Tag Archives: Autoimmune Disease

Bile acids and gut microbes could potentially treat multiple sclerosis, according to new research in mice

Multiple sclerosis is characterized by an immune system gone haywire. A patient’s immune system starts treating the protective coating of the nerves – called myelin – as dangerous. The subsequent nerve damage can cause a variety of symptoms, including muscle weakness, pain and vision loss. MS currently has no cure, and doctors still don’t completely understand what causes it.

While there is a genetic component to MS, environmental factors also play a big role in determining whether someone will develop the disease. Recent evidence suggests that what’s in your digestive tract may also be a meaningful contributor to disease risk.

My colleagues and I at the University of Virginia are working to understand the two-way communication between the human body and the bacteria that live in its digestive system. In our recently published research, we found that bile acid in the intestines could be harnessed to protect people at high risk of MS from developing the disease, offering a new avenue for drug development.

Trillions of bacteria live in the human gut. They help the body with everything from digesting food to preventing the overgrowth of infectious and dangerous bacteria. They also “educate” the immune system to recognize what is dangerous and what is not. If this process is disturbed, the immune system may become overactive and start to treat natural parts of the body as dangerous. This is called autoimmunity.

Scientists believe that one way bacteria and the immune system communicate with each other is through the aryl hydrocarbon receptor, or AHR, which resides in most cells of the body. This protein acts like an emergency call center – when it encounters certain chemicals, it will identify the appropriate response and send a signal to the cell recommending what it should do.

While researchers have shown that signals from AHR influence multiple sclerosis development, how it does so is unclear. To better understand what AHR is doing specifically in the guts of patients with MS, we genetically engineered mice that are missing AHR in some of their immune cells. By silencing AHR’s activity, we could understand what role it may be playing in autoimmunity.

We expected to learn more from this experiment about the molecular communication of immune cells. Instead we found something surprising: The gut environment in these mice had changed. Specifically, the chemical composition of their guts had been altered, indicating that the metabolism of gut bacteria had shifted. This meant that AHR is not only sensing what’s going on in the gut, but the receptor is also actively shaping its environment.

More importantly, we found that mice without AHR were able to recover from MS. In our mouse model of MS, we induced autoimmunity by immunizing mice against myelin, the protective layer surrounding neurons. This meant that the immune system of the mice was primed to attack myelin, leading to the poor muscle control and paralysis seen in MS. We wanted to test whether the gut microbiome played a role in why mice without AHR were able to recover. When we transplanted the gut bacteria from the digestive tracts of mice without AHR into mice with AHR, we found that the mice with AHR were also able to recover from paralysis. This meant that the gut microbiome was driving recovery from MS.

We also found that the guts of mice without AHR had high levels of bile acids – chemicals produced in the liver and secreted into the intestines that help with digestion. Bile acids are often broken down by the resident bacteria in the gut.

One bile acid in particular, called taurocholic acid, was especially concentrated in mice without AHR. To test whether taurocholic acid offered protection against MS, we fed this chemical to mice with AHR as they started to develop autoimmunity to myelin. While control mice that were fed saline became paralyzed from the waist down, the mice that were fed taurocholic acid just got a little wobbly before they recovered.

With further investigation, we discovered that these mice were able to recover their motor control because their immune cells were not as strong. Exposing their immune cells to bile acids shortened the life span of the cells, thus preventing them from causing as much damage to myelin and motor neurons.

While we still do not understand why bile acids weaken immune cells, we believe it may be a key step to understanding how to interrupt autoimmunity in MS and other autoimmune disorders.

Current available therapies for autoimmune disorders like MS are immunosuppressant drugs that quiet the immune response. While these drugs can reduce relapse and delay disease progression, they can also put patients at high risk of infection and difficult side effects. With the COVID-19 pandemic, the danger of having a weakened immune system has become even more apparent.

Finding other avenues to quiet an overactive immune system, such as through bile acids, could help researchers create safer drugs that could help prevent or treat disease. The body produces eight different bile acids that each have different chemical properties. Our team is working to identify whether taurocholic acid is truly the best option for treating MS or if another bile acid – or a combination of several – would be more effective.

Bile acids are far from ready to be used as treatment in people. But we believe that the key to preventing multiple sclerosis may be inside us already.

Andrea Merchak

The Conversation

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of …

Rheumatoid arthritis (RA)  is a complex, chronic inflammatory disease that is thought to affect about one percent of the world’s population. RA happens when a person’s own antibodies attack joint tissue, causing painful swelling, stiffness, and redness. Some research has suggested that there is a link between RA and gum disease.

Image credit: Pixabay

Gum disease is estimated to affect up to 47 percent of adults, and in the disorder, oral microbes can move to the blood after the gums start to bleed. An increase in disease activity has been observed in RA patients who also have gum disease. Gum disease has been shown to be more common in RA patients who carry a certain type of antibodies, called anti-citrullinated protein antibodies (ACPAs), though ACPAs are often found in the blood of individuals with RA. The presence of ACPAs can often predate the diagnosis of RA by a few years.

