12 Medical Tests for Psoriatic Arthritis, Explained
Why Are Autoimmune Disorders More Common In Women?
Inflammation is our body's defense mechanism against phenomena it recognizes as foreign. However, as with any complicated system, an error may arise. Inflammation helps our body fight off bacteria, viruses, and other toxins.
But suppose our immune response continues after the threat has passed. In that case, it can cause damage to your healthy tissue or precipitate an autoimmune disorder that occurs when the body's immune system attacks and destroys healthy body tissue because it misinterprets it as an invader.
Women have up to four times more autoimmune disorders than men. Many explanations are proposed for this difference, including sex hormones, women's extra X chromosome, environmental factors, and differences in our gut environment. Understanding the mechanism for this difference is essential because autoimmune disorders are a leading cause of morbidity and mortality in young and middle‐aged women.
The Antibody TheoryWomen have higher levels of circulating antibodies than men. Women's antibody levels spike after giving birth, and this is also a time when more autoimmune disorders are diagnosed. Women produce much more estrogen than men, and estrogen increases antibody production, while androgens (like testosterone) decrease it.
The exception is men who have a condition called Klinefelter's syndrome. Men born with this condition have an extra copy of the X chromosome, and they, too, have higher levels of antibodies. In addition, their prevalence for autoimmune disorders is like that of women.
Researchers at the Mayo Clinic and the University of Alabama published an article investigating this question from an evolutionary perspective. They wondered why nature would preserve excess antibody production in women during the prime child-bearing years and hypothesized that the answer is related to infections.
Historically, infections are a leading cause of death for infants and adults. Even in the modern world, almost 70% of infant deaths are attributed to infections. So, from an evolutionary perspective, women having higher antibodies means they are more likely to fight off infections, and if breastfed, their infants have the same advantage.
The Additional X Chromosome TheoryWomen have two X chromosomes, while men are XY. The X chromosome contains more genetic material than the Y and carries more immune-related genes. Because of this, the X chromosome has a greater possibility of gene-related mutations.
A study at the University of California, Los Angeles (UCLA) discovered that a gene located on the X chromosome might help to explain why women are more prone to develop multiple sclerosis (MS) than men. They found a gene called Kdm6a that is more frequently expressed in women's immune cells. When scientists conducted an animal study using female mice without the Kdm6a gene bred to mimic a disease like MS, the animals experienced reduced inflammation and less damage to their spinal cords.
A Stanford University study published earlier this month supports the theory behind women's extra X chromosome as the reason for women's increased risk of autoimmune disorders. They reported on a molecule called Xist found on X chromosomes, which is only transcribed into RNA proteins when two XX chromosomes are present. The job of this molecule is to shut down the extra X chromosome in a process called X-chromosome inactivation.
The study's lead author, Howard Chang, found that sometimes Xist can generate odd RNA combinations that bind to other proteins, creating complexes that can trigger a robust immune response. Chang learned that some proteins associated with Xist are linked to autoimmune disorders.
To eliminate the sex difference, his group studied male mice genetically altered with an Xist protein and bred for susceptibility to autoimmune disorders. Once the researchers chemically activated the Xist complex in those animals, they developed symptoms like human lupus, an autoimmune disorder. When the researchers stimulated the Xist molecule in male mice bred to be resistant to autoimmunity, they did not have the same result. This supports the evidence in humans. Women are more susceptible to autoimmune disorders, but not every woman develops one.
This Begs the Question, What Does It All Mean?It means that genetics are but one element that, in combination with others, can cause an autoimmune disorder. Like most medical conditions, the causes of autoimmune disease are multifactorial.
In addition to genetics, other factors shown to contribute to this disease class are environmental such as diet, smoking, exercise, or lack thereof, stress, poor sleep, pollutants, infections such as COVID-19, and increased alcohol use. There are, however, ways to minimize your risk of developing one of these disorders.
The bottom line is that if you are born a genetic female, you are more likely than your male counterpart to develop an autoimmune disorder. However, genes are not the sole cause of this class of disease. Several modifiable environmental factors can be practiced to decrease your overall risk.
Small Study Adds To Growing Hope CAR-T Cell Therapy Could Revolutionize Autoimmune Disease Treatment
People with autoimmune disorders don't usually get to talk about a cure. There's symptom management, hopeful periods of remission often followed by relapses, but rarely a lasting fix for the way their immune system attacks healthy cells. If the immune system is an army, then those with conditions like lupus, multiple sclerosis, or rheumatoid arthritis are often fighting a never-ending war of friendly fire.
