A killer T cell (centre) hunting a target cell. Credit: NIH Image Gallery CREDIT NIH Image Gallery
Gene variants associated with leukaemia can produce ‘rogue’ immune cells that drive autoimmune diseases, according to a new study from the Garvan Institute of Medical Research.
Scientists had previously noticed that leukaemia patients were also likely to develop an autoimmune disease, such as rheumatoid arthritis or aplastic anaemia. Research into this link revealed that immune cells called killer T cells – responsible for destroying harmful cells and pathogens – were a key player.
This new research provides insight into the role these killer T cells play in leukaemia and autoimmune disease. Gene variations affecting a protein that controls the growth of killer T cells can turn them rogue, the researchers found.
“We showed that these rogue killer T cells are driving the autoimmunity. They’re probably one of the cell types most directly contributing to autoimmune disease,” says Dr Etienne Masle-Farquhar, a postdoctoral researcher in the Immunogenomics and Genomic Medicine Labs at Garvan.
“Our research also narrows down a few pathways that might be helpful in targeting these cells for future treatments,” he says.
The findings are published in the journal, Immunity.
Cancers can grow when tumour cells are not identified or destroyed by the immune system. Autoimmune diseases occur when the immune system attacks the body’s own cells, mistaking them for harmful or foreign cells.
“We knew that people with various autoimmune diseases acquire these rogue killer T cells over time, but also that inflammation can cause immune cells to proliferate and develop mutations. We set out to discover whether the rogue T cells were causing these autoimmune conditions, or simply associated with them,” says Dr Masle-Farquhar.
The researchers used new high-resolution screening methods to look at blood from children with rare inherited autoimmune diseases.
They then used a technique called CRISPR/Cas9, a genome editing tool, in mouse models, to find out what happens when the protein STAT3 is genetically altered.
STAT3 is found throughout the body and is critical for various cell functions, including controlling the immune system’s B cells and T cells.
The team found that if these proteins are altered, they can cause rogue killer T cells to grow unchecked, resulting in enlarged cells that bypass immune checkpoints to attack the body’s own cells.
In addition, even just 1-2% of a person’s T cells going rogue could cause autoimmune disease.
“It’s never been clear what the connection between leukaemia and autoimmune disease is – whether the altered STAT3 protein is driving disease, or whether leukaemic cells are dividing and acquiring this mutation just as a by-product. It’s a real chicken-and-egg question, which Dr Masle-Farquhar’s work has been able to solve,” says Professor Chris Goodnow, Head of the Immunogenomics Lab and Chair of The Bill and Patricia Ritchie Foundation at Garvan.
“This gives some really good cracks in the coalface of where we might do better in terms of stopping these diseases, which are sometimes life threatening,” he says.
Future applications could include better targeting of medication, like already TGA-approved JAK inhibitors, based on the presence of these mutations. “We can now go and look for T cells with STAT3 variations. That’s a big step forward in defining who’s the bad guy,” says Professor Goodnow.
The study also identified two specific receptor systems – ways for cells to talk to one another – that are linked to stress.
“Part of what’s driving these rogue cells to expand as killer T cells is the stress-sensing pathways. There is a lot of correlation between stress, damage and ageing. Now we have tangible evidence of how that’s connected to autoimmunity,” Professor Goodnow says.
The team’s research may help develop screening technologies that clinicians could use to sequence the complete genome of every cell in a blood sample, to identify which cells might turn rogue and cause disease.
Further study is needed to determine whether rogue killer T cells are involved in all autoimmune diseases, and what proportion of people with rheumatoid arthritis and other autoimmune conditions have rogue cells and STAT3 variations.
Although the complement system forms part of the innate immune system, it can cause damage to the body in some cases. This is because unwanted complement activation contributes to many autoimmune and chronic inflammatory diseases. Now, researchers have described molecular details of a recently approved class of drugs that can inhibit the complement system. These findings pave the way for further optimization of such inhibitors.
