Cellular stress increases the probability of developing autoimmune diseases

Autoimmune disease awareness
Autoimmune disease awareness


A team of researchers led by Marc Veldhoen, Instituto de Medicina Molecular (iMM), Lisboa, have found that cellular stress enhances the activation of certain type of immune cells implicated in many chronic inflammatory conditions, increasing the risk of autoimmune diseases.

T cells, a type of white blood cell, can be tuned into different activation modes thereby tailoring immune responses to adequately deal with infections. However, some of these activation modes can particularly contribute to autoimmune diseases such as arthritis, diabetes and multiple sclerosis.

The Veldhoen lab has been studying T cell activation modes for many years and had already noticed that one particular activation status, termed Th17, is much more robust than other states leading researchers to hypothesize that these cells are more resistant to adverse conditions than other T cell counterparts.

By controlling external conditions such as osmotic pressure and sugar concentration in the culture medium as well as oxygen pressure, the team revealed that Th17 cells are preferentially generated under adverse conditions when compared to optimal conditions. Moreover, by using mouse models of autoimmunity Veldhoen and colleagues demonstrated that if cell stress was inhibited, lower numbers of Th17 cells were generated and the animals had reduced disease symptoms.

There has been an increasing focus from both academia and pharmaceutical companies over the past years on Th17 cells, since they are implicated in several chronic inflammatory conditions. In fact, studies interfering with the biology of these cells have shown promise for therapeutic applications in psoriasis and arthritis, for example.

These novel findings offer additional pharmacological targets to reduce cellular stress at sites of inflammation by reducing Th17 generation and preserving other T cell responses which may hold important clinical implications.

Molecule linked to autoimmune disease relapses identified at Stanford

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The ebb and flow of such autoimmune diseases as multiple sclerosis, lupus and rheumatoid arthritis has long been a perplexing mystery. But new findings from the Stanford University School of Medicine bring scientists closer to solving the puzzle, identifying a molecule that appears to play a central role in relapses.

The study, to be published in the Dec. 3 advance online edition of Nature Immunology, lays the groundwork for a way to determine when a relapse is about to occur, and could eventually lead to a treatment to prevent relapses. “Right now, there is no good blood test to evaluate when a person is going to have a flare-up,” said senior author Larry Steinman, MD, professor of neurology and neurological sciences. “If we had one, we might be able to give them prophylactic preventive medication.”

The current study had its genesis five years ago: In a paper published in 2001 in the journal Science, Steinman found that a protein called osteopontin was abundant in multiple sclerosis-affected brain tissue, but not in normal tissue. Since then, other groups have confirmed that osteopontin is elevated just prior to and during a relapse of the disease in M.S. patients.

Although the protein had been known to play a role in bone growth, it was unclear why it would be associated with multiple sclerosis, which results when the immune system attacks the protective myelin sheath surrounding nerve cells.

To explore this question, Eun Mi Hur, PhD, who was then a graduate student in Steinman’s lab, began using a mouse model of multiple sclerosis (experimental autoimmune encephalomyletis, or EAE) to investigate how osteopontin could cause these flare-ups. She and Steinman gave osteopontin to mice that had already experienced paralysis, similar to that of an M.S. patient, and found that the mice then experienced a relapse of the disease.

The researchers also found that the relapse would occur sometimes in an area of the brain other than the site of the original attack. For example, after receiving the osteopontin, some animals that had previously suffered paralysis became blind from a condition called optic neuritis. One feature of multiple sclerosis is that the flare-ups can affect different parts of the nervous system at different times.

“When I saw that all mice with EAE relapsed and died from the disease after about a month of osteopontin administration, I was surprised,” said Hur, the study’s first author who is now a postdoctoral scholar at Caltech. “I got a strong belief that a high level of osteopontin in patients’ blood and tissue is a major contributor of the relapse and progression of the disease.”

Through the mouse studies and molecular characterizations, Hur and Steinman showed that osteopontin – produced by immune cells and brain cells themselves – promotes the survival of the T cells that carry out the damaging attack on myelin; by increasing the number of these T cells, osteopontin increases their destructive potential. These results could be applicable to many other autoimmune diseases, including rheumatoid arthritis, type-1 diabetes and lupus.

