Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

BioRxiv : the Preprint Server for Biology
L. BarnabeiFrederic Rieux-Laucat


Systemic Lupus Erythematosus is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. Specific immunotherapies have variable efficiency because of the heterogeneity of the disease. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutants were abundant in the nucleus but poorly activated transcription of genes controlled by NF-kB consensus sequences. In contrast, the co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFNalpha-consensus sequences. These molecular mechanisms account for the overproduction of type-I IFN and expression of the related genes observed in the cells of the patients. Collectively, our findings indicate that overproduction of type-I IFN is the intial step in this new monogenic cause of early-onset SLE, thereby paving the way to the identification of new and specific thera...Continue Reading

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