Faculty, Staff and Student Publications
Publication Date
7-28-2022
Journal
Communications Biology
DOI
10.1038/s42003-022-03717-x
PMID
35902632
PMCID
PMC9334592
PubMedCentral® Posted Date
7-28-2022
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Alleles, Animals, Epitopes, Genetic Predisposition to Disease, HLA-DRB1 Chains, Humans, Interferon-gamma, Lupus Erythematosus, Systemic, Mice
Published Open-Access
yes
Recommended Citation
Miglioranza Scavuzzi, Bruna; van Drongelen, Vincent; Kaur, Bhavneet; et al., "The Lupus Susceptibility Allele DRB1*03:01 Encodes a Disease-Driving Epitope" (2022). Faculty, Staff and Student Publications. 2595.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/2595
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