Plasma microRNA Profiles as a Potential Biomarker in Differentiating Adult-Onset Still's Disease From Sepsis

Abstract

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease characterized by cytokine storm. However, a diagnostic test for AOSD in clinical use is yet to be validated. The aim of our study was to identify non-invasive biomarkers with high specificity and sensitivity to diagnosis of AOSD. MicroRNA (miRNA) profiles in PBMC from new-onset AOSD patients without any treatment and healthy controls (HCs) were analyzed by miRNA deep sequencing. Plasma samples from 100 AOSD patients and 60 HCs were used to validated the expression levels of miRNA by qRT-PCR. The correlations between expression levels of miRNAs and clinical manifestations were analyzed using advanced statistical models. We found that plasma samples from AOSD patients showed a distinct miRNA expression profile. Five miRNAs (miR-142-5p, miR-101-3p, miR-29a-3p, miR-29c-3p, and miR-141-3p) were significantly upregulated in plasma of AOSD patients compared with HCs both in training and validation sets. We discovered a panel including 3 miRNAs (miR-142-5p, miR-101-3p, and miR-29a-3p) that can predict the probability of AOSD with an area under the receiver operating characteristic (ROC) curve of 0.8250 in training and validation sets. Moreover, the expression levels of 5 miRNAs were significantly higher in active AOSD patients compared with those in inactive patients. In addition, elevated level of miR-101-3p was found in AOSD patients with fever, sore throat and arthralgia symptoms; the miR-101-3p was also positively correlated with the levels of IL-6 and TNF-α in serum. Furthermore, five miRNAs (miR-142-5p, miR-101-3p, miR-29c-3p, miR-29a-3p, and miR-141-3p) expressed in plasma were significantly higher in AOSD patients than in sepsis patients (P < 0.05). The AUC value of 4-miRNA panel (miR-142-5p, miR-101-3p, miR-29c-3p, and miR-141-3p) for AOSD diagnosis from sepsis was 0.8448, revealing the potentially diagnostic value to distinguish AOSD patients from sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as a potential non-invasive biomarker for diagnosis of AOSD and monitoring disease activity.

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

“…In a previous study, we first screened the susceptibility of genetic factors in AOSD using a genome-wide association study and revealed that the SNPs rs3115628 (HLA class I region) and rs9268832 (HLA class II region) were strongly associated with AOSD in the Chinese population (4). Moreover, we identified plasma microRNA profiles using microRNA sequencing in patients with AOSD (12). In the current study, we further explored the urine proteomics of AOSD by iTRAQ-labeling combined with LC-MS/MS analysis.…”

“…Pathogen-associated molecular patterns or danger-associated molecular patterns trigger inflammasome activation and the production of interleukin 1β (IL-1β) and IL-18, further improving the expression of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and IL-6 and the anti-inflammatory cytokines IL-10 and IL-37 ( 1 , 6 , 7 ). Additionally, a markedly high frequency of elevated serum molecules such as alarmins (S100A8/A9 and S100A12), chemokines (C-X-C motif chemokine ligand 9, 10, and 11), and microRNAs, which correlate with disease activity, was noticed in patients with AOSD ( 8 – 12 ).…”

Circulating Neutrophil Extracellular Traps Signature for Identifying Organ Involvement and Response to Glucocorticoid in Adult-Onset Still’s Disease: A Machine Learning Study

“…Routine inflammatory markers, cytokines, and several molecules reflecting innate immune activation are increased in patients with AOSD and used in clinical practice (20). Our previous study demonstrated that a combined microRNAs (miRNAs) panel in plasma could be a non-invasive biomarker for the diagnosis of AOSD and to differentiate it from sepsis, providing some evidences in the study of biomarkers in AOSD (21). However, biomarkers with high specificity and sensitivity for diagnosis of AOSD organ involvement is still to be determined.…”

Mathematical modeling of septic shock: an innovative tool for assessing therapeutic hypotheses

“…The pro-inflammatory response then indirectly stimulates the production rate of the energetic (E) response (K inE ) and the production rate of the anti-inflammatory (A) response (K inA ). The energetic response stimulates both pro-inflammation and antiinflammation, while anti-inflammation serves as the immuno-regulatory component of the system by restoring intracellular homeostasis post-transcriptional regulatory mechanism for gene expression in many cellular processes, including the immune response, as well as playing a crucial role in the endotoxin tolerance system [34][35][36][37][38][48][49][50]. For example, when miR146, miR155 and miR125b are stimulated by LPS in human monocytic cells [51][52][53], they can inhibit TLR4/IL-1R signaling via the post-transcriptional regulation of signaling proteins such as IL-1 receptor-associated kinase 1 (IRAK-1) and TNF receptor-associated factor 6 (TRAF6) [49,53].…”

“…In order to consider the increasing importance of epigenetic regulation (including microRNA; miRNA) in sepsis [34][35][36][37][38], the objective of the present study was to improve the model proposed by Calvano et al [28] by adding epigenetic regulatory loops. Moreover, we aimed to obtain further insights into the therapeutic options for modifying the pro-/anti-inflammatory balance by including a pharmacology modeling stratum.…”