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Here we show that in the presence of interferon gamma (IFN-\u03b3), a short\n                    <jats:italic>DRB1*03:01<\/jats:italic>\n                    -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-\u03b3 to na\u00efve\n                    <jats:italic>DRB1*03:01<\/jats:italic>\n                    transgenic mice causes increased serum levels of anti-double stranded DNA antibodies, glomerular immune complex deposition and histopathological renal changes that resemble human lupus nephritis. This study provides evidence for a noncanonical, antigen presentation-independent mechanism of HLA-disease association in SLE and could lay new foundations for our understanding of key molecular mechanisms that trigger and propagate this devastating autoimmune disease.\n                  <\/jats:p>","DOI":"10.1038\/s42003-022-03717-x","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T01:02:50Z","timestamp":1658970170000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9609-001X","authenticated-orcid":false,"given":"Bruna","family":"Miglioranza Scavuzzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-7617","authenticated-orcid":false,"given":"Vincent","family":"van Drongelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavneet","family":"Kaur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer Callahan","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel A.","family":"Mesquita-Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-8945","authenticated-orcid":false,"given":"J. 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