A new study investigated the connections between these observations. In this work, the researchers collected blood samples from a small group of ten people with RA, five with and five without gum disease. These samples were collected every week for one year, and the investigators assessed the expression of both human and bacterial genes in those samples.

Certain types of inflammatory immune cells carried gene expression signatures that were associated with the autoimmune flares of arthritis patients who also had periodontal disease, as well as the presence of certain oral bacteria in the blood.

Many of these oral bacteria were chemically altered by deimination; they were citrullinated. Citrullination can change the structure and function of proteins. Although citrullination can be a part of the normal function of tissues, high levels of citrullination have been linked to inflammation.

Citrullination can also create targets for ACPAs; when the normal, unconverted forms of the oral bacteria were incubated with ACPAs, the antibodies did not react, but when the citrullinated oral bacteria were exposed to ACPAs, there was a reaction. ACPAs appear to be bound to oral microbes in RA patients.

The findings have been reported in Science Translational Medicine.

The study noted that the immune response to oral microbes could be influencing RA flares, that oral microbes can trigger a specific antibody reaction in patients with both RA and gum disease, and that RA flares cause varying immune signatures, which could reflect different flare triggers.

It could be that gum disease repeatedly causes the immune system to respond, and as the immune system keeps reacting and repeatedly increasing inflammation, RA may eventually begin to emerge. More work will be needed, however, to fully understand whether gum disease is playing a causative role in the development of RA.

Source: Science Translational Medicine

Carmen Leitch

Targeting T cell iron metabolism may offer a new approach for treating lupus

Targeting iron metabolism in immune system cells may offer a new approach for treating systemic lupus erythematosus (SLE) -; the most common form of the chronic autoimmune disease lupus.

A multidisciplinary team of investigators at Vanderbilt University Medical Center has discovered that blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of SLE. The findings were published Jan. 13 in the journal Science Immunology.

Lupus, including SLE, occurs when the immune system attacks a person’s own healthy tissues, causing pain, inflammation and tissue damage. Lupus most commonly affects skin, joints, brain, lungs, kidneys and blood vessels. About 1.5 million Americans and 5 million people worldwide have a form of lupus, according to the Lupus Foundation of America.

Treatments for lupus aim to control symptoms, reduce immune system attack of tissues, and protect organs from damage. Only one targeted biologic agent has been approved for treating SLE, belimumab in 2011.

It has been a real challenge to come up with new therapies for lupus. The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”

Jeffrey Rathmell, PhD, Professor of Pathology, Microbiology and Immunology and Cornelius Vanderbilt Chair in Immunobiology

Rathmell’s group has had a long-standing interest in lupus as part of a broader effort to understand mechanisms of autoimmunity.

When postdoctoral fellow Kelsey Voss, PhD, began studying T cell metabolism in lupus, she noticed that iron appeared to be a “common denominator in many of the problems in T cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high iron levels, even though patients are often anemic.

“It was not clear why the T cells were high in iron, or what that meant,” said Voss, first author of the Science Immunology paper.

To explore T cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other investigators at VUMC:

  • Eric Skaar, PhD, and his team are experienced in the study of iron and other metals;

  • Amy Major, PhD, and her group provided a mouse model of SLE; and

  • Michelle Ormseth, MD, MSCI, and her team recruited patients with SLE to provide blood samples.

First, Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.

The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.

“We see a lot of complications coming from that -; the mitochondria don’t function properly, and other signaling pathways are altered,” Voss said.

An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.

“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” Voss said. “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did.”

In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10.

The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells, to avoid any potential off-target effects (the transferrin receptor mediates iron uptake in many cell types). They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.

Skaar is the Ernest W. Goodpasture Professor of Pathology and director of the Vanderbilt Institute for Infection, Immunology, and Inflammation. Major, associate professor of Medicine, and Ormseth, assistant professor of Medicine, are faculty members in the Division of Rheumatology and Immunology. Rathmell is the director of the Vanderbilt Center for Immunobiology.

Other authors of the study include Allison Sewell, Evan Krystofiak, PhD, Katherine Gibson-Corley, DVM, PhD, Arissa Young, MD, Jacob Basham, MD, Ayaka Sugiura, PhD, Emily Arner, PhD, William Beavers, PhD, Dillon Kunkle, PhD, Megan Dickson, Gabriel Needle, and W. Kimryn Rathmell, MD, PhD.

The research was supported by the National Institutes of Health (grants DK105550, AI153167, DK101003, AI150701, CA253718) and the Lupus Research Alliance William Paul Distinguished Innovator Award to Jeffrey Rathmell.

