Elevated serum levels of soluble membrane cofactor protein (CD46, MCP) in patients with systemic lupus erythematosus (SLE)

AbstractAPOBEC3 (A3) enzymes are best known for their role as antiviral restriction factors and as mutagens in cancer. Although four of them, A3A, A3B, A3F and A3G, are induced by type-1-interferon (IFN-I), their role in inflammatory conditions is unknown. We thus investigated the expression of A3, and particularly A3A and A3B because of their ability to edit cellular DNA, in Systemic Lupus Erythematosus (SLE), a chronic inflammatory disease characterized by high IFN-α serum levels. In a cohort of 57 SLE patients, A3A and A3B, but also A3C and A3G, were upregulated ~ 10 to 15-fold (> 1000-fold for A3B) compared to healthy controls, particularly in patients with flares and elevated serum IFN-α levels. Hydroxychloroquine, corticosteroids and immunosuppressive treatment did not reverse A3 levels. The A3AΔ3B polymorphism, which potentiates A3A, was detected in 14.9% of patients and in 10% of controls, and was associated with higher A3A mRNA expression. A3A and A3B mRNA levels, but not A3C or A3G, were correlated positively with dsDNA breaks and negatively with lymphopenia. Exposure of SLE PBMCs to IFN-α in culture induced massive and sustained A3A levels by 4 h and led to massive cell death. Furthermore, the rs2853669 A > G polymorphism in the telomerase reverse transcriptase (TERT) promoter, which disrupts an Ets-TCF-binding site and influences certain cancers, was highly prevalent in SLE patients, possibly contributing to lymphopenia. Taken together, these findings suggest that high baseline A3A and A3B levels may contribute to cell frailty, lymphopenia and to the generation of neoantigens in SLE patients. Targeting A3 expression could be a strategy to reverse cell death and the generation of neoantigens.

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Elevated serum levels of cyclo (His-Pro), an endogenous inhibitor of pituitary prolactin secretion, in systemic lupus erythematosus patients

Lupus ◽

10.1177/096120339700600308 ◽

1997 ◽

Vol 6 (3) ◽

pp. 258-260 ◽

Cited By ~ 6

Author(s):

L.J. Jara ◽

C. Prasad ◽

L.R. Espinoza

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Elevated Serum ◽

Serum Levels ◽

Prolactin Secretion ◽

Endogenous Inhibitor ◽

Systemic Lupus ◽

Pituitary Prolactin

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Elevated serum complement levels and higher gene copy number of complement C4B are associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

Lupus Science & Medicine ◽

10.1136/lupus-2019-000333 ◽

2019 ◽

Vol 6 (1) ◽

pp. e000333 ◽

Cited By ~ 3

Author(s):

Evan Mulvihill ◽

Stacy Ardoin ◽

Susan D Thompson ◽

Bi Zhou ◽

Gakit Richard Yu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Elevated Serum ◽

Gene Copy Number ◽

Serum Levels ◽

Gene Copy ◽

Childhood Onset ◽

Systemic Lupus ◽

Effective Response ◽

Atorvastatin Treatment

ObjectiveSystemic lupus erythematosus (SLE) features high frequency of cardiovascular disease (CVD) and fluctuating complement levels. The clinical trial Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) aimed to evaluate whether atorvastatin treatment reduced the progression of atherosclerosis in 221 patients with childhood-onset SLE (cSLE), using carotid intima media thickness (CIMT) as surrogates. We leveraged APPLE biorepository and trial data to investigate the relationship between complement and CVD in cSLE.MethodsGene copy numbers (GCNs) for total C4, C4A and C4B were measured by TaqMan-based real-time PCR and Southern blotting, and analysed with laboratory and clinical parameters through Student’s t-test and χ2 analyses. Effects of total C4, C4A and C4B GCNs on the response to placebo or atorvastatin treatment and progression of CIMT were examined by regression analyses.ResultsAt baseline, C4 protein levels strongly correlated with GCNs of total C4 (p=1.8×10−6). Each copy of C4 gene increased mean serum C4 by 3.28 mg/dL. Compared with those without hypertension (N=142), individuals with hypertension demonstrated significantly elevated serum levels for C4 and C3 at baseline and serially (C4: P=5.0×10−25; C3: P=5.84×10−20). Individuals with ≥2 C4B genes had 2.5 times the odds of having hypertension (p=0.016) and higher diastolic blood pressure (p=0.015) compared with those with C4B deficiency. At the study end, subjects with ≥2 C4B and atorvastatin treatment had significantly slower increase in CIMT compared with those treated with placebo (p=0.018).ConclusionscSLE with hypertension had elevated serum levels of C4 and C3 and higher GCN of C4B; cSLE with ≥2 C4B genes would benefit from statins therapy to prevent atherosclerosis.

