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.
Show 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.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- SLE non-coding Genetic Risk Variant Determines the Epigenetic Dysfunction of an Immune Cell Specific Enhancer that Controls Disease-critical microRNA Expression 97%
- Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases 96%
- The immune profile of circulating autoreactive CD4 T cells is imprinted through tissue activation during autoimmune liver diseases 96%
Similar papers in this journal
- Extrafollicular responses are sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus 95%
- BCR, not TCR, repertoire diversity is associated with favorable COVID-19 prognosis 95%
- Uncoupling splicing from transcription using antisense oligonucleotides reveals a dual role for I exon donor splice sites in antibody class switching 95%
Similar papers in this journal
Similar papers in this journal
- JAK inhibition decreases the autoimmune burden in Down syndrome 95%
- Regulatory T cells suppress the formation of potent KLRK1 and IL-7R expressing effector CD8 T cells by limiting IL-2 95%
- MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis 95%
Similar papers in this journal
- A multilayered post-GWAS analysis pipeline defines functional variants and target genes for systemic lupus erythematosus (SLE) 95%
- B cell numbers predict humoral and cellular response upon SARS-CoV-2 vaccination among patients treated with rituximab 95%
- A Novel human IL-23A Overexpressing Mouse Model of Systemic Lupus Erythematosus 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.