The lupus susceptibility allele DRB103:01 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 transcr...

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Veröffentlicht in:Communications biology 2022-07, Vol.5 (1), p.751-15, Article 751
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-022-03717-x