The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope
Bruna Miglioranza Scavuzzi, Vincent van Drongelen, Bhavneet Kaur, Jennifer Callahan Fox, Jianhua Liu, Raquel Agnelli Mesquita‐Ferrari, J. Michelle Kahlenberg, Evan A. Farkash, Fernando Benavides, Frederick W. Miller, Amr H. Sawalha, Joseph Holoshitz
Abstract
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 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.