Indeed, the effect of osteopontin may severely alter the way the immune system works. Normally, after the immune system does its job – eradicating a microbe, for instance – the response is then dialed down. If this didn’t happen, the immune response would go on indefinitely. Imagine a cold or an attack of poison oak that would last forever.

One of the ways that the immune response is muffled is that the activated T cells die in a process known as apoptosis. That is precisely what osteopontin seems to prevent. Osteopontin lets the T cells linger in the blood, ready to attack again. “We don’t know exactly what triggers that new attack but the cells certainly are around and ready to do it,” said Steinman. So scientists now face the challenge of figuring out how and why osteopontin is produced. “We’re back to the chicken-and-the-egg problem,” said Steinman. “We know the egg, so why did the chicken lay it” That is a trickier problem to work out.”

Even without knowing the answer to that question, there is one inviting practical use of their observations: Osteopontin could be used as a marker of an impending relapse. What’s more, if the protein could be blocked, it might thwart the relapse from ever occurring. Steinman’s lab is working to develop antibodies to inactivate the protein’s effect. “It’s still a long road between saying we want to do it and getting the antibodies, getting it approved by the FDA and getting it tested,” said Steinman, “but we are determined to do that.”

Still, Steinman offered a caveat. Researchers may find that blocking osteopontin has undesirable side effects. The protein may serve other purposes in addition to promoting survival of immune cells. It could also be vital to the body’s ability to produce myelin, a function that could cause severe problems if disrupted. “Like a lot of important biological molecules, osteopontin has a Janus-like quality – a bad side and a good side,” Steinman said. “We’re going to be extremely lucky if we give the antibody opposing osteopontin and derive just the good side: We stop the autoimmune attack but don’t interfere with the survival of other cells.”

Further study will determine whether thwarting osteopontin’s effect yields new types of treatments for autoimmune diseases, but regardless, it is likely to lead to discoveries in a host of areas. “I think osteopontin will turn out to be important in a lot of processes, spanning autoimmunity to stem cells,” said Steinman. “It’s probably going to turn out to be a very basic growth factor.”

Long term exposure to air pollution linked to heightened autoimmune disease risk

Polluted Air is a Possible Cause of Dementia

Long term exposure to air pollution is linked to a heightened risk of autoimmune disease, particularly rheumatoid arthritis, connective tissue and inflammatory bowel diseases, finds research published online in the open access journal RMD Open.

Environmental air pollution from vehicle exhaust and industrial output can trigger adaptive immunity–whereby the body reacts to a specific disease-causing entity. But sometimes this adaptive response misfires, prompting systemic inflammation, tissue damage, and ultimately autoimmune disease. 

Examples of autoimmune disease include rheumatoid arthritis; systemic lupus erythematosus; inflammatory bowel diseases, such as ulcerative colitis; connective tissue disease, such as osteoarthritis; and multiple sclerosis.

Both the incidence and prevalence of these conditions have steadily increased over the past decade, the reasons for which aren’t entirely clear. And whether air pollution is linked to a heightened risk of autoimmune disease remains a matter of debate, say the researchers.

To try and shed some light on the issues, the researchers mined the national Italian fracture risk database (DeFRA) and retrieved comprehensive medical information on 81,363 men and women submitted by more than 3500 doctors between June 2016 and November 2020.

Most were women (92%) with an average age of 65, and 17866 (22%) had at least one co-existing health condition. 

Each participant was linked to the nearest air quality monitoring station run by the Italian Institute of Environment Protection and Research via their residential postcode. 

The researchers were particularly interested in the potential impact of particulate matter (PM10 and PM2.5). Levels of 30µg/m3 for PM10 and 20µg/m3 for PM2.5 are the thresholds generally considered harmful to human health.

Some 9723 people (12%) were diagnosed with an autoimmune disease between 2016 and 2020.

Information on air quality was obtained from 617 monitoring stations in 110 Italian provinces. Average long term exposure between 2013 and 2019 was 16 µg/m3 for PM2.5 and 25 µg/m3 for PM10.

