Human cells expressing inflammatory cytokines (stained green). CREDIT Professor Martin Laboratory; Trinity College Dublin

Scientists from Trinity College Dublin have made an important breakthrough in understanding how inflammation is regulated. They have just discovered that a key immune alarm protein previously believed to calm down the immune response does the opposite.

Their work has numerous potential impacts, especially in understanding and responding to autoimmune disorders and inflammation.

While our immune system serves a very important function in protecting us from infection and injury, when immune responses become too aggressive, this can lead to damaging inflammation, which occurs in conditions such as rheumatoid arthritis and psoriasis. Inflammation is triggered when our bodies produce “alarm proteins” (interleukins), which ramp up our defences against infection and injury by switching on different immune system components.

Understanding how and when such alarm proteins are produced and how they activate our immune system has led to breakthroughs in treating many immune conditions.

Now, scientists from the Smurfit Institute of Genetics at Trinity College Dublin, led by Seamus Martin, Smurfit Professor of Genetics, have found that Interleukin-37 has an unexpected function as an immune-activating molecule, as previous studies suggested that this interleukin instead served as an “off switch” for the immune system.

Professor Martin said:

“Interleukins play key roles in regulating our immune systems in response to bacterial and fungal infections. However, Interleukin-37 has long remained an enigma, as it isn’t found in mammals such as mice. This has presented a major obstacle to figuring out what it does as much of what we know about the human immune system has first been discovered in model organisms whose biological make-ups are similar to ours.”

Before the new study, Interleukin-37 was thought to have immune-suppressive functions, but how it switched off inflammation was hotly debated. However, the Trinity scientists now report that, when activated in the correct way, Interleukin-37 displays potent pro-inflammatory activity.

Professor Martin added:

“This pro-inflammatory impact was highly unexpected. Our work shows that the protein binds to an interleukin receptor in the skin known to play a key role in driving psoriasis. And, to add further intrigue to the story, this brings the total number of immune alarm molecules that signal via this particular interleukin receptor to four.

“Why there are so many interleukins that bind to the same receptor is a mystery, but if we were to speculate it may be because this receptor serves a very important sentinel function in our skin, and that one alarm protein may simply not be enough to respond to the many different infectious agents that our skin encounters. Our skin is the major barrier between our bodies and the outside world that microbes must breach if they are to gain entry to our bodies and, in many respects, represents the first line of defense in our immune systems.” 

As such, Interleukin-37 and other immune alarm proteins may have evolved to become distinct variations on the same theme that enable our bodies to detect different types of infection by activating enzymes that are distinct to each infectious agent.

Breathing in common workplace dusts and fumes from agents such as vapours, gases, and solvents, may heighten the risk of developing rheumatoid arthritis, suggests research published online in the Annals of the Rheumatic Diseases.

What’s more, they seem to boost the detrimental impact of smoking and genetic susceptibility to the disease, the findings indicate.

Rheumatoid arthritis (RA) is a chronic autoimmune joint disorder characterised by painful and disabling inflammation. It affects up to 1% of the world’s population.

While it’s known that cigarette smoking increases the risk of developing rheumatoid arthritis, it isn’t known what impact breathing in workplace dusts and fumes might have.

In a bid to find out, the researchers drew on data from the Swedish Epidemiological Investigation of RA. This comprises 4033 people newly diagnosed between 1996 and 2017 and 6485 others matched for age and sex, but free of the disease (comparison group). 

Personal job histories were provided and used to estimate the amount of individual exposure to 32 airborne workplace agents, using a validated technique. 

Each participant was assigned a Genetic Risk Score (GRS), according to whether they carried genes that could increase their chances of developing rheumatoid arthritis.

Rheumatoid arthritis is characterised by the presence or absence of anti-citrullinated protein antibodies or ACPA for short. ACPA positivity denotes a worse prognosis with higher rates of erosive joint damage.

Nearly three quarters of those with rheumatoid arthritis testing positive (73%) and negative (72%) for ACPA had been exposed to at least one workplace dust or fume compared with around two thirds (67%) of people in the comparison group.

