No abstract

We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.

The TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-κB–dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.

Evidence suggests that immunogenicity to mRNA-based SARS-CoV-2 vaccination in immunosuppressed patients may be reduced. This study assessed the response to 2 doses of mRNA-based SARS-CoV-2 vaccine among 133 participants with underlying chronic inflammatory disease, many of whom were receiving glucocorticoids, B-cell depletion therapy, or other immunosuppressant therapy.

Dendritic cells (DCs), known to support immune activation during infections, may also regulate immune homeostasis in resting animals. Here we show that mice lacking A20 specifically in DCs spontaneously exhibited DC activation and expansion of activated T cells. DC-specific epistasis experiments using A20fl/fl Myd88fl/fl Cd11c-Cre compound mice revealed that A20 restricts both MyD88-independent signals, which drive DC and T cell activation, and MyD88-dependent signals, which drive T cell expansion. In addition, A20fl/fl Cd11c-Cre mice spontaneously developed lymphocyte-dependent colitis, sero-negative ankylosing arthritis and enthesitis, conditions stereotypical for human inflammatory bowel disease (IBD). These findings indicate that DCs require A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.