Journal reference:

Voss, K., et al. (2023) Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus. Science Immunology. doi.org/10.1126/sciimmunol.abq0178.

Our immune system has to be able to rapidly mount a response to pathogenic invaders, wounds, and other …

Our immune system has to be able to rapidly mount a response to pathogenic invaders, wounds, and other injuries. But it also has to be carefully controlled. When the body overreacts to an infection, it can cause a condition known as sepsis, which can be deadly. Sepsis is estimated to have caused about 11 million deaths around the world in 2017 alone. Now, scientists are learning more about the immune molecules and cells that trigger sepsis. The findings have been reported Science Immunology.

Image credit: Pixabay

Cytokines are immune signaling molecules. Tumor necrosis factor (TNF) is a widely studied cytokine that has many roles. TNF is activated by a crucial component of bacterial cell walls, called lipopolysaccharide (LPS), and recruits immune cells to fight infection. TNF can aid in the repair of tissue and cell survival, but it also has to be regulated. Overactive TNF signaling has been implicated in inflammatory diseases like rheumatoid arthritis. The uncontrolled production of cytokines, including TNF, can also cause a cytokine storm, a dangerous situation.

There is no standardized definition for a cytokine storm, in part because it can be difficult to define the line between a normal and abnormal immune response. But there are commonly accepted clinical features of cytokine storms, such as fever, headache, fatigue, anorexia, rash, diarrhea, and respiratory symptoms that often progress to more serious problems including, but not limited to catastrophic hemorrhages, shock, hypoxemia, renal failure, or liver damage.

While scientists have developed TNF blockers that have been useful for some autoimmune disorders including rheumatoid arthritis, those drugs don’t prevent cytokine storms that arise in conditions like severe COVID-19 cases or sepsis. The mechanisms of TNF are still not well-understood.

In the new study, researchers induced death in mice from TNF. But when mice did not express either of two proteins that are linked to the immune response to LPS, called TRIF and CD14, survival improved. Previous work has shown that TRIF and CD14 help regulate a protein complex that is related to LPS-induced inflammation and cell death.

Blood cells called myeloid cells are known to produce a lot of TNF. The research also showed that if mice lacked neutrophils and macrophages, two kinds of myeloid cells, symptoms of sepsis were reduced and survival improved when mice were given a lethal dose of TNF. The study authors suggested that macrophages and neutrophils are, therefore, contributing significantly to TNF-mediated death in mice.

It may also be possible to treat sepsis by targeting TRIF and CD14, which could reduce cell death and inflammation.

Sources: New England Journal of Medicine, Medical Xpress via The Conversation, Science Immunology

Carmen Leitch

Gut bacteria have been linked to an ever-increasing number of diseases. Research is now going beyond establishing a …

Gut bacteria have been linked to an ever-increasing number of diseases. Research is now going beyond establishing a link between a disorder and the community of gut microbes, and has begun to identify specific organisms that are responsible for certain conditions. Scientists have now shown that a strain of bacteria in the Subdoligranulum genus can lead to the production of autoantibodies, which appears to cause the development of rheumatoid arthritis. The findings have been reported in Science Translational Medicine.

Image cresit: Pixabay

Rheumatoid arthritis is an autoimmune disease in which the joints are erroneously attacked by the immune system, and the inflammation and damage that occurs in affected joints causes pain, the loss of mobility, and other serious problems. Disruption of mucosal immunity, in the gut, has been proposed to be one cause of rheumatoid arthritis.

In this work, the researchers obtained blood samples from people who are at risk of developing RA, and the autoantibodies were isolated from those samples.

The scientists found that the autoantibodies were causing a response in certain bacteria in the Lachnospiraceae/Ruminococcaceae families. Further work revealed that bacteria of the genus Subdoligranulum, a member of those families that was isolated from the feces of people ate risk for RA, could bind to the autoantibodies and cause the activation of CD4+ T cells. This was occurring in individuals with RA, but not in healthy people.

The Subdoligranulum bacteria was put in an animal model, and the animals began to develop the same RA risk markers found in the blood of people who are at risk for RA. Some of the animals also developed RA.

“Through studies in humans and animal models, we were able to identify these bacteria as being associated with the risk for developing RA. They trigger an RA-like disease in the animal models, and in humans, we can show that this bacterium seems to be triggering immune responses specific to RA,” said study leader Kristine Kuhn, MD, Ph.D., an associate professor at CU School of Medicine.

This microbe could be a good therapeutic target for RA treatment, noted Kuhn. Now, the scientists want to assess large populations of people who are at risk for RA to see if the Subdoligranulum microbes are also linked to other factors like genetics, mucosal immunity, and environmental conditions that can lead to RA. It may help scientists find prevention strategies or other ways to stop the microbes from causing disease, added Kuhn.

Sources: CU Anschutz Medical Campus, Science Translational Medicine

Carmen Leitch