AB0186 CORRELATIONS BETWEEN RENAL TRANSCRIPTOMIC PROFILES AND OUTOCOMES IN A MOUSE MODEL OF SYSTEMIC LUPUS ERYTHEMATOSUS

Background: Factors contributing to poor renal outcomes in lupus nephritis (LN) are poorly understood. In our previous research, we found an association between the presence of activated immune effectors in the lupus kidney and disease severity. Here we investigated correlations between patterns of renal genes expression and biological parameters of renal disease activity in a mouse model of systemic lupus erythematosus (SLE). Methods: We collected blood, urine, kidneys and spleens from 33 B6/Sle1.Sle2.Sle3 congenic mice, before disease onset at 3 months (n=8), and at different stages of disease progression, at 6 (n=7), 9-10 (n=12) and 17-18 (n=5) months. RNA was extracted from kidneys, and hybridized on Mouse Gene 2.0 ST exon arrays. Unsupervized hierarchical clustering studies and pathways analyses were performed on Genespring and DAVID softwares. Spleen and kidney CD8 T cell activation and differentiation markers were evaluated by flow cytometry (CD8, CD69, CD62L, CD44, CD122, CD25, CD44, CCR7, CD279, CD152, CD11a, CD103). Plasma urea and albuminuria were measured by immunoassay. Results: 712 (out of 33,793) transcripts were overexpressed in kidneys from diseased mice (age > 6 months). These transcripts were significantly enriched in the following pathways: response to type I interferons, antigen processing and presentation, activation and regulation of B cells, complement activation, and regulation of cytotoxicity mediated by T cells. Proportions of renal CD8 T cells with an effector phenotype were significantly increased in the kidneys from 6 months and older compared to younger mice, and compared to paired spleens. Proportions of renal effector CD8 T cells correlated significantly with transcripts involved in interferon signature, adaptive immune responses, cytotoxic T cells, chemotaxis, and correlated negatively with pathways associated with renal tubular cell functions. Finally, we found a correlation between biological parameters of kidney function (plasma urea, albuminuria) and transcripts involved in pro-fibrotic pathways, chemokines and adaptive immune responses. Conclusion: Our results confirm the link between the presence of activated immune effectors in the kidney and renal outcomes in a mouse model of SLE, similar to our previous observations in human LN, and warrant further functional studies on the role of kidney-infiltrating T and B cells in this model. Acknowledgement: This research was funded in part by grants from Fonds de la Recherche Scientifique – FNRS, Fondation Roi Baudouin and Fondation Saint-Luc. Disclosure of Interests: None declared