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Elevated Serum Levels of Interferon-Regulated Chemokines Are Biomarkers for Active Human Systemic Lupus Erythematosus

PLoS Medicine ◽

10.1371/journal.pmed.0030491 ◽

2006 ◽

Vol 3 (12) ◽

pp. e491 ◽

Cited By ~ 198

Author(s):

Jason W Bauer ◽

Emily C Baechler ◽

Michelle Petri ◽

Franak M Batliwalla ◽

Dianna Crawford ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Elevated Serum ◽

Serum Levels ◽

Human Systemic Lupus Erythematosus ◽

Systemic Lupus

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Pro-inflammatory S100 proteins are associated with glomerulonephritis and anti-dsDNA antibodies in systemic lupus erythematosus

Lupus ◽

10.1177/0961203316655208 ◽

2016 ◽

Vol 26 (2) ◽

pp. 139-149 ◽

Cited By ~ 23

Author(s):

H Tydén ◽

C Lood ◽

B Gullstrand ◽

A Jönsen ◽

F Ivars ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Clinical Phenotype ◽

Elevated Serum ◽

Serum Levels ◽

Systemic Lupus ◽

Time Points ◽

Paired Samples ◽

Dsdna Antibodies

Objectives Systemic lupus erythematosus (SLE) is associated with elevated levels of S100A8/A9, pro-inflammatory proteins mainly secreted by activated polymorphonuclear neutrophils (PMNs). The underlying mechanisms for increased S100A8/A9 levels and their relation to the clinical phenotype have not been carefully investigated. We assessed S100A8/A9 and S100A12 levels in SLE patient sera in relation to disease activity, clinical phenotype, presence of anti-dsDNA antibodies and ability to promote phagocytosis of necrotic cells (NCs) by PMNs. Methods Serum levels of S100A8/A9 and S100A12 were measured by ELISA in paired samples of 100 SLE patients at time points of higher and lower disease activity. Serum-mediated phagocytosis of NCs by PMNs was analysed by flow cytometry. Clinical data were recorded at time points of blood sampling. Results Serum levels of S100A8/A9 and S100A12 were increased in SLE patients with high disease activity compared to paired samples at low disease activity ( p = 0.01 and p = 0.008, respectively). Elevated levels of S100A8/A9 were particularly seen in patients with anti-dsDNA antibodies ( p = 0.01) and glomerulonephritis before treatment ( p = 0.02). Immunosuppressive therapy was associated with a reduction of S100A8/A9 serum levels ( p = 0.002). The ability of serum to support phagocytosis of NCs by PMNs was related to increased S100A8/A9 levels ( p = 0.01). Conclusions Elevated serum levels of S100A8/A9 may be used to monitor disease activity and response to treatment in SLE patients, especially in patients with glomerulonephritis. S100A12 may be a marker of disease activity in SLE. Increased S100A8/A9 levels may reflect immune-pathological processes involving phagocytosis of immune complexes by PMNs.

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Interleukin 6 (IL-6) Deficiency Delays Lupus Nephritis in MRL-FaslprMice: The IL-6 Pathway as a New Therapeutic Target in Treatment of Autoimmune Kidney Disease in Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.090194 ◽

2009 ◽

Vol 37 (1) ◽

pp. 60-70 ◽

Cited By ~ 101

Author(s):

HANNES CASH ◽

MANFRED RELLE ◽

JULIA MENKE ◽

CHRISTOPH BROCHHAUSEN ◽

SIMON A. JONES ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Nephritis ◽

Adhesion Molecule ◽

Lupus Erythematosus ◽

Interleukin 6 ◽

Therapeutic Target ◽

Elevated Serum ◽

Serum Levels ◽

Control Group ◽

Systemic Lupus

Objective.To investigate the pathophysiological effect of interleukin 6 (IL-6) on lupus nephritis in MRL-Faslprmice.Methods.We generated IL-6-deficient MRL-Faslprmice using a backcross/intercross breeding scheme. Renal pathology was evaluated using immunohistochemistry detection for macrophages, lymphocytes, vascular cell adhesion molecule-1 (VCAM-1), and TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick end-labeling) for apoptotic cells, and renal IgG and C3 deposition by immunofluorescence staining. Expression of inflammatory markers in the spleen was analyzed by quantitative real-time reverse transcription-polymerase chain reaction. Serum cytokine concentrations were detected by FACS analysis.Results.IL-6 deficiency was highly effective in prolonging survival and ameliorating the clinical, immunological, and histological indicators of murine systemic lupus erythematosus. During the study period of 6 months, MRL-FaslprIL-6 −/− mice showed delayed onset of proteinuria and hematuria compared to IL-6-intact control mice. Survival rate was 100% in IL-6-deficient MRL-Faslprmice and 25% in the control group at 6 months of age. The absence of IL-6 resulted in significant reduction of infiltrating macrophages in the kidney (p < 0.05), a decrease in renal IgG and C3 deposition, and a reduction of CD4+ and CD8+ lymphocytes. The parenchymal adhesion molecule VCAM-1 was found to be downregulated in kidneys of MRL-FaslprIL-6 −/− compared to IL-6-intact mice. We found elevated serum levels of IL-10 and interferon-γ in IL-6-deficient mice, while splenic mRNA showed an overall downregulation of immunoregulatory genes.Conclusion.IL-6 is a strong promoter of lupus nephritis and may be a promising new therapeutic target in the treatment of human lupus nephritis.

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