Analysis of the data showed that exposure to workplace agents was not only associated with a heightened risk of developing rheumatoid arthritis, but also seemed to boost that risk further by interacting with smoking and genetic susceptibility.

Exposure to any workplace agent was associated with a 25% heightened risk of developing  ACPA positive rheumatoid arthritis, overall. And this risk increased to 40% in men.

Specifically, 17 out of 32 agents, including quartz, asbestos, diesel fumes, gasoline fumes, carbon monoxide, and fungicides, were strongly associated with an increased risk of developing ACPA positive disease. Only a few agents—quartz dust (silica), asbestos, and detergents—were strongly associated with ACPA negative disease.

The risk increased in tandem with the number of agents and duration of exposure, with the strongest associations seen for exposures lasting around 8–15 years. Men tended to have been exposed to more agents, and for longer, than women. 

‘Triple exposure’ to a workplace agent, plus smoking, plus a high GRS, was associated with a very high risk of ACPA positive disease, ranging from 16 to 68 times higher, compared with ‘triple non-exposure’. 

In particular, the risk of developing ACPA positive rheumatoid arthritis for the triple exposed was 45 times higher for gasoline engine exhaust fumes, 28 times for diesel exhaust, 68 times higher for insecticides and 32 times higher for quartz dust (silica). The corresponding range for ACPA negative disease wasn’t significant.

This is an observational study, and as such, can’t establish cause. The researchers also acknowledge several limitations to their findings: the study relied on personal recall; and while the exposure estimates were derived using a validated method, the results can be relatively crude.

And given that there are often several workplace agents in the air at any one time, it is difficult to pinpoint which ones might be the potential triggers.

Nevertheless, the researchers conclude:“Occupational inhalable agents could act as important environmental triggers in RA development and interact with smoking and RA-risk genes, leading to excessive risk for ACPA-positive RA.” 

They add: “Our study emphasises the importance of occupational respiratory protections, particularly for individuals who are genetically predisposed to RA.” 

The study findings have several important implications for disease development and prevention, notes Dr Jeffrey Sparks, of Brigham and Women’s Hospital, Boston, USA, in a linked editorial. 

“First, each occupational inhalable agent had a unique profile of the way it interacted with RA risk genes and with smoking….These unique interactions suggest that if the relationship between inhalable agents and RA is indeed causal, they may do so via distinct pathways.”

Alluding to the stronger associations found for ACPA positivity, Dr Sparks comments that the findings further support the growing belief that ACPA positive disease may be very different from ACPA negative rheumatoid arthritis.

Greater public health efforts are needed to curb the risk of developing rheumatoid arthritis, he concludes.

“First, environmental health initiatives should reduce public exposure to ambient pollutants, including carbon monoxide and gasoline exhaust. Second, occupational health initiatives should mitigate occupational hazards, including detergents and asbestos. Third, public health initiatives should continue to reduce cigarette smoking,” he writes.

People with rheumatoid arthritis are at increased risk of cardiovascular (CV) disease, with studies indicating an approximate 50 percent increase in risk of CV events such as heart attack and stroke. Some immunomodulators—drugs that decrease inflammation—have been shown to reduce CV risk in the general population. Researchers from Brigham and Women’s Hospital led a consortium that conducted a randomized clinical trial among people with rheumatoid arthritis to assess the impact of two anti-inflammatory strategies. All 115 patients in the trial had moderate or high disease activity despite being on low-dose methotrexate. Participants continued to take methotrexate and were randomized to additionally receive a TNF inhibitor (TNFi) or hydroxychloroquine and sulfasalazine (triple therapy). Both groups had statistically significant reductions in disease activity and in arterial inflammation, with no differences noted between the groups.

“Our results highlight the importance of conducting clinical trials specifically among patients with RA rather than the general population,” said corresponding author Daniel H. Solomon of the Division of Rheumatology, Inflammation and Immunology. “Prior trials in the general population have shown differential effects on CV risk between different immunomodulators, but in our trial, two different immunomodulator treatment strategies produced similar reductions in CV risk.”

