A study published in Nature on October 28, 2026, by researchers at La Jolla Institute for Immunology and the University of Washington reveals that neutrophils in 33 of 34 lupus patients harbour novel RNA splicing mutations. These cryptic splice variants generate non-self neoantigens that trigger T cell and B cell autoimmune attacks against healthy tissues, supporting a new neoantigen hypothesis for lupus pathogenesis.
Cryptic RNA splicing discovery in lupus neutrophils
- ▪Cryptic RNA splicing events detected in neutrophils from systemic lupus erythematosus patients were completely absent in neutrophils from healthy control volunteers and patients with rheumatoid arthritis.
- ▪A study published in Nature on October 28, 2026, by researchers at La Jolla Institute for Immunology and the University of Washington identified 271 cryptic RNA splicing events in 130 genes within neutrophils from 33 of 34 systemic lupus erythematosus patients.
Neoantigens trigger autoimmune T and B cell responses
- ▪The computational tool RiboSplitter demonstrated that cryptic RNA splicing events in systemic lupus erythematosus neutrophils generate novel peptide sequences that act as neoantigens.
- ▪Antibody-producing B cells in systemic lupus erythematosus patients recognize and target splicing-derived neoantigens expressed on neutrophils.
- ▪T cells recognise splicing-derived neoantigens on mutated neutrophils as foreign threats, mounting an attack that drives autoimmune inflammation in systemic lupus erythematosus patients.
- ▪In silico analysis revealed that 86 cryptic splice-derived peptides across 46 genes in systemic lupus erythematosus patients bound with high affinity to patient-specific major histocompatibility complex class I or II molecules.
Research into neoantigens
- ▪Tomas Mustelin's laboratory discovered widespread RNA splicing mutations in lupus patients' neutrophils, prompting Stephen Schoenberger to investigate whether these mutations generated T cell-targeting neoantigens.
- ▪A study co-led by Stephen Schoenberger and Tomas Mustelin provides evidence supporting the neoantigen hypothesis, where autoimmunity stems from T cells responding normally to foreign-appearing neoantigens rather than an immune tolerance failure.
Interferon pathway involvement and transcriptional profiling
- ▪Pathway analysis of aberrantly spliced genes in systemic lupus erythematosus neutrophils showed a strong bias for type I interferon-inducible genes, including IFI44L, MX1, OAS1, RSAD2, XAF1, IFI27, and IFIT1.
- ▪Neutrophils in systemic lupus erythematosus display widespread genomic hypomethylation and a type I interferon-weighted transcriptional profile resembling neutrophils from SARS-CoV-2-infected individuals.
Neutrophil dynamics in lupus
- ▪Systemic lupus erythematosus is characterized by autoantibodies targeting nuclear proteins, nucleic acid-associated proteins, and double-stranded DNA released during inflammatory cell death processes like NETosis and ferroptosis.
- ▪Although neutropoiesis is accelerated in systemic lupus erythematosus, many patients suffer from neutropenia, indicating an elevated rate of neutrophil consumption.
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