The complement system defends the body against microbial intruders, but it can also attack the body’s own cells for various reasons and therefore contribute to clinical complications. These complications range from age-related and chronic inflammatory diseases such as macular degeneration to the rejection of organ transplants. In such cases, it would make sense from a medical perspective to shut the complement system down in a controlled manner with the use of drugs.
Despite the wide range of medical applications, there has long been only a single substance class of “complement inhibitors,” which are in any case only authorized for a few very rare diseases. It wasn’t until 2021 that a new therapeutic option came to the market in the form of the compstatins, a class of drugs that bring a central factor of the complement system to a standstill. The discovery and development of this substance family is rooted in research by Professor John Lambris’ group at the University of Pennsylvania, USA.
Now, a research group led by Professor Daniel Ricklin at the University of Basel has worked with Lambris and an international team of researchers in order to study these compstatins’ mode of action in detail. Writing in the journal Nature Communications, the researchers describe how different variants of this family of active substances interact with the central factor of the complement system and how exactly they operate at the molecular level.
Optimizing active substances and facilitating research
On the one hand, the results pave the way for the further optimization of active substances in the compstatin family. “On the other hand, the findings also help us understand why compstatins have a highly specific effect on the human complement system,” Ricklin explains.
What is beneficial in therapy can prove to be a hindrance in basic research because it impedes working with model organisms. With this in mind, an interdisciplinary research project at the Department of Pharmaceutical Sciences aims to provide clinical research with new variants of the inhibitor that can help gain a better understanding of various diseases and pave the way for novel therapeutic strategies.
After a heart attack, people with an autoimmune disease were more likely to die, develop heart failure or have a second heart attack compared to people without an autoimmune disease, according to new research published today in the Journal of the American Heart Association, an open access, peer-reviewed journal of the American Heart Association.
Autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosis and psoriasis, are known to increase risk of cardiovascular disease, likely due to multiple factors. People with an autoimmune disease have a higher prevalence of traditional cardiovascular risk factors (such as high blood pressure, Type 2 diabetes or kidney disease), in addition to aspects of autoimmune disease that are also linked to higher cardiovascular risk, such as chronic inflammation, autoimmune antibodies and long-term use of steroid medications. A new study examined whether having an autoimmune disease, compared to not having one, affects a person’s health status after a heart attack.
“The evidence about the risk of adverse events after heart attack for people with autoimmune disorders is less robust than evidence for people without these disorders, and mainly from small or single-center studies,” said Amgad Mentias, M.D., M.Sc., senior author of the study and an assistant professor of medicine at the Cleveland Clinic Lerner College of Medicine in Cleveland. “We conducted our study to examine, in a large cohort, whether there is any difference in the treatment of heart attack patients with versus without autoimmune diseases, and whether there is a difference in risk of death, heart failure or recurrent heart attacks over the long-term.”
The researchers identified 1,654,862 people in the U.S. ages 65 and older in the Medicare Provider Analysis and Review (MedPAR) File who were admitted to the hospital with a heart attack diagnosis between 2014 and 2019. MedPAR is a government database of every hospital inpatient bill in the U.S. submitted to Medicare for payment. Of those records, 3.6% (60,072) had an inflammation-causing autoimmune disease noted in their charts within the previous year. The most common condition was rheumatoid arthritis, followed by systemic lupus, psoriasis, systemic sclerosis and myositis/dermatomyositis. They found several important differences among people with vs. without autoimmune disease who had heart attacks:
People with an auto immune disease were slightly younger – average age was 77.1 years vs. 77.6 years for those without an autoimmune disease.
More of those with an autoimmune disease were women (66.9% vs. 44.2%).
Those with autoimmune disease were more likely to have had a non-ST-elevation myocardial infarction (NSTEMI) heart attack (updated from 77.1 to 77.3) (77.3% vs. 74.9%), and they were less likely to have an ST-elevation myocardial infarction (STEMI) heart attack (18.7% vs. 22.1%).