Exposure to PM2.5  wasn’t associated with a heightened risk of an autoimmune disease diagnosis. But PM10 was associated with a 7% heightened risk for every 10µg/m3 increase in levels, after accounting for potentially influential factors.

Long term exposure to PM10 above 30 µg/m3 and to PM2.5 above 20 µg/m3 were associated with, respectively, a 12% and 13% higher risk of autoimmune disease. 

And long term exposure to PM10 was specifically associated with a heightened risk of rheumatoid arthritis, while long term exposure to PM2.5 was associated with a heightened risk of rheumatoid arthritis, connective tissue diseases, and inflammatory bowel diseases.

Overall, long term exposure to traffic and industrial air pollutants was associated with an approximately 40% higher risk of rheumatoid arthritis, a 20% higher risk of inflammatory bowel disease, and a 15% higher risk of connective tissue diseases.

This is an observational study, and as such, can’t establish cause. And the researchers acknowledge several limitations which might have affected their findings.

These include: the lack of information on the dates of diagnosis and start of autoimmune disease symptoms; that air quality monitoring might not reflect personal exposure to pollutants; and that the findings might not be more widely applicable because study participants largely comprised older women at risk of fracture. 

But air pollution has already been linked to immune system abnormalities, and smoking, which shares some toxins with fossil fuel emissions, is a predisposing factor for rheumatoid arthritis, they explain.

Fight friendly fire with fire: an antibody for treating autoimmune disease

Fig.


Anti-RGMa antibody treatment ameliorates NMO pathophysiology CREDITTakahide Itokazu

Autoimmune diseases are the molecular equivalent of “friendly fire”: the body attacks itself instead of harmful invaders. Now, researchers from Japan have found that interrupting the complex interplay between different immune cell types can help prevent the damage that this friendly fire causes in one type of autoimmune disease.

In a study published in this month in Annals of Neurology, researchers from Osaka University have revealed that treatment with an antibody to a protein called repulsive guidance molecule-a (RGMa) dramatically improves symptoms of neuromyelitis optica, a devastating autoimmune disorder, in an experimental rat model.

Neuromyelitis optica (NMO) is an inflammatory disorder that can cause pain, paralysis, and even death. In most cases, NMO is caused by antibodies that the body develops to a protein called aquaporin-4 (AQP4). These anti-AQP4 antibodies leak into the tissue at sites of nerve damage that also show massive accumulation of neutrophils. This neutrophil build-up is associated with the death of cells called astrocytes, which ultimately causes NMO symptoms.

“We recently found that injecting rats with an antibody to RGMa can decrease the severity of NMO symptoms,” says lead author of the study Shosuke Iwamoto. “However, it was still unclear how this treatment works mechanistically, whether by affecting AQP4, astrocytes, or some other factor.”

To address this, the researchers used a clinically relevant rat model of NMO  to test the effects of the anti-RGMa antibody on disease symptoms, as well as gene and protein expression.

“Our findings revealed a new molecular mechanism of NMO pathophysiology in which RGMa stimulates macrophages to attract neutrophils to the lesions, where they kill off astrocytes,” explains Toshihide Yamashita, senior author.

Importantly, treating rats with an antibody to RGMa prevented these effects, resulting in fewer neutrophils around nerve lesions, less astrocyte killing, and a decrease in symptoms like movement problems and pain.

“Our findings suggest that anti-RGMa antibodies may represent an effective therapeutic strategy for NMO-associated neuropathic pain and motor deficits in patients with NMO,” says Iwamoto.

Given that the severity of acute NMO attacks greatly affects patients’ long-term outcomes, treatments targeting RGMa that help reduce the severity of the attack or enhance the recovery process are crucial for improving their quality of life. Treatment with an anti-RGMa antibody could potentially even be helpful in preventing NMO relapses in the chronic stage of the disease.

How to deal with autoimmune disease flare!

How to deal with autoimmune disease flares- A Rheumatologist POV - YouTube


Flares happen. We do everything we can to prevent them and to understand why they occur. But sometimes they just happen. This is true regardless of the inflammatory or autoimmune disease: lupus, arthritis, fibromyalgia, vasculitis and all the others. As frustrating as they can be, there are things you can do to manoeuvre your way through them with care and grace.