The lupus susceptibility allele DRB103:01 encodes a disease-driving epitope

• Published in: Communications biology 2022-07, Vol.5 (1), p.751-15, Article 751
• Main Authors: Miglioranza Scavuzzi, Bruna, van Drongelen, Vincent, Kaur, Bhavneet, Fox, Jennifer Callahan, Liu, Jianhua, Mesquita-Ferrari, Raquel A., Kahlenberg, J. Michelle, Farkash, Evan A., Benavides, Fernando, Miller, Frederick W., Sawalha, Amr H., Holoshitz, Joseph
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/21; 13/51; 13/95; 14/1; 14/63; 38; 38/39; 38/77; 38/90; 38/91; 631/250/38; 64/60; 692/699/249; 82; 82/1; 82/29; 82/51; 82/80; 96; 96/1; 96/106; 96/2; 96/21; 96/34; Alleles; Animals; Antigen presentation; Autoimmune diseases; Biology; Biomedical and Life Sciences; Cell death; Drb1 protein; Endoplasmic reticulum; Epitopes; Epitopes - genetics; Genetic Predisposition to Disease; Histocompatibility antigen HLA; HLA-DRB1 Chains - genetics; Humans; Inflammation; Interferon-gamma - genetics; Life Sciences; Lupus; Lupus Erythematosus, Systemic - genetics; Lupus nephritis; Macrophages; Mice; Mitochondria; Molecular modelling; Nephritis; Protein folding; Risk factors; Serum levels; Systemic lupus erythematosus; Transcriptomes; Transgenic mice; γ-Interferon
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03717-x

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. In the presence of IFN-γ, a short DRB1*03:01-encoded allelic epitope is found to activate a characteristic lupus transcriptome in macrophages and trigger a cascade of systemic lupus erythematosus-associated cellular aberrations.