An NSTEMI, the most common type of heart attack recorded in the database, is caused by partial blockage of one of the coronary arteries that feeds oxygen-rich blood to the heart muscle. A STEMI heart attack, usually more dangerous, is from a complete blockage of one or more of the heart’s main arteries.
The researchers matched each heart attack patient record with autoimmune disease to records of three heart attack patients without autoimmune disease based on age, sex, race and type of heart attack. After matching (and excluding people who had not been enrolled in Medicare for at least one year prior to their heart attack), the investigators compared health outcomes for about 2 years. The final dataset included 59,820 heart attack records of people with an autoimmune disorder and 178,547 of those without an autoimmune disorder.
The analysis found that people with an autoimmune disease were:
15% more likely to die from any cause;
12% more likely to be hospitalized for heart failure;
8% more likely to have another heart attack; and
6% more likely to have an additional artery-opening procedure (if they had received one at the time of their heart attack).
“Patients with autoimmune disease and cardiovascular disorders are preferably managed by a cardio rheumatologist in conjunction with a rheumatologist to optimize cardiovascular health. Traditional CVD risk factors are accentuated in this population and how these risk factors manifest is also unique,” said lead study author Heba Wassif, M.D., M.P.H., an assistant professor of medicine at the Cleveland Clinic Lerner College of Medicine and director of cardio-rheumatology at the Cleveland Clinic.
“For example, cholesterol levels are affected by inflammation, therefore patients with active inflammatory disease have lower levels of cholesterol, a phenomenon known as the lipid paradox,” Wassif said. “Physical activity, which is highly recommended to improve cardiovascular outcomes, may be limited by joint pain. Furthermore, some disease modifying agents may increase cardiovascular risk. Knowledge of these nuances and a team-based approach may improve outcomes.”
The researchers also found that people with an autoimmune disease were less likely to have heart catheterization to assess narrowed coronary arteries or to undergo an artery-opening procedure or bypass surgery regardless of the type of heart attack.
“It is possible that the people with an autoimmune disease were not healthy enough to undergo those procedures, or their coronary anatomy was less amenable to interventions to reopen narrowed or clogged vessels,” Mentias said. These issues may place them at higher risk of procedure-related complications. “When feasible, however, if someone is a suitable candidate, these procedures should be considered as options. The presence of autoimmune disease by itself should not preclude someone from potentially life-saving procedures.”
The researchers did not have information on the anatomy of patients’ coronary arteries, which limited the ability to assess whether anatomical differences may have influenced decision-making about vessel-opening procedures. The analysis is also limited by not having laboratory data on the severity and activity of patients’ autoimmune disease, making it impossible for the researchers to assess whether the risk of complications and death following heart attack is higher in patients with severe forms of autoimmune disease compared with those who have a milder form or disease in remission.
“Future research is needed on medications and interventions that might reduce the heightened risk for poor outcomes in heart attack patients with autoimmune disease,” Wassif said, “such as investigating whether different immune modulators and immune-suppressant therapies used to control and treat the autoimmune disease have any impact in improving post-heart-attack outcomes.”
Time of day affects severity of autoimmune disease
If you have celiac disease, inadvertently consuming even a single crumb of bread can lead to gastrointestinal upset for weeks or months. For those who suffer from lupus, a flare can damage kidneys—or even worse. People with rheumatoid arthritis suffer from debilitating joint pain.
If you have celiac disease, inadvertently consuming even a single crumb of bread can lead to gastrointestinal upset for weeks or months. For those who suffer from lupus, a flare can damage kidneys—or even worse. People with rheumatoid arthritis suffer from debilitating joint pain.
They are very different ailments, but all have one thing in common: they are autoimmune diseases, conditions when the body’s immune system attacks not external pathogens but the body itself.
Increasingly, researchers are finding other diseases that have a root cause in autoimmune function. Some 24 million Americans are affected by more than 80 autoimmune diseases, according to the National Institute of Environmental Health Sciences, and it seems as if more people are being diagnosed with them than before.
