A Pathogenic Cytokine Network Is Associated with Pro-Inflammatory B Cells in Systemic Lupus Erythematosus Patients

Abstract

Objective: This report presents translational research showing that a pathogenic cytokine network could stratify systemic lupus erythematosus (SLE) patients associated with B cell dysfunction. Methods: Forty-five patients with SLE and 48 healthy volunteers (HV) were recruited from 10 centers in Europe. Cytokines analyses on patient's sera were performed using the Luminex technology. Autoantibodies measurement was realized on analyzer IDS-iSYS chemiluminescent. Patient's phenotyping was performed on whole blood. Functional profiles were explored using flow cytometry and quantitative RT-PCR. Cytokines in supernatants were measured using a multiplex bead-based assay. Results: To better understand how the cytokine microenvironment could be associated with different disease status in patients, we profiled 12 cytokines using the Luminex technology in serum from 45 SLE patients and 48 HV. We thus documented a unique pathogenic cytokine cluster in a group of patient delineated by CXCL10, IL-6, and IFN-γ. This pathogenic network was associated with pro-inflammatory helper B cells and an increase in systemic autoreactivity. We thus designed an in vitro model to study cytokine networks involved in pro- and anti- inflammatory B-cell functions. We demonstrated that CD4+ CD45RA+ naive T cells (TRA) polarized B cells toward pro-inflammatory B cells defined by a memory-like phenotype and an exacerbated production of CXCL-10, IFN-γ, and IL-2. Conclusion: This composite analysis brings new insights on human B cell functional heterogeneity and, on the other hand, proposes a better stratification of SLE patients according to their functional cytokine microenvironment suggesting that combined biomarkers would be a great value to design new personalized treatments. Clinical Trial Number: Registered on clinicaltrials.gov NCT 02890121 and NCT 02890147. Funding Statement: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking PRECISESADS under grant agreement n° 115565, resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies in kind contribution. Declaration of Interests: The authors declare no competing interests. Ethical Approval Statement: The study was performed in accordance with the Declaration of Helsinki and was approved by ethical committees at each site for respective sub-cohorts. All patients gave their informed consent for participating in the study, which was registered on clinicaltrials.gov NCT 02890121 and NCT 02890147.