scholarly journals Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement, and SLE disease activity

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Mingjiao Zhang ◽  
Hongyu Jie ◽  
Yong Wu ◽  
Xinai Han ◽  
Xing Li ◽  
...  
Keyword(s):  
Disease Activity ◽  
Lupus Erythematosus ◽  
Antinuclear Antibodies ◽  
Mononuclear Cells ◽  
Mrna Level ◽  
Renal Involvement ◽  
Pcr Analysis ◽  
Peripheral Blood Mononuclear ◽  
Autoantibody Production ◽  
Regulated Necrosis

Abstract Background Necroptosis is a form of regulated necrosis that is involved in various autoimmune diseases. Mixed lineage kinase domain-like pseudokinase (MLKL) has been identified as a key executor of necroptosis; however, the significance of MLKL in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) has not been investigated. In this study, we aimed to determine the mRNA level of MLKL in PBMCs and examine its relationship with clinical features and serological parameters in SLE. Methods Real-time transcription-polymerase chain reaction (RT-PCR) analysis was used to determine the expression of MLKL mRNA in PBMCs from 59 patients with SLE, 25 patients with rheumatoid arthritis (RA), and 30 age- and sex-matched healthy controls (HC). Spearman’s correlation test was performed to assess the correlation of MLKL mRNA with clinical variables. The receiver operating characteristic (ROC) curve was created to evaluate the diagnostic value. Results Our results showed MLKL mRNA in PBMCs was upregulated in SLE patients compared to that in RA and HC individuals. SLE patients positive for antinuclear antibodies had significantly higher MLKL mRNA than antibody-negative patients. In SLE patients, MLKL mRNA was found to be upregulated in patients with lupus nephritis (LN) as compared with patients without LN, and also higher in active patients than in stable patients. MLKL mRNA level was significantly and positively correlated with c-reaction protein (CRP) (r = 0.3577, p = 0.0237), erythrocyte sedimentation rate (ESR) (r = 0.4091, p = 0.0043), serum immunoglobulin G (IgG) concentration (r = 0.3546, p = 0.0289), and the numbers of positive antinuclear antibodies (ANAs) (r = 0.3945, p = 0.0432). ROC analysis showed that MLKL mRNA in PBMCs had an area under the curve of 0.9277 (95% CI 0.8779–0.9775, p < 0.001) to discriminate SLE from controls. Conclusions These results suggest that increased MLKL mRNA level in the PBMCs of SLE patients is correlated with renal involvement and disease activity, identifying a subgroup of patients with SLE or LN who may benefit from early diagnosis and therapies targeting MLKL.

scholarly journals Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement and SLE disease activity

2020 ◽  
Author(s):  
Mingjiao Zhang ◽  
Hongyu Jie ◽  
Yong Wu ◽  
Xinai Han ◽  
Xing Li ◽  
...  
Keyword(s):  
Disease Activity ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Characteristic Curve ◽  
Mrna Level ◽  
Renal Involvement ◽  
Area Under The Curve ◽  
Peripheral Blood Mononuclear ◽  
Autoantibody Production ◽  
Regulated Necrosis

Abstract Background Necroptosis is a form of regulated necrosis that is involved in various autoimmune diseases. Mixed lineage kinase domain-like pseudokinase (MLKL) has been identified as a key executor of necroptosis, however, the significance of MLKL in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) has not been investigated. In this study, we aimed to determine the mRNA level of MLKL in PBMCs and examine its relationship with clinical features and serological parameters in SLE. Methods Real-time transcription-polymerase chain reaction analysis (RT-PCR) was used to determine expression of MLKL mRNA in PBMCs from 59 patients with SLE, 25 patients with rheumatoid arthritis (RA) and 30 age- and sex-matched healthy controls(HC). Spearman's correlation test was performed to assess the correlation of MLKL mRNA with clinical variables. The receiver operating characteristic curve (ROC) was created to evaluate the diagnostic value. Results Our results showed MLKL mRNA in PBMCs was upregulated in SLE patients compared to that in RA and HC individuals. SLE patients positive for anti-nuclear antibodies had significantly higher MLKL mRNA than antibody-negative patients. In SLE patients, MLKL mRNA was found to be upregulated in patients with lupus nephritis (LN) as compared with patients without LN, and also higher in active patients than in stable patients. MLKL mRNA level was significantly and positively correlated with c-reaction protein (CRP) (r = 0.3577, p = 0.0237), erythrocyte sedimentation rate (ESR) (r = 0.4091, p = 0.0043), serum immunoglobulin G (IgG) concentration (r = 0.3546, p = 0.0289) and the numbers of positive antinuclear antibodies (ANAs) (r = 0.3945, p = 0.0432). ROC analysis showed that MLKL mRNA in PBMCs had an area under the curve of 0.9277 (95% CI 0.8779–0.9775, p < 0.001) to discriminate SLE from controls. Conclusions These results suggest that increased MLKL mRNA level in the PBMCs of SLE patients is correlated with renal involvement and disease activity, identifying a subgroup of patients with SLE or LN who may benefit from early diagnosis and therapies targeting MLKL.

scholarly journals Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement and SLE disease activity

2020 ◽  
Author(s):  
Mingjiao Zhang ◽  
Hongyu Jie ◽  
Yong Wu ◽  
Xinai Han ◽  
Xing Li ◽  
...  
Keyword(s):  
Disease Activity ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Characteristic Curve ◽  
Mrna Level ◽  
Renal Involvement ◽  
Area Under The Curve ◽  
Peripheral Blood Mononuclear ◽  
Autoantibody Production ◽  
Regulated Necrosis