Normally, when our bodies are faced with pathogens—such as bacteria or viruses—our immune systems kick into high gear to protect us from these invaders. But sometimes our immune systems confuse parts of our tissues and organs as foreign invaders and attack them instead. The inflammatory response that can knock out an invading bacterium ends up damaging our own health.
Pilar Alcaide, a Kenneth and JoAnn G. Wellner Professor at Tufts University School of Medicine, is an immunologist, focusing on how the immune system impacts cardiovascular health. She also has a personal understanding of these types of diseases. When she was around 6 years old, she was diagnosed with the skin condition psoriasis—an autoimmune disease. It was unusual for a young person to experience the severe psoriasis type she was diagnosed with, and a reminder that these diseases affect all kinds of people.
Alcaide explains more about autoimmune diseases, what causes them, who gets them the most, and what can be done about them.
Do scientists know why this autoimmune response happens?
Pilar Alcaide: There are many different types of autoimmune diseases. A classic one is when there is a mutation on a gene—such as the one that causes Type 1 diabetes. People who have that mutation, their pancreas is attacked by the immune system, with the result that insulin production stops.
Typically autoimmune diseases that are determined by just one gene are developed from birth or from a young age. But for many other autoimmune diseases, genetics is only one part of the cause. For instance, I had severe psoriasis as a child, but most people have mild, moderate, or severe forms of the disease later in life, so it is thought that environment plays a strong role in its development.
In many cases, autoimmune diseases develop with age over time, meaning it’s often a combination of genetics, environment, and physiological and mental stress. There’s a lot of research demonstrating that the level of stress plays an important role—the environment and stress.
A lot of these autoimmune diseases have flares, when your immune system, for whatever reason, is responding more aggressively than normal.
How does the immune system work normally?
Say a virus or a pathogen hits you. Your body realizes there is a pathogen, and the immune system starts releasing proteins called cytokines. Some of these cytokines will induce fever, which is good—a lot of viruses die at high temperatures. A fever also tells your body that you cannot fight the infection without other internal help.
Then other cells called lymphocytes come to help kill the infection. Pro-inflammatory lymphocytes are specialized, and typically they go to where the trigger was.
But then your body needs to turn off the response. When the pro-inflammatory lymphocytes have done their job, anti-inflammatory lymphocytes arrive and suppress the response.
What happens when it goes haywire in an autoimmune response?
The first barrier of protection to self—our tissues and organs—is what we call immune tolerance. That’s when anti-inflammatory cells recognize, say, “This is a skin protein. It’s OK. You don’t need to respond to that.” That’s homeostasis—the body at equilibrium.
But in some cases, a genetic mutation causes a protein to appear that is very similar to something that is part of us, but not quite. Then the inflammatory cells recognize it as a foreign thing, as if it were a pathogen, and they start inflammation.
If you are infected with something, you need inflammation, and when you clear that infection, you need anti-inflammation. With autoimmunity diseases, if you skip this tolerance phase, inflammation develops.
The skin, for example, closely interacts with nerves and both produce substances that act on each other’s receptors. For example, neuropeptides can alter immune cells in the skin that produce cytokines and trigger an inflammatory response.
Can you talk about some of the environmental factors that researchers have found?
Most of the research that has been done is around environmental toxins that come from smoke or air pollution in large cities. Those toxins break up into small molecules, and certain immune cells have receptors for those small molecules.
That triggers the activity of these immune cells, which release cytokines that induce inflammation wherever they are. Nutrition is also key—some foods induce inflammation, while other healthy foods don’t.
Why does the autoimmune response happen in some people versus others?
There are a lot of risk factors. One is genetics. You can have a genetic mutation that triggers a response.
You could also have hidden mutations or hidden factors that are normally silent—you don’t realize that there’s this constant battle of anti-or pro-inflammation inside you, because it’s hidden.
