After spending years tracing the origin and migration pattern of an unusual type of immune cell in mice, researchers headed by a team at The Ohio State University College of Medicine have shown how the activity of “good” microbes in the gut is linked to rheumatoid arthritis (RA) and, potentially, other autoimmune diseases.
Scientists first reported in 2016 that specific gut microbes known as commensal bacteria, which cause no harm and often contribute to host health, set off production and release of a gut-originated T cell that drives up body-wide autoimmune disease in mice. Since then, the team has focused on explaining this unexpected twist in the typically harmonious relationship between these microbes and the body.
The gut is where the action begins, but the overall outcome can be attributed to T cells’ “plasticity”—their flexibility to respond to a changing environment, such as in our body’s barrier, the gut.
The research indicates that reprogrammed T helper cells adopt characteristics of a new T helper cell type while preserving some of their original traits, making them “super powerful and potent—and if you are dealing with autoimmune disease, that’s bad news,” said senior and corresponding study author Hsin-Jung Joyce Wu, BVM, PhD professor of internal medicine, division of rheumatology and immunology, at The Ohio State University College of Medicine. “This is really the first time it’s been shown that T cell plasticity, which typically occurs in the gut, can have this dramatic impact outside the gut with systemic impact on autoimmune disease.”
The newly reported findings likely have relevance to human patients, Wu said. Many of the gene expressions detected in these abnormal cells in mice also exist in the same cells in people with rheumatoid arthritis. Wu is senior author of the team’s paper in Nature Immunology, titled “Aberrant T follicular helper cells generated by TH17 cell plasticity in the gut promote extraintestinal autoimmunity.” In their paper the team concluded, “Our findings offered a mechanism whereby T cell plasticity, a process originating in the gut and aided by gut microbiota, powerfully promotes autoimmunity at gut-distal sites.”
“Autoimmune diseases have risen steeply in the industrialized world,” the authors wrote. An estimated 18 million people worldwide are affected by rheumatoid arthritis, a chronic autoimmune disease-causing inflammation throughout the body and pain in the joints. Like other autoimmune diseases, RA is caused by the immune system attacking the body’s tissues and organs. Though the exact cause is unknown, genetics and environmental exposures—such as smoking and changes of gut commensal bacteria, or dysbiosis—are among the risk factors.
The abnormal T cells in question is called a T follicular helper 17 (TFH17) cell—meaning it functions as a TFH cell but also displays T helper 17 (TH17) cell signatures. Several previous studies have reported that the human equivalent of these types of cells are found in the blood of patients with autoimmune diseases, and are linked to more severe symptoms, but little has been known about the cells’ backstory. “An excessive TFH cell response can lead to overproduction of autoantibodies (auto-Ab) and autoimmunity,” the team further noted, while “Much remains unknown regarding T follicular helper 17 (TFH17) cells commonly found in autoimmune patients.”
These cells have been a puzzle, Wu said, because the conventional TFH cells are expected to be nonmobile, and just reside in B cell follicles to help B cells, another immune cell type critical for the development of RA. “T follicular helper (TFH) cells are a subset of CD4+ T cells, specializing in B cell help,” they pointed out. “Unlike other T effector cells, conventional TFH cells are not very mobile as they are mostly confined to the B cell follicles where they originated.”
However, in contrast with conventional TFH cells, the TFH17 cells also have the traveling capabilities of T helper 17 cells, which are known to migrate rapidly to infection sites where they produce the proinflammatory protein IL-17. “Circulating T follicular helper 17 (cTFH17) cells are a subset of T cells sharing both TFH and T helper 17 (TH17) cell signatures, which are found in the blood of numerous types of autoimmune patients,” the investigators explained.
Following their 2016 study, work in Wu’s lab has now discovered that the systemic TFH cells traced back to Peyer’s patches (PP), lymphoid tissue in the small intestine, and induced by typically harmless microbes called segmented filamentous bacteria (SFB), are enriched with TFH17 cells.
Studies in fate-mapping mouse models showed that the hybrid cells derived from T helper 17 cells in the gut transformed into T follicular helper cells inside Peyer’s patches, and that the segmented filamentous bacteria enhanced the cell reprogramming process. “… using the TH17 cell fate-mapping mice to track TH17-derived cells, we found that a large proportion of TH17 cells transdifferentiated into the TFH cells in PPs,” they further stated. “This TH17 cell reprogramming was driven by the transcription factor c-Maf and SFB further enhanced this process.”
