Exosomal Specificity of MiR-15a-5p as marker of Activity, Renal Damage and Disease Flares in Systemic Lupus Erythematosus

Introduction: Little is known about the biofluid specificity of microRNAs (miRNAs) in systemic lupus erythematosus (SLE) and the biofluid influence on miRNA diagnosis and prognosis accuracy. Our aim was to analyze the effect of biofluid on miRNA expression and to identify a specific miRNA profile in plasma exosomes related to SLE activity, renal damage and disease flares over a 60-month follow-up period. Methods: Non-coding RNA sequencing analysis was used to determine miRNA in plasma and plasma exosomes in a discovery cohort of SLE patients and healthy subjects. Potential miRNAs were selected based on the differential expression between biofluids and were validated by quantitative polymerase chain reaction in a higher validation cohort. Results: From the small RNA-sequencing, the 25 miRNAs with the highest fold-change expression between biofluids were identified. Nine miRNAs were validated in a larger cohort (n=115, of whom 30 had nephritis), and were found to be increased in exosomal fraction and patient groups. Further analysis revealed a panel combining three miRNAs for lupus nephritis diagnosis (miR-101-3p, miR-144-5p and miR-15a-5p) gave an area under the curve that improves the readout of the single miRNAs (0.964, p<0.0001). However, only miR-15a-5p had a strong discriminatory power of renal injury between patients (0.81, p<0.0001). Finally, exosomal miR-15a-5p was associated with histological features, chronicity index and flares (odds ratio 4.24, p<0.001), high levels being a strong independent predictor of 60-month follow-up flares (hazard ratio 4.24, p<0.001). Conclusion: This novelty study demonstrated a biofluid exosome specificity of miRNA profile related to SLE with nephritis. Highlighting, exosomal miR-15a-5p levels with a strong association with proteinuria, renal histological features and high accuracy in the diagnosis of renal damage and detection of lupus flares. The detection of altered miRNAs levels in exosome-enriched fraction improved the diagnostic accuracy of renal damage in SLE.