Scientists at La Jolla Institute for Immunology and the University of Washington have identified a potential mechanism behind lupus, finding that mutated neutrophils may trigger the immune system to attack its own cells. Their study, published in Nature, reveals that splicing mutations in neutrophils produce neoantigens that T and B cells recognize as foreign, potentially fueling the autoimmune response.
Mutated Neutrophils and the Autoimmune Trigger
The researchers analyzed blood samples from 34 patients with systemic lupus erythematosus (SLE) and discovered that 33 had widespread splicing mutations in their neutrophils, a type of white blood cell key for fighting infection. These mutations altered RNA processing, causing sections of genetic code to be incorrectly fused together. The resulting peptides resembled foreign proteins, prompting immune cells to treat the neutrophils as a threat.
Stephen Schoenberger, an immunology expert at LJI, explained that this creates a dangerous cycle. When neutrophils, which are already pro-inflammatory, display mutated proteins, T cells detect them as antigens while simultaneously sensing tissue damage signals. “T cells sense a foreign antigen plus inflammation or ‘danger’ signals,” Schoenberger noted, highlighting the conditions necessary for immune attack.
The team used advanced techniques to confirm that these mutated neutrophils indeed expressed neoantigens—novel protein fragments that the immune system cannot recognize as self. B cells, which produce antibodies, were also found to be primed to target these altered cells, compounding the inflammatory response.
The Neoantigen Hypothesis in Autoimmunity
This finding supports a growing theory called the “neoantigen hypothesis,” which suggests autoimmune diseases may arise not from immune tolerance failures but from the immune system correctly identifying mutated self-proteins as threats. Mustelin and Schoenberger’s collaboration began when Mustelin’s lab observed unusual RNA splicing errors in lupus patients’ neutrophils. Schoenberger then investigated whether these mutations generated immunogenic neoantigens, a key step in his lab’s cancer immunotherapy research.
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In their experiments, the researchers demonstrated that T cells from lupus patients responded robustly to these neoantigens, while B cells also produced antibodies targeting the mutated proteins. This dual recognition could explain the persistent inflammation and organ damage seen in lupus, where immune complexes and interferon signaling are already known to play central roles.
However, the study leaves a critical question unresolved: whether these neoantigens drive lupus or are a consequence of existing inflammation. Schoenberger emphasized that neutrophils are already involved in a self-amplifying loop involving autoantibodies, NETs, and interferons. “The big question is whether neoantigens are a cause or consequence of this process?” he said.
Therapeutic Implications and Future Research
The study’s findings suggest a potential pathway for developing targeted therapies. By focusing on neoantigen-specific immune responses, researchers might design treatments that block T and B cells from attacking mutated neutrophils. Such interventions could reduce inflammation and prevent organ damage in lupus patients.
Autoimmunity as a Misdirected Defense Mechanism
The study also highlights the role of RNA splicing errors in generating these neoantigens. Normally, splicing removes non-coding RNA sections, but in lupus patients, faulty splicing joins genetic code abnormally. This error produces peptides that resemble foreign proteins, triggering immune recognition. The findings offer a new angle for exploring lupus mechanisms and potential interventions.