Background Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune disease characterized by a breakdown of tolerance to nuclear antigens. Antigen-presenting cells including dendritic cells (DCs) are aberrantly activated in SLE patients, and promote the activation of autoreactive T and B cells. Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh responses in SLE remain elusive.
Objectives To identify the mechanisms responsible for Tfh activation in human SLE.
Methods Adult SLE patients (total 61: 53 females and 8 males) and pediatric SLE patients (total 38: 34 females and 4 males) who met the American College of Rheumatology revised criteria for SLE (Hochberg, 1997) were enrolled. All clinical and biologically relevant information were collected. For the analysis of OX40L expression, whole blood samples were stained with anti- CD14-PC5, CD16-FITC, CD11c-APC, HLA-DR-PC7, and OX40L-PE mAbs, and red blood cells were lysed with Versalyse. For the analysis of blood Tfh cells, whole blood samples were stained with anti-CXCR5-AF488, CCR6-PE, CXCR3- PC5, CCR4-PC7, CD3-AF700, CD8-APCH7, CD4-Pacific Blue CD45RA-ECD, ICOS-APC and CD45-Pacific Orange. Naïve and memory Th cells were sorted by flow cytometry, stimulated overnight in the presence or absence of sOX40L. Extensive phenotype and transcriptomic analysis was done.
Results We show that the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid APCs, but not by B cells, in blood as well as in inflamed tissues in adult and pediatric active SLE patients. OX40L stimulation induced human CD4+ helper T (Th) cells to express Tfh-associated molecules, and was sufficient to induce them to become functional B cell helpers. We found that OX40 signals promote the expression of Tfh molecules by enhancing TCR signals, in addition to the modulation of NF-kB pathway. Finally, we show that immune complexes (ICs) containing ribonucleoprotein (RNP) present in lupus sera induce OX40L expression by myeloid APCs through activation of TLR7. Thus, our study shows that the RNP IC-OX40L axis likely provides an amplification loop of the generation of autoantibodies in SLE.
Conclusions Our study provides a rationale that therapeutic modalities targeting the RNP-containing IC-OX40L-OX40 axis and TLR7 could impact the development of autoantibodies and therefore be beneficial for human SLE.
Acknowledgements This work was supported by grants from Arthritis fundation and Société Française de Rhumatologie.
Disclosure of Interest None declared
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