But then something happens, like an environmental trigger, such as a hydrocarbon—the chief component of oil and natural gas, for example—that activates receptors that your immune cells express. Then they will become pro-inflammatory, and then you have autoimmunity.
Another trigger involves the microbiota—the microorganisms in our intestines. Your gut is the reservoir for immune cells—you have tons of bacteria in your gut and your immune cells live with them. They’re the so-called good bacteria.
But then you eat something that somehow disrupts that, and all of a sudden, your immune cells start recognizing the bacteria as foreign. That happens, for instance, in Crohn’s disease and ulcerative colitis, though those diseases aren’t exclusively triggered that way.
Is the incidence of autoimmune disease increasing? And if so, is it because people are recognizing it more, or is it because there is more overall?
That’s a tough one. Autoimmune diseases have always been diagnosed, but maybe now there’s more diagnosis—perhaps because more people go more often to the doctor.
But it’s clear that lifestyles have changed—working hard, not taking time for yourself, more stress, unhealthy fast food, more pollution—that definitely doesn’t help. And the environment is presenting more triggers.
Do women get autoimmune diseases more than men?
Yes, with a few exceptions. Typically, more women than men get autoimmune diseases. But when men get it, it is way more severe than for women.
That’s true, for example, with lupus, which women are 10 times more likely to get than men. Lupus is a very complex autoimmune disease, and an example of one influenced by several genetic and environmental factors. You have a variety of immune responses happening, including damage to many organs. It starts in the skin, but then it can go to your kidneys. It’s massive.
But when a man gets it, it’s way more severe, with kidney damage, especially African American men. They have the worst prognosis of all with lupus.
What are treatments for autoimmune diseases?
Because this is a pro-inflammatory condition, people try to dampen inflammation with steroids. Methotrexate was one example, and cyclosporine and many other drugs—those are broad anti-inflammatory drugs.
The issue is that you cannot take them forever, because you suppress everything. So, you could use them in case of flares. But with either topical or systemic corticosteroids, the minute you stop taking them, the inflammation comes back.
In the past decade or so, as researchers started understanding the individual roles of specific immune cell subsets, and the cytokines they make, it became very clear that in most autoimmune diseases, the early players that are super inflammatory are specific cells, and they’ve developed blocking antibodies towards those.
Now those are very commonly used. They’re called biologicals, because, unlike the global immunosuppressors, they recognize cytokines that our own body makes.
Do the biologicals used in treatment for autoimmune disease have downsides?
Yes, they do. One is that, because of their immunosuppressive nature, sometimes when you take them for too long, some lymphomas form—cancer of the lymph nodes—because lymphoid tissue is where immune cells divide. They also have other side effects such as higher risk of infections.
I think that developing the biologicals was one of the biggest breakthroughs in medicine, because there were people, especially with arthritis and psoriatic arthritis, who couldn’t really live a normal life until these treatments became available.
The gold standard would be to find something that is more tissue specific, that you wouldn’t dampen inflammation systemically. But for some autoimmune diseases, you need to dampen it systemically as well.
Are there other treatments?
Yes. For skin disorders, phototherapy is something that works very well. A certain wavelength of light, mimicking that of the sun, suppresses inflammation. That’s a very noninvasive treatment that suppresses inflammation in your skin.
Phototherapy with natural or artificial light is used in vitiligo, which is an autoimmune disorder where people get depigmentation of the skin. It also works very well in certain types of psoriasis.
Researchers are also trying to develop a vaccine for psoriasis. I was in a trial when I was a kid, but unfortunately it didn’t work—more work understanding of the drivers of autoimmunity need to be done by immunologists.
Are autoimmune diseases more common in higher income countries vs. poorer countries?
It’s hard to tell, because a lot of people in poor countries are not diagnosed. Some autoimmune diseases are related to ethnicity. For instance, autoimmune skin disease like vitiligo and psoriasis are prevalent in the Middle East. Some autoimmune diseases are not so easy to diagnose, but in the skin it’s so easy to see.
