Splicing-derived neutrophil neoantigens drive T and B cell autoimmunity in lupus

Researchers found that neutrophils from patients with systemic lupus erythematosus (SLE) contain aberrantly spliced gene transcripts that produce novel peptides, or neoantigens, which trigger both T and B cell immune responses, potentially driving the autoimmune disease. These neoantigens were detected on MHC class I molecules in patient samples, and T cells from SLE patients expanded and reacted to the peptides, while healthy donor T cells showed little response. SLE patient serum also contained IgG autoantibodies recognizing these novel sequences, indicating B cell involvement and class-switch. The findings suggest that dysregulated mRNA splicing in SLE neutrophils generates neoantigens that drive autoimmune immunity, offering a new model for SLE pathogenesis where immune activation targets these "foreign" peptides. This mechanism may explain the disease's fluctuating course and broad symptoms, and could inform future therapeutic strategies.