Our findings reveal that reminiscent of SE-coding DRB1 alleles in RA, the SLE-risk allele DRB1*03:01 encodes what we designated here as a ‘lupus epitope’ (LE) in the TAHR of the DRβ chain that, in the presence of interferon gamma (IFN-γ), activates signature lupus transcriptomes in mouse and human macrophages, and triggers SLE-characteristic cellular aberrations, including ER stress, UPR, mitochondrial dysfunction, necroptosis and production of pro-inflammatory cytokines. This evidence concerns the gene IFNG and systemic lupus erythematosus.