The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope

Miglioranza Scavuzzi, B.; van Drongelen, V.; Kaur, B.; Callahan Fox, J.; Liu, J.; Mesquita-Ferrari, R. A.; Kahlenberg, J. M.; Farkash, E. A.; Benavides, F.; Miller, F. W.; Sawalha, A.; Holoshitz, J.

doi:10.1101/2022.05.31.494172

bioRxiv · 10.1101/2022.05.31.494172

The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope

Miglioranza Scavuzzi, B.·van Drongelen, V.·Kaur, B.·Callahan Fox, J.·Liu, J.·Mesquita-Ferrari, R. A.·Kahlenberg, J. M.·Farkash, E. A.·Benavides, F.·Miller, F. W.·Sawalha, A.·Holoshitz, J.

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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-{gamma}), 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-{gamma} to naive 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.

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Miglioranza Scavuzzi, B., van Drongelen, V., Kaur, B., Callahan Fox, J., Liu, J., Mesquita-Ferrari, R. A., Kahlenberg, J. M., Farkash, E. A., Benavides, F., Miller, F. W., Sawalha, A., Holoshitz, J.. 2022-05-31. The lupus susceptibility allele DRB1*03:01 encodes a disease-driving epitope. https://doi.org/10.1101/2022.05.31.494172

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