Urinary Proteomics Identifying Novel Biomarkers for the Diagnosis of Adult-Onset Still’s Disease

Sun, Yue; Wang, Fan; Zhou, Zhongzheng; Teng, Jialin; Su, Yutong; Chi, Huihui; Wang, Zhihong; Hu, Qiongyi; Jia, Jieshuang; Liu, Tingting; Liu, Honglei; Cheng, Xiaobing; Shi, Hui; Tan, Yun Long; Yang, Chengde; Ye, Junna

doi:10.3389/fimmu.2020.02112

Cited by 21 publications

(21 citation statements)

References 44 publications

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“…As already demonstrated elsewhere (32), cells in whole blood remained comparably unresponsive to recombinant IL-1β, likely due to blockade or decoy of IL-1β by endogenous IL-1Ra and IL-1R2, respectively. Studies in context with other in ammatory conditions such as on Adultonset Still's Disease (AOSD) (33) or Crohn's Disease (34) similarly suggest an association of IL-1β and LRG1 expression. In contrast, studies linking LRG1 with IL-6 or TNF signaling report rather contradictory results (33,35,36), which are thus partly in line (34,35) with the weak associations observed among our KD data.…”

Section: Discussionmentioning

confidence: 97%

An Immunological Axis Involving Interleukin 1β and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial

Kessel

Koné‐Paut

Tellier

et al. 2022

Preprint

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Purpose A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki Disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. Methods Patients’ and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1β were analyzed for single or multiple marker (n=22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. Results Inflammation in IVIG-resistant KD (n=16) is hallmarked by over-expression of innate immune mediators (particularly IL-6>CXCL10>S100A12>IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n=13) and MIS-C (n=4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1β signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1β resulted in concentration-dependent LRG1 release. Conclusion Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modelling to associate with IL-1β signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.

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Section: Discussionmentioning

confidence: 97%

An Immunological Axis Involving Interleukin 1β and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial

Kessel

Koné‐Paut

Tellier

et al. 2022

Preprint

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“…Besides, collecting urine samples is more convenient and causes less pain in patients than while collecting blood samples. We previously reported a study in adult-onset Still’s disease (AOSD) and found that urine α-1-acid glycoprotein 1 (LRG1), orosomucoid 1 (ORM1), and ORM2 might be new biomarkers of AOSD ( 11 ). Similarly, in this study, we analyzed urine proteomics to identify new biomarkers that might help differentiate TAPS from OAPS.…”

Section: Discussionmentioning

confidence: 99%

“…All the patients recruited in our study were treatment-naïve, without receiving any anticoagulant therapy. Proteomics analysis was performed by protocol as previously used by our group to identify differentially expressed proteins in the urine ( 11 ). In the validation cohort, urine samples of 19 patients with primary OAPS, 21 patients with primary TAPS, 13 HCs with positive aPL antibodies (APL carriers), 20 patients with miscarriages (non-autoimmune), 21 patients with thrombosis (non-autoimmune), 30 patients with SLE, 30 patients with RA and 30 HCs were tested by enzyme-linked immunosorbent assay (ELISA).…”

Section: Methodsmentioning

confidence: 99%

Urine Proteomics Differentiate Primary Thrombotic Antiphospholipid Syndrome From Obstetric Antiphospholipid Syndrome

et al. 2021

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Antiphospholipid syndrome (APS) is a multisystem disorder characterized by thrombosis and/or recurrent fetal loss. This clinical phenotype heterogeneity may result in differences in response to treatment and prognosis. In this study, we aimed to identify primary thrombotic APS (TAPS) from primary obstetric APS (OAPS) using urine proteomics as a non-invasive method. Only patients with primary APS were enrolled in this study from 2016 to 2018 at a single clinical center in Shanghai. Urine samples from 15 patients with TAPS, 9 patients with OAPS, and 15 healthy controls (HCs) were collected and analyzed using isobaric tags for relative and absolute quantification (iTRAQ) labeling combined with liquid chromatography-tandem mass spectrometry analysis to identify differentially expressed proteins. Cluster analysis of urine proteomics identified differentiated proteins among the TAPS, OAPS, and HC groups. Urinary proteins were enriched in cytokine and cytokine receptor pathways. Representative secreted cytokines screened out (fold change >1.20, or <0.83, p<0.05) in these differentiated proteins were measured by enzyme-linked immunosorbent assay in a validation cohort. The results showed that the levels of C-X-C motif chemokine ligand 12 (CXCL12) were higher in the urine of patients with TAPS than in those with OAPS (p=0.035), while the levels of platelet-derived growth factor subunit B (PDGFB) were lower in patients with TAPS than in those with OAPS (p=0.041). In addition, correlation analysis showed that CXCL12 levels were positively correlated with immunoglobulin G anti-β2-glycoprotein I antibody (r=0.617, p=0.016). Our results demonstrated that urinary CXCL12 and PDGFB might serve as potential non-invasive markers to differentiate primary TAPS from primary OAPS.

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“…However, no exact and reliable criteria exist yet. We define AOSD disease clinically active or inactive based on our understanding of this disease in our clinical work (34,35,(44)(45)(46)(47). Grouping AOSD disease activity status by our method was somewhat arbitrary and divergent, so it may cause the results to be biased with other research units.…”

Section: Discussionmentioning

confidence: 99%

Serum Heparin-Binding Protein as a Potential Biomarker to Distinguish Adult-Onset Still’s Disease From Sepsis

et al. 2021

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Adult-onset Still’s disease (AOSD) is a systemic, multifactorial, autoinflammatory disease for which the etiopathogenesis is not well understood. Given the similarities in clinical and laboratory features between this disease and sepsis, and the differences in treatment strategies for these two diseases, specific diagnostic markers are crucial for the correct diagnosis and management of AOSD. Previous studies have shown plasma heparin-binding protein (HBP) is a promising potential biomarker for AOSD; thus, this study aimed to detect serum HBP levels in patients with AOSD or sepsis to assess its potential as a biomarker for differential diagnosis. We found that serum HBP levels were significantly higher in patients with active AOSD than that in those with inactive AOSD. Patients with sepsis had higher serum HBP levels compared with those who had active or inactive AOSD. We calculated the area under the receiver operating characteristic (ROC) curve to assess whether HBP could be used to differentiate active from inactive AOSD; this was 0.811 with sensitivity 0.650, specificity 0.811, and cutoff HBP value of 35.59 ng/ml. The area under the ROC curve for HBP as a biomarker to differentiate AOSD from sepsis was 0.653, with sensitivity 0.759, and specificity 0.552, and cutoff HBP value of 65.1 ng/ml. Taken together, the results of our study suggest that serum HBP could be a useful diagnostic biomarker to evaluate disease activity in patients with AOSD, and to differentiate AOSD from sepsis.

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Urinary Proteomics Identifying Novel Biomarkers for the Diagnosis of Adult-Onset Still’s Disease

Cited by 21 publications

References 44 publications

An Immunological Axis Involving Interleukin 1β and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial

An Immunological Axis Involving Interleukin 1β and Leucine-Rich-α2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial

Urine Proteomics Differentiate Primary Thrombotic Antiphospholipid Syndrome From Obstetric Antiphospholipid Syndrome

Serum Heparin-Binding Protein as a Potential Biomarker to Distinguish Adult-Onset Still’s Disease From Sepsis

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