But over the last few years, researchers in Germany have begun testing the potential of CAR-T therapy — a cutting-edge cancer treatment in which a patient's immune T cells are genetically modified in a lab to better attack disease targets — to help those with autoimmune disorders. Their latest findings, published Wednesday in the New England Journal of Medicine, provide evidence that has led experts to consider, tentatively, using the c-word.
In a study of 15 patients — eight with lupus, four with systemic sclerosis (scleroderma), and three with idiopathic inflammatory myositis, a rare muscle disease — researchers eliminated or reduced symptoms and disease biomarkers with a single infusion of CAR-T cells designed to target B cells, immune cells that play a key role in driving autoimmunity. There were no relapses among lupus patients, who were monitored for up to two years after treatment. The myositis and sclerosis patients, who had shorter-term follow-up (usually about three to six months but up to a year) saw their symptoms significantly lessen.
"It's wonderful. I mean, some people would think that this might be too good to be true, but it actually does look true," said Carola Vinuesa, an immunologist and geneticist at the Francis Crick Institute in London, who was not involved with the research.
Patients included in the case study were experiencing severe forms of these diseases that affected at least two organs, with "not many treatment options left," according to Fabian Müller, a hematologist-oncologist at University Hospital Erlangen and first author on the paper.
For patients with myositis, muscles are damaged by elevated levels of an enzyme called creatine kinase. Extreme disease can leave a person bedridden, struggling to breathe. One of the team's patients with myositis, a 42-year old man, could barely stand before treatment and was only able to walk about 30 feet. Two or three months later, he was walking so much that he reported foot pain at a follow-up appointment, because his bones hadn't yet gotten used to his stronger muscles, Müller said. Now, that patient walks 6 miles to work each day, just because he can, he said.
A patient with lupus, which can affect joints, skin, kidneys, lungs, and more, was experiencing heart failure before treatment. But afterward, her fatigue and other symptoms disappeared and she's back to life as normal. A patient with scleroderma, which makes someone's skin tight, hard, or stiff, is walking confidently again now that he feels like he is standing on steady ground once more.
The findings build on results the researchers presented at the annual American Society of Hematology meeting late last year. When the team first began publishing their research, experts were cautiously intrigued. Before the infusion of CAR-T cells, patients receive chemotherapy to prepare and clear their immune system. It was possible that early positive results were simply due to the proven benefits of chemo. But now, with positive results lasting for as long as two years, it's becoming more clear that the therapy is driving the improvements.
But it's still unclear exactly why the CAR-T therapy seems to work so much better than previous treatments that target B cells using monoclonal antibodies. Perhaps an antibody "doesn't have the ability to actively traffic into tight spaces and can only see what's in the blood or what's getting a lot of blood, whereas the CAR-T cells have access to other tissues," said Mark Leick, a physician at the Hematopoietic Cell Transplant and Cell Therapy Program at Massachusetts General Hospital.
Previous monoclonal antibody therapies target B cells via a protein they carry known as CD20. Müller and his team made CAR-T cells that would target B cells carrying a different protein, CD19. This difference could be part of the "deeper depletion" of B cells seen in CAR-T therapy, said John Isaacs, a rheumatologist and professor at Newcastle University who wrote a commentary on the study also published Wednesday in NEJM. Alternatively, CAR-T cells could simply be more lethal than antibodies, he said.
Critically, patients did not appear to lose immunity to diseases they'd previously been vaccinated against, "which is like a dream," said Vinuesa. The team did observe a decrease in the level of SARS-CoV-2 antibodies in patients' bodies after treatment, but two patients who received vaccines afterward saw those levels rise.
Experts say it's still too early to label CAR-T therapy as a real cure for the autoimmune disorders. Still, "it does look like probably the best treatment there's been," Vinuesa said. Patients who took handfuls of pills every day before are now treatment-free. "It definitely gives [the patients] an incredible break from disease."
Longer term follow-up on bigger groups of patients is needed, which researchers across the globe are now racing to perform, said PJ Utz, a physician who runs a research lab at Stanford University studying autoimmunity. He knows of three companies pursuing CAR-T therapy for autoimmune disorders, including Kyverna Therapeutics, which filed for its initial public offering last month.
"I've been working on these diseases for 30 years now. And we always say, 'We want to cure them, we want to cure them.' We've never had anything like this where a disease completely disappears," said Utz, who was not involved in the study.
As for the team of researchers pioneering the research, they aren't legally able to form any company, Müller said, because they are using technology from German biotech Miltenyi to build the chimeric antigen receptors (CAR) and produce them in patient T cells. Still, they're working on a Phase 1/2 expansion trial with another two dozen patients and longer follow-up periods, Müller said.