That’s the difference versus something like Crohn’s disease—many people in poorer countries don’t know they have it, because even if their stomach hurts or they bleed, they may think it’s a parasite.
I think certain autoimmune diseases are definitely diagnosed more in the U.S. That might have to do with the lifestyle as well, but also because of the ability to diagnose it.
Are autoimmune diseases more difficult to diagnose than other diseases?
I think they’re difficult to diagnose because if it’s systemic, there are a lot of cross relations between that and other diseases.
So, let’s say that you develop a rash, and you don’t think it’s autoimmunity. But then the rash is on your face and spreads. If you also had a lot of pain in your kidneys, then it could be lupus.
And there are people who present with more than one autoimmune disease. People with psoriasis very often develop rheumatoid arthritis. And people with Crohn’s disease often develop that as well.
Rheumatoid arthritis is one of the most prevalent autoimmune diseases. It’s different from osteoarthritis, which is triggered by mechanical stress in the joints. People who have psoriasis in the joints often develop psoriatic arthritis—very much like rheumatoid arthritis.
There are just so many different autoimmune diseases—more than are probably realized.
That’s why it’s critical to learn as much as we can about the immune system, how it works in normal conditions, and how it reacts to different insults, so we can investigate how to modulate it, dampening or enhancing its response when needed to treat autoimmunity.
Most of the diseases that kill the majority of the people are somehow immune-related, so understanding immunity will help prevent and treat not only autoimmunity but also other chronic inflammatory diseases.REQUEST AN EXPERT
Approximately 23.5 million people in the U.S. have an autoimmune disease, and some studies suggest that number could be rising. New research using a mouse model for multiple sclerosis has uncovered a potential new area to explore for possible treatments for autoimmune disorders. The study is published ahead of print in the American Journal of Physiology-Cell Physiology. It was chosen as an APSselect article for May.
“The research team delved further into the connection between nephronectin and the immune system, identifying its role in a chain of cellular processes that stimulate an immune response. Finding therapeutics that disrupt these mechanisms could uncover novel treatment options for autoimmune diseases.”
Autoimmune diseases occur when the body’s immune system attacks its own healthy tissues, organs or cells. Treatments currently available for autoimmune diseases can come with serious side effects, such as an increased risk of contracting contagious diseases.
In earlier studies, researchers found that several mouse models of different autoimmune diseases had elevated levels of nephronectin. They also found that blocking nephronectin reduced inflammation in a mouse model of arthritis. Nephronectin is a protein known to be critical to kidney development but also appears in other parts of the body.
In the current study, the research team delved further into the connection between nephronectin and the immune system, identifying its role in a chain of cellular processes that stimulate an immune response. Finding therapeutics that disrupt these mechanisms could uncover novel treatment options for autoimmune diseases.
The researchers established that blocking nephronectin “significantly inhibited the development” of experimental autoimmune encephalitis—used as a model for multiple sclerosis—in mice. They then identified a number of proteins that bind to nephronectin. Among these was selenoprotein P, a glycoprotein that is known to stimulate the production of the antioxidant glutathione peroxidase 1.
Through further analysis, the researchers found evidence for a mechanism by which nephronectin influences the immune response. When nephronectin binds to selenoprotein P, it creates a feedback loop that alters the balance of signals to the immune system. This imbalance stimulates white blood cells to be more active than they should be. This activity then exacerbates the severity of EAE.
“Our findings also suggest that the nephronectin–[reactive oxygen species] axis may be a potential therapeutic target for treating autoimmune diseases,” researchers wrote.
We use cookies on our website to give you the most relevant experience by remembering your preferences and repeat visits. By clicking “Accept”, you consent to the use of ALL the cookies.
This website uses cookies to improve your experience while you navigate through the website. Out of these, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. We also use third-party cookies that help us analyze and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these cookies. But opting out of some of these cookies may affect your browsing experience.
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website.
