Mutated neutrophils may trigger immune self-attack in lupus patients

Scientists at La Jolla Institute for Immunology (LJI) and the University of Washington (UW) have uncovered a striking molecular anomaly in people with lupus: their neutrophils, a frontline population of immune cells, are riddled with mutations that arise from faulty RNA splicing. According to the new research, published in Nature, these mutations cause the neutrophils to produce peptides that look foreign to the rest of the immune system. Other immune cells, including T cells and antibody-producing B cells, appear to respond to these aberrant molecules as though they were threats, mounting an attack against the body’s own cells. The researchers suggest that this internal battle may help drive the painful inflammation, debilitating joint pain and other serious symptoms that characterize the disease, although they emphasize that they cannot yet say for certain whether the mutated neutrophils are a root cause of lupus.

The study examined blood samples from 34 patients with systemic lupus erythematosus (SLE), the most common form of lupus. When the researchers scrutinized each patient’s RNA code, they found that 33 of the 34 lupus patients carried neutrophils loaded with splicing mutations that did not appear in samples from healthy study volunteers. Splicing is a fundamental process by which cells remove sections of RNA code that are not meant to be read, allowing the genetic instructions to be interpreted correctly for building proteins and peptides. In the lupus patients, something had gone wrong with this process: sections of RNA code were mistakenly jammed together, producing jumbled instructions that the mutated neutrophils then tried to read as templates for making peptides.

The peptides generated from these garbled instructions are unlike anything human cells normally produce. To the immune system, they look foreign. In immunology, molecules that arise from mutations and can be recognized by immune cells are called neoantigens. Neoantigens are best known in cancer research, where tumor cells often display them and immunotherapies can be designed to help the immune system attack them. LJI Professor Stephen Schoenberger, Ph.D., who co-led the new study with UW School of Medicine Professor Tomas Mustelin, M.D., Ph.D., is an expert on how the immune system targets such mutation-derived antigens. For this study, the two laboratories joined forces to ask whether neoantigens could also play a role in autoimmune disease.

The collaboration built on an observation from Mustelin’s lab: patients with lupus had an unusual number of mutations arising through faulty RNA splicing in their neutrophils. Schoenberger then used advanced tools in his laboratory to determine whether these mutations produced neoantigens that T cells might perceive as a threat. The answer, according to the researchers, was yes. The mutated neutrophils expressed a flood of neoantigens that flashed danger signs to the immune system. Schoenberger explained that this creates what he described as 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, because T cells sense a foreign antigen together with inflammation or danger signals.

The immune response did not stop with T cells. The researchers also found that antibody-producing B cells were ready to fight the mutated neutrophils as well. This matters because autoimmune diseases are defined by self-attack: people develop painful inflammation and organ damage when their T cells and B cells begin to assault other cells in the body. Normally, T cells and B cells patrol the body for molecules that belong to viruses, bacteria and other pathogens. T cells in particular hunt down peptides presented at the surface of target cells, and they launch their attacks when they sense new or foreign peptides in the context of inflammation or tissue damage, assuming that these unfamiliar molecules come from pathogens. In lupus, the new findings suggest, this surveillance machinery may be locking onto targets generated by the patients’ own mutated cells.

This framing leads to what the researchers describe as a different kind of hypothesis for autoimmunity. Scientists have long known that T cells and B cells drive autoimmune disease, but it has been unclear why these cells lose their tolerance to the body’s own organs and start attacking healthy tissue. The new work suggests that, in lupus patients, T cells and B cells might actually be performing their normal function, but against unfortunate targets. These cells are built to sense potentially harmful antigens, and neoantigens fit that description. Rather than a failure of immune tolerance, Schoenberger argued, autoimmunity can be caused by the immune system doing exactly what it is supposed to do, which is to mount an attack on non-self, on things that are foreign. This perspective aligns with a growing school of thought in autoimmune disease research known as the neoantigen hypothesis.

Despite the strength of the association, the researchers are careful about causality. They cannot say for sure whether the mutated neutrophils are a root cause of lupus, although they note that this kind of self-attack is the hallmark of autoimmune disease. It could be that mutated neutrophils are triggering the development of inflammation in lupus cases, but more research is needed before scientists know for sure. Schoenberger emphasized that autoimmune diseases are very complicated and that the new findings will give researchers a fresh perspective on the role of neutrophils in SLE. He also raised the possibility that the arrow of causation could point the other way: neutrophils might be responding to inflammation that is already causing tissue damage, meaning the splicing mutations and the neoantigens they generate could be a consequence of the disease process rather than its origin.

That caveat is grounded in what is already known about neutrophil behavior in lupus. As Schoenberger noted, neutrophils clearly participate in a self-amplifying inflammatory circuit in SLE, one involving autoantibodies, immune complexes, nucleic acids, type I interferons and neutrophil extracellular traps, the web-like structures often abbreviated as NETs. Within that established circuit, the big question now, he said, is whether neoantigens are a cause or a consequence of the process. For now, the study stands as an important clue rather than a settled explanation.

The clinical context gives the finding considerable weight. Lupus affects around 1.5 million Americans, and nine out of ten people diagnosed with the disease are female. The root cause of lupus remains unknown, and there is no cure. Against that backdrop, a mechanism that could explain why the immune system turns on the body’s own tissues represents a potentially significant advance. The study, titled T and B cells recognize neoantigens from aberrant mRNA splicing in lupus neutrophils, was published in Nature with first author Rayan Najjar among a long list of contributors, and it was supported by the National Institutes of Health and the Briger Foundation for Oncology Research. If follow-up work confirms that splicing-derived neoantigens drive the autoimmune attack, the discovery could reshape how scientists think about the driving cause of lupus and, potentially, other autoimmune conditions.

Subject of Research: RNA splicing mutations in lupus neutrophils that generate neoantigens recognized by T and B cells

Article Title: Mutated immune cells raise red flags in lupus

Article References: Mutated immune cells raise red flags in lupus. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: lupus, systemic lupus erythematosus, neutrophils, neoantigens, RNA splicing, autoimmunity, T cells, B cells, inflammation, Nature study, La Jolla Institute for Immunology, immune tolerance