LJI Professor Stephen Schoenberger, Ph.D.
Photo Credit: Courtesy of La Jolla Institute for Immunology
Scientific Frontline: Extended "At a Glance" Summary: RNA Splicing Mutations in Lupus Neutrophils
The Core Concept: Patients with systemic lupus erythematosus possess mutated neutrophils caused by faulty RNA splicing, which generate abnormal peptides that the immune system perceives as foreign threats.
Key Distinction/Mechanism: Rather than arising from a spontaneous failure of immune tolerance, the autoimmune response in lupus may occur because T cells and B cells are functioning correctly but targeting "neoantigens"—unfamiliar peptides generated by transcription errors within the patient's own pro-inflammatory neutrophils.
Origin/History: This mechanism was detailed in an October 2026 study published in Nature, co-led by researchers at the La Jolla Institute for Immunology and the University of Washington.
Major Frameworks/Components:
- Systemic lupus erythematosus (SLE) pathogenesis and widespread inflammatory tissue damage.
- Faulty RNA splicing errors that mistakenly jam together sections of genetic code in neutrophils.
- The generation and presentation of neoantigens that trigger targeted T cell and B cell immune attacks.
- The "neoantigen hypothesis" of autoimmunity, which posits that the immune system mounts a standard defense against genuinely abnormal, non-self targets rather than mistakenly attacking healthy tissues.
Branch of Science: Molecular Immunology
Future Application: Identifying the precise RNA splicing errors and resulting neoantigens could lead to targeted immunotherapies for lupus that neutralize specific antigens or correct cellular anomalies, rather than relying on broad immunosuppression.
Why It Matters: This research fundamentally shifts the understanding of lupus etiology, providing a concrete molecular mechanism and suggesting that destructive inflammation is a secondary response to underlying genetic transcription errors in immune cells.
Scientists at the La Jolla Institute for Immunology (LJI) and the University of Washington (UW) have discovered that patients with lupus possess unusual mutations that may turn their bodies into battlegrounds.
These mutations are widespread in immune cells called neutrophils. Other immune cells perceive the mutated neutrophils as a threat and attempt to fight back. This internal battle may contribute to the development of painful inflammation, debilitating joint pain, and other serious lupus symptoms throughout the body.
“This may get to the very crux of the disease pathogenesis,” says LJI professor Stephen Schoenberger, PhD, who co-led the new Nature study with UW School of Medicine professor Tomas Mustelin, MD, PhD.
The researchers cannot definitively state whether the mutated neutrophils are a root cause of lupus, but they note that this kind of “self-attack” is the hallmark of autoimmune disease.
Where the Mutations Come From
In warfare, heat-seeking missiles are effective because they can lock onto their targets. The immune system’s T cells and B cells fight disease in a similar manner. Immune cells also possess sensors, and they patrol the body for molecules that belong to viruses, bacteria, and other pathogens.
T cells are particularly important fighters; they hunt down molecules called peptides, which are presented at the surface of target cells. Peptides are fundamental biological building blocks. Human cells synthesize peptides, as do bacteria and viruses.
T cells launch their attacks when they sense new or “foreign” peptides in the context of inflammation or tissue damage. T cells then assume these unfamiliar peptides originate from pathogens, locking onto their targets, which scientists call “antigens.”
The new study demonstrates what occurs when this process malfunctions.
The researchers examined blood samples from 34 patients with systemic lupus erythematosus (SLE), the most common form of lupus. A close examination of each patient’s RNA code revealed that 33 of the 34 lupus patients had neutrophils riddled with “splicing” mutations that did not appear in samples from healthy study volunteers.
Cells read RNA as the instructions for synthesizing peptides. Cells rely on “splicing” to remove sections of RNA code that are not meant to be read.
For an unknown reason, the lupus patients in this study exhibited aberrant errors in their RNA. These errors led to splicing mutations, in which sections of the RNA code were mistakenly jammed together. Mutated neutrophils would then attempt to “read” this jumbled code as instructions to synthesize peptides.
