Tag Archives: Mucosal Immunology

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.

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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

Our immune system is built to detect foreign invaders, pathogens, and debris, and then eliminate them. So how …

Our immune system is built to detect foreign invaders, pathogens, and debris, and then eliminate them. So how does it deal with the trillions of microbial cells that make a home for themselves in our gastrointestinal tract? Scientists have now found an answer to that question, and the evidence they revealed has also changed what we know about the interactions between immune receptors and a protein that helps move bacteria around, called flagellin. The findings have been reported in Science Immunology.

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There are many beneficial microbes in the human gut microbiome, and we need many of those microorganisms to help us break down food and absorb nutrients, for example. But there are also pathogenic gut germs. The immune system can recognize those pathogenic microbes with different receptors, one of which is called toll-like receptor 5 (TLR5). TLR5 attaches to flagellin, a protein found in the flagellum of bacteria, a structure that propels bacterial cells. When TLR5 binds to flagellin, an inflammatory response is triggered.

But many bacteria have flagellin, not only pathogens. Some bacteria have adapted and can make flagellin that will not bind to TLR5, so no immune response is initiated. But many harmless or so-called commensal bacteria generate flagellin that will still bind to TLR5. So how are these microbes tolerated by the immune system?

In this work, researchers delved deeply into flagellins, and analyzed those made by different bacteria. After assessing 116 flagellin proteins, they found that about half of them were not like any that were known; they could bind to TLR5 normally, but surprisingly, did not lead to an inflammatory response. The study authors have called these flagellin proteins “silent flagellins.” This has shown how the immune system tolerates commensal gut bacteria, even when those microbes share common features with pathogens.

This research has upended what we knew about TLR5 binding, which was once thought to be enough to trigger an inflammatory cascade.

“We now know that bacterial flagellin can interact with TLR5 at least three in different ways: bind and induce an immune response, bind and not induce an immune response, and evade by not binding,” noted senior study author Ruth Ley, director of the Department of Microbiome Science at the Max Planck Institute for Biology Tübingen.

“It is remarkable how tunable the response of the TLR5 receptor is,” added Ley.

After analyzing the genomes of many gut microbes, the researchers found that silent flagellins are a typical part of human gut microbes.

Sources: Max Planck Society, 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.

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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