Rieux-Laucat, F. | bioRxiv Science

bioRxiv2020

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

Systemic Lupus Erythematosus (SLE) 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. 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 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-{kappa}B consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFN-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets. SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFN-consensus sequences.

immunology↗

bioRxiv2019

Network Analysis Of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause Of Intestinal Inflammation

BACKGROUND & AIMSGenome-wide association studies (GWAS) have uncovered multiple loci associated with inflammatory bowel disease (IBD), yet delineating functional consequences is complex. We used a network-based approach to uncover traits common to monogenic and polygenic forms of IBD in order to reconstruct disease relevant pathways and prioritize causal genes.\n\nMETHODSWe have used an iterative random walk with restart to explore network neighborhood around the core monogenic IBD cluster and disease-module cohesion to identify functionally relevant GWAS genes. Whole exome sequencing was used to screen a cohort of monogenic IBD for germline mutations in top GWAS genes. One mutation was identified and validated by a combination of biochemical approaches.\n\nRESULTSMonogenic IBD genes clustered siginificantly on the molecular networks and had central roles in network topology. Iterative random walk from these genes allowed to rank the GWAS genes, among which 14 had high disease-module cohesion and were selected as putative causal genes. As a proof of concept, a germline loss of function mutation was identified in PTPN2, one of the top candidates, as a novel genetic etiology of early-onset intestinal autoimmunity. The mutation abolished the catalytic activity of the enzyme, resulting in haploinsufficiency and hyper-activation of the JAK/STAT pathway in lymphocytes.\n\nCONCLUSIONSOur network-based approach bridges the gap between large-scale network medicine prediction and single-gene defects and underscores the crucial need of fine tuning the JAK/STAT pathway to preserve intestinal immune homeostasis. Our data provide genetic-based rationale for using drugs targeting the JAK/STAT pathway in IBD.

immunology↗