Diagnostic and prognostic tests in systemic lupus erythematosus

Wahezi, Dawn M.; Putterman, Chaim

doi:10.1016/j.berh.2017.10.002

Cited by 30 publications

(22 citation statements)

References 97 publications

(118 reference statements)

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“…Conventional serologic ANAs are of limited sensitivity and/or speci city for diagnosis and monitoring in SLE [27]. Here we reported that MLKL mRNA in the PBMCs could differentiate between SLE patients and HC individuals, the AUC was as high as 0.9277 (95% CI 0.878-0.978) with high sensitivity (81.36%) and speci city (93.3%).…”

Section: Discussionmentioning

confidence: 87%

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

Zhang

Jie

et al. 2020

Preprint

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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.

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Section: Discussionmentioning

confidence: 87%

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

Zhang

Jie

et al. 2020

Preprint

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“…Conventional serologic ANAs are of limited sensitivity and/or specificity for diagnosis and monitoring in SLE [27]. Here we reported that MLKL mRNA in the PBMCs could differentiate between SLE patients and HC individuals, the AUC was as high as 0.9277 (95% CI 0.878-0.978) with high sensitivity (81.36%) and specificity (93.3%).…”

Section: Discussionmentioning

confidence: 88%

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

Zhang

Jie

et al. 2020

Preprint

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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.

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“…Secreted antibodies can also be sequenced from other compartments, as shown recently for paired saliva and serum anti-Ro60 precipitins from patients with primary SS [43]. Overall, this first comprehensive proteomic analysis of precipitating anti-dsDNA IgV peptide repertoires in lupus serum offers a fresh approach for characterizing and monitoring anti-dsDNA clonal populations with MS precision and accuracy, and for comparing their molecular signatures with other high-throughput 'omics' technologies [47]. As the high-affinity, somatically mutated anti-dsDNA autoantibodies profiled herein can be considered to reflect germinal centre-dependent responses, a priority will be to investigate IgV peptide signatures as companion diagnostics for biological therapeutics thought to block autoimmune germinal centre reactions, notably via CD40 ligand blockade [44,45].…”

Section: Discussionmentioning

confidence: 96%

“…In this regard, we have recently used MRM/MS with HCDR3 peptides to track serum rheumatoid factor (RF) clonotypes in patients with primary SS and mixed cryoglobulinaemia, and shown that pathogenic RF signatures appear years before clinical presentation [46]. Overall, this first comprehensive proteomic analysis of precipitating anti-dsDNA IgV peptide repertoires in lupus serum offers a fresh approach for characterizing and monitoring anti-dsDNA clonal populations with MS precision and accuracy, and for comparing their molecular signatures with other high-throughput 'omics' technologies [47].…”

Section: Discussionmentioning

confidence: 99%

Precipitating anti-dsDNA peptide repertoires in lupus

Wang

Colella

Beroukas

et al. 2018

Clinical and Experimental Immunology

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Anti-double-stranded (ds)DNA autoantibodies are prototypical serological markers of systemic lupus erythematosus (SLE), but little is known about their immunoglobulin variable (IgV) region composition at the level of the secreted (serum) proteome. Here, we use a novel proteomic workflow based on de novo mass spectrometric sequencing of anti-dsDNA precipitins to analyse IgV subfamily expression and mutational signatures of high-affinity, precipitating anti-dsDNA responses. Serum anti-dsDNA proteomes were oligoclonal with shared (public) expression of immunoglobulin (Ig)G heavy chain variable region (IGHV) and kappa chain variable region (IGKV) subfamilies. IgV peptide maps from eight subjects showed extensive public and random (private) amino acid replacement mutations with prominent arginine substitutions across heavy (H)- and light (L)-chains. Shared sets of L-chain complementarity determining region 3 (CDR3) peptides specified by arginine substitutions were sequenced from the dominantly expressed IGKV3-20 subfamily, with changes in expression levels of a clonal L-chain CDR3 peptide by quantitative multiple reaction monitoring (MRM) paralleling the rise and fall of anti-dsDNA levels by Farr radioimmunoassays (RIA). The heavily mutated IgV peptide signatures of precipitating anti-dsDNA autoantibody proteomes reflect the strong selective forces that shape humoral anti-dsDNA responses in germinal centres. Direct sequencing of agarose gel precipitins using microlitre volumes of stored sera streamlines the antibody sequencing workflow and is generalizable to other precipitating serum antibodies.

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Diagnostic and prognostic tests in systemic lupus erythematosus

Cited by 30 publications

References 97 publications

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

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

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

Precipitating anti-dsDNA peptide repertoires in lupus

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