Our finding that alternative splicing of the IRF5 transcript results in expression of isoforms, like V2 and V3 examined in this study, able to escape TRIM21-mediated degradation and therefore not inhibited by TRIM21 upon TLR activation, suggests that the presence of SLE-specific, degradation-resistant IRF5 isoforms may mediate the enhanced production of type I IFN and proinflammatory cytokines known to play a critical role in SLE development and pathogenesis. This evidence concerns the gene TRIM21 and systemic lupus erythematosus.