Highlights:
Lupus affects around 1.5 million Americans, and nine out of ten people diagnosed with the disease are female. The root cause of lupus is unknown, and there is no cure.
New research published in Nature shows that lupus patients have mutated immune cells that may spark the kind of internal self-attack that leads to tissue damage in lupus.
This discovery gives scientists a potential clue to the driving cause of the disease.
LA JOLLA, CA—Scientists at La Jolla Institute for Immunology ( LJI ) and the University of Washington (UW) have discovered that patients with lupus have unusual mutations that may turn their bodies into battlegrounds.
These mutations are widespread in immune cells called neutrophils. Other immune cells see the mutated neutrophils as a threat—and they try 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, Ph.D., who co-led the new Nature study with UW School of Medicine Professor Tomas Mustelin, M.D., Ph.D.
The researchers cannot say for sure whether the mutated neutrophils are a root cause of lupus, but they point to the fact that this kind of "self-attack" is the hallmark of autoimmune disease.
Where the mutations come from
In war, heat-seeking missiles are effective because they can lock onto their targets. Your immune system's T cells and B cells fight disease in a similar way. Immune cells have sensors too, and they patrol the body for molecules that belong to viruses, bacteria, and other pathogens.
Your T cells are especially important fighters, and they hunt down molecules called peptides, which are presented at the surface of target cells. Peptides are fundamental building blocks in biology. Human cells make peptides—and so 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 come from pathogens, and they lock onto their targets, which scientists call "antigens."
The new study shows what can happen when this process goes wrong.
The researchers examined blood samples from 34 patients with systemic lupus erythematosus (SLE), the most common form of lupus. A close look at each patient's RNA code revealed that 33 of the 34 lupus patients had neutrophils riddled with "splicing" mutations that didn't appear in samples from healthy study volunteers.
Our cells read RNA as the instructions for making peptides. Cells actually rely on "splicing" to remove sections of RNA code that aren't meant to be read.
For some reason, the lupus patients in this study had strange errors in their RNA. These errors led to splicing mutations, where sections of the RNA code were mistakenly jammed together. Mutated neutrophils would then try to "read" this jumbled code as instructions to make peptides.
The resulting peptides are unlike anything our cells normally make. In fact, these peptides look "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, called "neoantigens." In some cases, neoantigens can do us a favor. 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 joined forces to study whether neoantigens could play a role in autoimmune disease.
Mustelin's lab had found that patients with lupus had an unusual number of mutations that arose through faulty RNA splicing in their neutrophils. Schoenberger then used cutting-edge tools in his lab to study whether these mutations led to neoantigens that T cells might see 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 went on to find that antibody-producing B cells were ready to fight the neutrophils as well.
What this means in lupus
Autoimmune diseases are defined by self-attack. People develop painful inflammation and organ damage when T cells and B cells begin to attack other cells in the body.
It could be that mutated neutrophils are triggering the development of inflammation in lupus cases, but more research needs to be done before scientists know for sure.
Schoenberger emphasizes that autoimmune diseases are very complicated. These new findings will 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 gives scientists an important clue as they work to understand and treat autoimmune disease.
A different kind of hypothesis for autoimmunity
Neutrophils normally help fight disease. But to T cells and B cells, mutated neutrophils appeared to be the source of disease itself. This finding is in line 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 disease, but it was unclear why these cells would lose their "tolerance" to the body's own organs and start attacking healthy tissues.
Mustelin and Schoenberger's work suggests that T cells and B cells might be performing their normal function, but against unfortunate targets, in lupus patients. These cells are meant to sense potentially harmful antigens—and neoantigens fit the bill.
"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.
Publication details:
Additional authors of the study, " T and B cells recognize neoantigens from aberrant mRNA splicing in lupus neutrophils ," include first author 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 Gurghian, Gabriela Cervantes, Sadie J. Van den Bogaerde, Samir Adhikari, Mikhail V. Pogorelyy, and Paul G. Thomas.
This study was supported by the National Institutes of Health (grants AR075134, AR077266, AR074939, AR081654, and AR007108) and the Briger Foundation for Oncology Research.
About La Jolla Institute for Immunology
La Jolla Institute for Immunology (LJI) was founded in 1988 as an independent, nonprofit research organization. LJI is based in San Diego, CA, and is home to world-class scientists solely focused on immunology. LJI scientists are harnessing the power of the immune system to defeat cancer, autoimmune, infectious, and neurodegenerative diseases.
Our breakthroughs in immunology make life without disease possible. Visit lji.org