A new blood test called PrismRA will allow patients to get the correct therapy faster.

Scientists at Scripps Research have reported success in initial tests of a new, nanotech-based strategy against autoimmune diseases.

The scientists, who reported their results on November 23, 2022, in the journal ACS Nano, engineered cell-like “nanoparticles” that target only the immune cells driving an autoimmune reaction, leaving the rest of the immune system intact and healthy. The nanoparticles greatly delayed, and in some animals even prevented, severe disease in a mouse model of arthritis.

“The potential advantage of this approach is that it would enable safe, long-term treatment for autoimmune diseases where the immune system attacks its own tissues or organs—using a method that won’t cause broad immune suppression, as current treatments do,” says study senior author James Paulson, PhD, Cecil H. and Ida M. Green Chair of Chemistry in the Department of Molecular Medicine at Scripps Research.

Autoimmune diseases such as rheumatoid arthritis are caused when the immune system mistakenly attacks a person’s own tissues or organs. These illnesses affect an estimated 10 million people in the U.S. alone. Treatments are available and can be effective for many patients, but they tend to suppress the immune system indiscriminately, creating an enhanced susceptibility to infections and cancers—among other side effects.

Paulson and his team have taken an approach that targets the immune system more narrowly. Many autoimmune diseases are triggered or driven by immune attacks on just one protein in the patient’s body, known as a “self-antigen.” The idea underlying the nanoparticle strategy is to eliminate or deactivate only the immune cells that attack that self-antigen—an approach that could be at least as effective as broad immune suppression, without the side effects. Autoimmune diseases that are dominated by immune responses to a single self-antigen include some forms of arthritis, the skin blister disease known as pemphigus and the thyroid ailment Graves’ disease.

The researchers, including first author Katarzyna Brzezicka, PhD, a postdoctoral research associate in the Paulson lab, research assistant Britni Arlian, and other lab members, designed nanoparticles that could deactivate two types of immune cells: B cells and T cells. On its surface, each nanoparticle bore copies of a target self-antigen, plus a sugar-related molecule that can bind to a special “off switch” receptor on B cells called CD22. B cells, which make antibodies and are specific to different antigens, will effectively shut themselves off if they encounter both the particular antigen they target and the binding partner of CD22 at the same time.

Each nanoparticle also was laced with a powerful compound called rapamycin to stimulate the production of immune cells called regulatory T cells. T_reg cells, as they’re also known, are responsible for suppressing other T cells needed to generate an autoimmune attack. The overall aim of the study was to effectively knock out only the B and T cells that recognize the self-antigen, leaving the rest of the B- and T-cell populations intact.

The researchers first demonstrated that their nanoparticle-based strategy could tolerize the mouse immune system to a chicken protein, ovalbumin, that would otherwise trigger a strong response. Next, they tested the strategy in a widely used mouse model of arthritis, in which the mouse immune system is genetically predisposed to attack a self-antigen called GPI. The scientists showed that treatment of the mice with GPI-tolerizing nanoparticles at the age of three weeks greatly delayed the development of arthritis signs that would normally appear a week or two later. In fact, about a third of the mice remained arthritis-free for the maximum follow-up period of 300 days. Tests confirmed that the treatment dramatically reduced the mice’s production of anti-GPI antibodies, and at the same time boosted their T_reg populations.

Paulson says his team plans to follow up these highly promising results with further optimization of the nanoparticle strategy.

“We were able to ‘cure’ a third of these animals in this early demonstration, and I think there’s the potential to combine our nanoparticles with other immune modulator treatments to make it even more effective,” Paulson says. “So that will our next step—as well as demonstrating our technology against other autoimmune diseases caused by unwanted immune responses to a self-antigen.”

“Suppression of Autoimmune Rheumatoid Arthritis with Hybrid Nanoparticles That Induce B and T Cell Tolerance to Self-Antigen” was co-authored by Katarzyna Brzezicka, Britni Arlian, Shengyang Wang, Merissa Olmer, Martin Lotz, and James Paulson, all of Scripps Research.