The resulting peptides are unlike anything human cells normally produce. In fact, these peptides appear “foreign” to the immune system.
How the New Study Worked
Schoenberger is an expert on how the immune system targets antigens that arise due to mutations, known as “neoantigens.” In some cases, neoantigens can be beneficial. Cancer cells often express neoantigens, and Schoenberger has pioneered efforts to improve cancer immunotherapy by identifying neoantigens that the immune system can attack.
For the new study, Schoenberger and Mustelin collaborated to investigate whether neoantigens could play a role in autoimmune disease.
Mustelin’s laboratory discovered that patients with lupus possessed an unusual number of mutations arising through faulty RNA splicing in their neutrophils. Schoenberger then utilized cutting-edge tools in his laboratory to study whether these mutations led to neoantigens that T cells might perceive as a threat.
Indeed, the mutated neutrophils expressed a flood of neoantigens that flashed “danger” signs to the immune system.
As Schoenberger explains, this created a potential recipe for disaster.
“When a cell type whose function is pro-inflammatory, such as neutrophils, also expresses potentially immunogenic mutations, the conditions for immune attack are met: T cells sense a foreign antigen plus inflammation or ‘danger’ signals,” says Schoenberger.
The researchers subsequently discovered that antibody-producing B cells were also prepared to fight the neutrophils.
What This Means in Lupus
Autoimmune diseases are defined by self-attack. Individuals develop painful inflammation and organ damage when T cells and B cells begin to attack other cells in the body.
It is possible that mutated neutrophils trigger the development of inflammation in lupus cases, but further research is necessary before scientists can reach a definitive conclusion.
Schoenberger emphasizes that autoimmune diseases are highly complex. These new findings provide researchers with a new perspective for understanding the role of neutrophils in SLE.
“Neutrophils clearly participate in a self-amplifying inflammatory circuit in SLE, involving autoantibodies, immune complexes, nucleic acids, type I interferons, and neutrophil extracellular traps (NETs),” says Schoenberger. “So now the big question is whether neoantigens are a cause or consequence of this process. Neutrophils might be responding to inflammation that’s already causing tissue damage.”
The new study provides scientists with a critical clue as they work to understand and treat autoimmune disease.
A Different Kind of Hypothesis for Autoimmunity
Neutrophils normally help fight disease. However, to T cells and B cells, the mutated neutrophils appeared to be the source of disease itself. This finding aligns with a growing school of thought in autoimmune disease research: the “neoantigen hypothesis” of autoimmunity.
Scientists have long known that T cells and B cells drive autoimmune diseases, but it remained unclear why these cells would lose their “tolerance” to the body’s own organs and begin attacking healthy tissues.
Mustelin and Schoenberger’s work suggests that T cells and B cells might be performing their normal functions in lupus patients, but against unfortunate targets. These cells are designed to sense potentially harmful antigens, and neoantigens fit the criteria.
“Rather than a failure of immune tolerance, autoimmunity can be caused by the immune system doing exactly what it’s supposed to do, which is to mount an attack on non-self, on things that are foreign,” says Schoenberger.
Funding: This study was supported by the National Institutes of Health (grants AR075134, AR077266, AR074939, AR081654, and AR007108) and the Briger Foundation for Oncology Research.
Published in journal: Nature
Title: T and B cells recognize splicing-derived neutrophil neoantigens in lupus
Authors: Rayan Najjar, Xiaoxing Wang, Farheen Shaikh, Ning Wang, Ethan Le, Jie An, Mohammad Pourshamsi, Cecilia Mustelin, Fatemeh Moadab, Spencer Mirabile-Brightman, Leslie Montero, Karla S. Zavala, Vincent Gureghian, Gabriela Cervantes, Sadie J. Van den Bogaerde, Samir Adhikari, Mikhail V. Pogorelyy, Paul G. Thomas, Stephen P. Schoenberger, and Tomas Mustelin
Source/Credit: La Jolla Institute for Immunology | Madeline McCurry-Schmidt
Edited by: Scientific Frontline
Reference Number: imgy102826_01