Wu noted, “The key is T cell plasticity only happens in very few places, which is why it’s been overlooked—the dominant place to find them is in the gut barrier. And that’s one of few places in the body where the environment can change from one second to the next, and therefore induction of T cell plasticity occurs to accommodate the ever-changing environmental challenge.”
The team then used fluorescent tagging of cells in the arthritic mouse model to observe the cells’ movement from the gut to the rest of the body. “That’s how we knew they were really traveling,” Wu said. Importantly, these cells also acquire a stronger capability to help B cells compared to conventional TFH cells. “That’s what makes them ultra-pathogenic TFH cells in RA, a systemic disease, because they are very mobile and can potently help B cells,” she said.
To demonstrate the hazard associated with these abnormal TH17-derived TFH (TFH17Der) cells, the researchers compared RA development in genetically susceptible mouse models injected with only conventional TFH cells (control group) or conventional TFH cells mixed in with around 20% of TH17-derived TFH cells.
Substituting a small number of the conventional cells with these aberrant TFH cells increased the arthritis-related ankle thickening in mice by 4.8-fold compared to control mice, a finding that took Wu and colleagues by surprise. “The biological significance of TFH17Der cells was demonstrated by the gain-of-function study showing that a minor percentage of the TFH17Der cells boosted ankle thickening by 4.8-fold compared to the control group,” they wrote.
Researchers also sequenced the gene expression profiles of the aberrant T follicular helper cells isolated from the gut of RA mouse models and found that they shared several similarities with those of TFH cells circulating in the blood of people with RA—including the gut signature, hinting that a similar mechanism is behind human disease as well. Compared with healthy controls, the investigators stated, “… the murine PP TFH17Der cell signature was also enriched in patients with RA … and cTFH cells isolated from patients with RA displayed enhanced gene expression associated with TFH cell function, TH17 cells and mucosal origin.”
“That, to me, was exciting, to find this cross-species signature, which suggests the translational potential of this research,” Wu said. “We are hoping to improve patients’ health and life. For the future, as TFH17 cells can be found in other type of autoimmune patients, such as lupus patients, if we can determine that these abnormal TFH cells are a potential target not just for RA, but across autoimmune diseases, that would be very useful.” The authors further stated, “It will be interesting to investigate whether the findings are applicable to other autoimmune diseases as well as conditions outside autoimmunity.”
The post Gut Microbiome Linked to Rheumatoid Arthritis Through Reprogrammed T Helper Cells appeared first on GEN - Genetic Engineering and Biotechnology News.
Scientists first reported in 2016 that specific gut microbes known as commensal bacteria, which cause no harm and often contribute to host health, set off production and release of a gut-originated T cell that drives up body-wide autoimmune disease in mice. Since then, the team has focused on explaining this unexpected twist in the typically harmonious relationship between these microbes and the body.
The gut is where the action begins, but the overall outcome can be attributed to T cells’ “plasticity”—their flexibility to respond to a changing environment, such as in our body’s barrier, the gut.
The research indicates that reprogrammed T helper cells adopt characteristics of a new T helper cell type while preserving some of their original traits, making them “super powerful and potent—and if you are dealing with autoimmune disease, that’s bad news,” said senior and corresponding study author Hsin-Jung Joyce Wu, BVM, PhD professor of internal medicine, division of rheumatology and immunology, at The Ohio State University College of Medicine. “This is really the first time it’s been shown that T cell plasticity, which typically occurs in the gut, can have this dramatic impact outside the gut with systemic impact on autoimmune disease.”
The newly reported findings likely have relevance to human patients, Wu said. Many of the gene expressions detected in these abnormal cells in mice also exist in the same cells in people with rheumatoid arthritis. Wu is senior author of the team’s paper in Nature Immunology, titled “Aberrant T follicular helper cells generated by TH17 cell plasticity in the gut promote extraintestinal autoimmunity.” In their paper the team concluded, “Our findings offered a mechanism whereby T cell plasticity, a process originating in the gut and aided by gut microbiota, powerfully promotes autoimmunity at gut-distal sites.”
“Autoimmune diseases have risen steeply in the industrialized world,” the authors wrote. An estimated 18 million people worldwide are affected by rheumatoid arthritis, a chronic autoimmune disease-causing inflammation throughout the body and pain in the joints. Like other autoimmune diseases, RA is caused by the immune system attacking the body’s tissues and organs. Though the exact cause is unknown, genetics and environmental exposures—such as smoking and changes of gut commensal bacteria, or dysbiosis—are among the risk factors.
