biostudies-literatureMiglioranza Scavuzzi BIntramural NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Environmental Health SciencesU.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS NIH HHS751https://www.ebi.ac.uk/biostudies/studies/S-EPMC9334592biostudies-literatureUnknown5(1)The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-γ), a short DRB1*03:01-encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also triggers a cascade of SLE-associated cellular aberrations, including endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, necroptotic cell death, and production of pro-inflammatory cytokines. Parenteral administration of IFN-γ to naïve DRB1*03:01 transgenic mice causes increased serum levels of anti-double stranded DNA antibodies, glomerular immune complex deposition and histopathological renal changes that resemble humCommunications biologyThe lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope.PMC9334592HHSN273201600123PR01AR059085ES101074R01 AR059085T32AR07080R33AR073014T32 AR007080R33 AR073014R61AR073014R01 AR074930Z01 ES101074R61 AR073014Miglioranza Scavuzzi BKahlenberg JMLiu JMesquita-Ferrari RAFarkash EAHoloshitz Jvan Drongelen VMiller FWBenavides FKaur BFox JCSawalha AHfalseThe lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope.The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-γ), a short DRB1*03:01-encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also triggers a cascade of SLE-associated cellular aberrations, including endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, necroptotic cell death, and production of pro-inflammatory cytokines. Parenteral administration of IFN-γ to naïve DRB1*03:01 transgenic mice causes increased serum levels of anti-double stranded DNA antibodies, glomerular immune complex deposition and histopathological renal changes that resemble hum2022-01-01T00:00:00Z2022 Jul2026-07-14T15:08:57.39Z2025-04-19T22:47:17.633ZS-EPMC93345923590263210.1038/s42003-022-03717-x