gene named olfactory 1/early B cell factor–associated zinc‐finger protein (OAZ), identified within the 16q interval in a Chinese cohort (), was highly expressed in patients with SLE and was associated with autoantibody production (). The suppression of OAZ expression in peripheral blood mononuclear cells (PBMCs) from patients with SLE could directly inhibit ANA secretion and reduce total IgG levels, supporting a role of OAZ in the regulation of B cell function ().…”

mentioning

confidence: 99%

Restored Immunosuppressive Effect of Mesenchymal Stem Cells on B Cells After Olfactory 1/Early B Cell Factor–Associated Zinc‐Finger Protein Down‐Regulation in Patients With Systemic Lupus Erythematosus

Feng

Che

Liu

et al. 2014

Arthritis & Rheumatology

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Objective. To evaluate whether olfactory 1/early B cell factor-associated zinc-finger protein (OAZ), a candidate lupus susceptibility gene involved in antinuclear antibody (ANA) production, plays a role in the regulation of B cells by mesenchymal stem cells (MSCs).Methods. MSCs derived from the bone marrow of patients with systemic lupus erythematosus (SLE) and healthy control subjects were expanded and incubated with small interfering RNAs specific for OAZ or a nontargeting sequence. Knockdown of messenger RNA levels of OAZ and its downstream genes was measured using real-time polymerase chain reaction, and protein levels of chemokine/cytokine and immunoglobulins were determined by enzyme-linked immunosorbent assay or Western blotting. The effects of modulating the OAZ levels in MSCs, by either silencing or overexpression, on B cell proliferation and terminal differentiation were assessed by coculturing MSCs with mouse spleen cells. Results. OAZ gene expression was highly enriched in MSCs compared with peripheral blood leukocytes and was increased in patients with

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Olf1/EBF associated zinc finger protein interfered with antinuclear antibody production in patients with systemic lupus erythematosus

Cited by 8 publications

References 48 publications

Inhibition of Aberrant Circulating Tfh Cell Proportions by Corticosteroids in Patients with Systemic Lupus Erythematosus

Inhibition of Aberrant Circulating Tfh Cell Proportions by Corticosteroids in Patients with Systemic Lupus Erythematosus

Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

Restored Immunosuppressive Effect of Mesenchymal Stem Cells on B Cells After Olfactory 1/Early B Cell Factor–Associated Zinc‐Finger Protein Down‐Regulation in Patients With Systemic Lupus Erythematosus

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