The abnormal T cells in question is called a T follicular helper 17 (TFH17) cell—meaning it functions as a TFH cell but also displays T helper 17 (TH17) cell signatures. Several previous studies have reported that the human equivalent of these types of cells are found in the blood of patients with autoimmune diseases, and are linked to more severe symptoms, but little has been known about the cells’ backstory. “An excessive TFH cell response can lead to overproduction of autoantibodies (auto-Ab) and autoimmunity,” the team further noted, while “Much remains unknown regarding T follicular helper 17 (TFH17) cells commonly found in autoimmune patients.”
These cells have been a puzzle, Wu said, because the conventional TFH cells are expected to be nonmobile, and just reside in B cell follicles to help B cells, another immune cell type critical for the development of RA. “T follicular helper (TFH) cells are a subset of CD4+ T cells, specializing in B cell help,” they pointed out. “Unlike other T effector cells, conventional TFH cells are not very mobile as they are mostly confined to the B cell follicles where they originated.”
However, in contrast with conventional TFH cells, the TFH17 cells also have the traveling capabilities of T helper 17 cells, which are known to migrate rapidly to infection sites where they produce the proinflammatory protein IL-17. “Circulating T follicular helper 17 (cTFH17) cells are a subset of T cells sharing both TFH and T helper 17 (TH17) cell signatures, which are found in the blood of numerous types of autoimmune patients,” the investigators explained.
Following their 2016 study, work in Wu’s lab has now discovered that the systemic TFH cells traced back to Peyer’s patches (PP), lymphoid tissue in the small intestine, and induced by typically harmless microbes called segmented filamentous bacteria (SFB), are enriched with TFH17 cells.
Studies in fate-mapping mouse models showed that the hybrid cells derived from T helper 17 cells in the gut transformed into T follicular helper cells inside Peyer’s patches, and that the segmented filamentous bacteria enhanced the cell reprogramming process. “… using the TH17 cell fate-mapping mice to track TH17-derived cells, we found that a large proportion of TH17 cells transdifferentiated into the TFH cells in PPs,” they further stated. “This TH17 cell reprogramming was driven by the transcription factor c-Maf and SFB further enhanced this process.”
Wu noted, “The key is T cell plasticity only happens in very few places, which is why it’s been overlooked—the dominant place to find them is in the gut barrier. And that’s one of few places in the body where the environment can change from one second to the next, and therefore induction of T cell plasticity occurs to accommodate the ever-changing environmental challenge.”
The team then used fluorescent tagging of cells in the arthritic mouse model to observe the cells’ movement from the gut to the rest of the body. “That’s how we knew they were really traveling,” Wu said. Importantly, these cells also acquire a stronger capability to help B cells compared to conventional TFH cells. “That’s what makes them ultra-pathogenic TFH cells in RA, a systemic disease, because they are very mobile and can potently help B cells,” she said.
To demonstrate the hazard associated with these abnormal TH17-derived TFH (TFH17Der) cells, the researchers compared RA development in genetically susceptible mouse models injected with only conventional TFH cells (control group) or conventional TFH cells mixed in with around 20% of TH17-derived TFH cells.
Substituting a small number of the conventional cells with these aberrant TFH cells increased the arthritis-related ankle thickening in mice by 4.8-fold compared to control mice, a finding that took Wu and colleagues by surprise. “The biological significance of TFH17Der cells was demonstrated by the gain-of-function study showing that a minor percentage of the TFH17Der cells boosted ankle thickening by 4.8-fold compared to the control group,” they wrote.
Researchers also sequenced the gene expression profiles of the aberrant T follicular helper cells isolated from the gut of RA mouse models and found that they shared several similarities with those of TFH cells circulating in the blood of people with RA—including the gut signature, hinting that a similar mechanism is behind human disease as well. Compared with healthy controls, the investigators stated, “… the murine PP TFH17Der cell signature was also enriched in patients with RA … and cTFH cells isolated from patients with RA displayed enhanced gene expression associated with TFH cell function, TH17 cells and mucosal origin.”
“That, to me, was exciting, to find this cross-species signature, which suggests the translational potential of this research,” Wu said. “We are hoping to improve patients’ health and life. For the future, as TFH17 cells can be found in other type of autoimmune patients, such as lupus patients, if we can determine that these abnormal TFH cells are a potential target not just for RA, but across autoimmune diseases, that would be very useful.” The authors further stated, “It will be interesting to investigate whether the findings are applicable to other autoimmune diseases as well as conditions outside autoimmunity.”
The post Gut Microbiome Linked to Rheumatoid Arthritis Through Reprogrammed T Helper Cells appeared first on GEN - Genetic Engineering and Biotechnology News.