Abstract Background: Necroptosis is a form of regulated necrosis that is involved in various autoimmune diseases. Mixed lineage kinase domain-like pseudokinase (MLKL) has been identified as a key executor of necroptosis, however, the significance of MLKL in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) has not been investigated. In this study, we aimed to determine the mRNA level of MLKL in PBMCs and examine its relationship with clinical features and serological parameters in SLE. Methods: Real-time transcription-polymerase chain reaction analysis (RT-PCR) was used to determine expression of MLKL mRNA in PBMCs from 59 patients with SLE, 25 patients with rheumatoid arthritis (RA) and 30 age- and sex-matched healthy controls(HC). Spearman's correlation test was performed to assess the correlation of MLKL mRNA with clinical variables. The receiver operating characteristic curve (ROC) was created to evaluate the diagnostic value. Results: Our results showed MLKL mRNA in PBMCs was upregulated in SLE patients compared to that in RA and HC individuals. SLE patients positive for anti-nuclear antibodies had significantly higher MLKL mRNA than antibody-negative patients. In SLE patients, MLKL mRNA was found to be upregulated in patients with lupus nephritis (LN) as compared with patients without LN, and also higher in active patients than in stable patients. MLKL mRNA level was significantly and positively correlated with c-reaction protein (CRP) (r=0.3577, p=0.0237), erythrocyte sedimentation rate (ESR) (r=0.4091, p=0.0043), serum immunoglobulin G (IgG) concentration (r=0.3546, p=0.0289) and the numbers of positive antinuclear antibodies (ANAs) (r=0.3945, p=0.0432). ROC analysis showed that MLKL mRNA in PBMCs had an area under the curve of 0.9277 (95% CI 0.8779 - 0.9775, p<0.001) to discriminate SLE from controls.Conclusions: These results suggest that increased MLKL mRNA level in the PBMCs of SLE patients is correlated with renal involvement and disease activity, identifying a subgroup of patients with SLE or LN who may benefit from early diagnosis and therapies targeting MLKL.

scholarly journals CD4+CD45RA−FOXP3low Regulatory T Cells as Potential Biomarkers of Disease Activity in Systemic Lupus Erythematosus Brazilian Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Helena L. Silva-Neta ◽  
Maria C. A. Brelaz-de-Castro ◽  
Mardonny B. O. Chagas ◽  
Henrique A. Mariz ◽  
Rodrigo G. de Arruda ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Linear Regression ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Potential Biomarkers

Heren, we analyzed Treg cells as potential biomarkers of disease activity in systemic lupus erythematosus (SLE) patients. Peripheral blood mononuclear cells from 30 SLE patients (15 active: SLEDAI > 6/15 SLE remission: SLEDAI< 6) and 15 healthy volunteers were purified. Treg immunophenotyping was performed using CD4, CD25, CD45, CD127, and FOXP3 markers. CD4+FOXP3+ Treg activation state was investigated based on CD45RA and FOXP3 expression. To increase the accuracy of our findings, a multivariate linear regression was performed. We showed a significant increase in the frequency of CD4+FOXP3+ Treg cells in SLE patients. However, unlike all other Treg cells phenotypes analyzed, only eTreg (CD4+FOXP3highCD45RA-) (p=0.01) subtype was inversely correlated with disease activity while Foxp3+nontreg (CD4+FOXP3lowCD45RA-) (p=0.003) exerted a direct influence in the outcome of the disease. Foxp3+nontreg cells were the most consistent SLE active indicator, confirmed by multiple linear regression analyses. In summary, our results demonstrate Foxp3+nontreg cells as new biomarkers in the search of an effective therapeutic strategy in SLE.

scholarly journals Hemoglobin drives inflammation and initiates antigen spread and nephritis in lupus

2020 ◽  
Author(s):  
Hritika Sharma ◽  
Anjali Bose ◽  
Uma Kumar ◽  
Rahul Pal
Keyword(s):  
T Cells ◽  
B Cells ◽  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Peripheral Blood Mononuclear ◽  
Autoantibody Production

AbstractHemoglobin (Hb) has well-documented inflammatory effects and is normally efficiently scavenged; clearance mechanisms can be overwhelmed during conditions of erythrocyte lysis, a condition that may occur in systemic lupus erythematosus. Whether Hb is preferentially inflammatory in lupus and additionally induces autoreactivity against prominent autoantigens was assessed. Peripheral blood mononuclear cells derived from SLE patients secreted higher levels of lupus-associated inflammatory cytokines when incubated with Hb, effects negated by haptoglobin. Hb (more particularly, ferric Hb) triggered the preferential release of lupus-associated cytokines from splenocytes, B cells, CD4 T cells, CD8 T cells and plasmacytoid dendritic cells isolated from aging NZM2410 mice, and also had mitogenic effects on B cells. Ferric Hb activated multiple signaling pathways which were differentially responsible for the generation of specific cytokines; inflammatory signaling also appeared to be cell-context dependent. Pull-downs, followed by mass spectrometry, revealed interactions of Hb with several lupus-associated autoantigens; co-incubation of ferric Hb with apoptotic blebs (structures which contain packaged autoantigens, believed to trigger lupus autoreactivity) revealed synergies (in terms of cytokine release and autoantibody production in vitro) that were also restricted to the lupus genotype. Infusion of ferric Hb into NZM2410 mice led to enhanced release of lupus-associated cytokines, the generation of a spectrum of autoantibodies, and enhanced-onset glomerulosclerosis. Given that the biased recognition of ferric Hb in a lupus milieu, in concert with lupus-associated autoantigens, elicits the generation of inflammatory cytokines from multiple immune cell types and stimulates the generation of potentially pathogenic autoantibodies, neutralization of Hb could have beneficial effects.

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