"There will be relapses coming. We're sure it can't be that good," he said of the treatment. Part of the team's continuing research will be figuring out how to address those relapses.
In cancer treatment, patients are considered cured if their disease hasn't returned after five years off all therapy. And since CAR-T is a treatment borrowed from cancer, perhaps rheumatologists should consider adopting that same definition for a cure, Utz said. Müller noted that he would consider lupus patients cured three to five years after stem cell transplants. By either definition, most of the patients in this study may be on their way.
Possible Trigger For Autoimmune Diseases Discovered: B Cells Teach T Cells Which Targets Must Not Be Attacked
Immune cells must learn not to attack the body itself. A team of researchers from the Technical University of Munich (TUM) and the Ludwig Maximilian University of Munich (LMU) has discovered a previously unknown mechanism behind this: other immune cells, the B cells, contribute to the "training" of the T cells in the thymus gland.
If this process fails, autoimmune diseases can develop. The study confirms this for Neuromyelitis optica, a disease similar to Multiple Sclerosis. Other autoimmune diseases may be linked to the failure of this new mechanism as well.
In children and adolescents, the thymus gland functions as a "school for T cells." The organ in our chest is where the precursors of those T cells that would later attack the body's own cells are discarded. Epithelial cells in the thymus present a large number of molecules that occur in the body to the future T cells. If any of them reacts to one of these molecules, a self-destruction program is triggered.
T cells that attack the body's own molecules remaining intact and multiplying, on the other hand, can cause autoimmune diseases.
In Nature, the team led by Thomas Korn, Professor of Experimental Neuroimmunology at TUM and a Principal Investigator in the SyNergy Cluster of Excellence, and Ludger Klein, Professor of Immunology at LMU's Biomedical Center (BMC), describe another previously unknown mechanism behind this.
In addition to the precursors of T cells, the thymus gland also contains other immune cells, the B cells. They develop in the bone marrow but migrate to the thymus in early childhood. "The function of B cells in the thymus gland has been a mystery that has puzzled immunologists for many years," says Thomas Korn. The researchers have now been able to show for the first time that B cells play an active role in teaching T cells, which targets, not to attack.
MS-like disease due to malfunction in tolerance formationNeuromyelitis optica is an autoimmune disease similar to multiple sclerosis (MS). While it is not yet known which molecules are attacked in MS, it is well-established that T cells respond to the protein AQP4 in neuromyelitis optica. AQP4 is most prominently expressed in cells of the nervous tissue, which then becomes the target of the autoimmune reaction. Frequently, the optic nerve is affected.
The researchers were able to show that in the thymus gland of humans and mice not only the epithelial cells but also B cells express and present AQP4 to the T cell precursors. If the B cells were prevented from doing so in animal experiments, AQP4-reactive T cell precursors were not eliminated, and the autoimmune disease developed. This was also the case when the epithelial cells still presented the molecule.
The team concludes from this that B cells in the thymus are a necessary condition for immune tolerance regarding AQP4.
"We suspect that this previously unknown process has evolved particularly to prevent dangerous interactions between autoreactive T and B cells in the lymph nodes and spleen, the so-called peripheral immune compartment," says Ludger Klein.
Once the immune system is developed, B and T cells can communicate and thus trigger highly effective immune reactions. This is useful when it comes to fighting pathogens quickly. On occasion, however, B cells may accidentally present the body's own proteins, such as AQP4. If the T cells that react to AQP4 had not been sorted out in the thymus, this could lead to a sudden and violent large-scale attack on the body.
Possible cause of other immune disorders"We assume that problems with the training of T cells by the B cells in the thymus can cause other autoimmune diseases as well," says Thomas Korn. "After all, the B cells in the thymus present a whole range of the body's own proteins. The corresponding interactions must be investigated in further studies."
According to the researchers, likely suspects include antiphospholipid syndrome (APS) and certain forms of cerebral amyloid angiopathy. "Looking further into the future, this interaction in the thymus might be exploited to treat existing autoimmune diseases in a very targeted manner," says Thomas Korn.
More information: Thomas Korn, B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4, Nature (2024). DOI: 10.1038/s41586-024-07079-8. Www.Nature.Com/articles/s41586-024-07079-8
Citation: Possible trigger for autoimmune diseases discovered: B cells teach T cells which targets must not be attacked (2024, February 21) retrieved 28 February 2024 from https://medicalxpress.Com/news/2024-02-trigger-autoimmune-diseases-cells.Html
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