Scientists outline work in immune system response and the gut-brain connection
By Amy Ratner, director of scientific affairs
The way the immune system responds to a virus can help researchers better understand celiac disease, according to University of Oxford, UK, scientists who are investigating a specific type of immune cell that causes damage in celiac disease.
Called a killer CD8 T-cell, this foot soldier in the immune system of those who have celiac disease directly causes cell death in the lining of the intestine, Michael Fitzpatrick, MD, an Oxford researcher said in an update of celiac disease studies presented at the recent Beyond Celiac Research Summit.
Fitzpatrick and Paul Klenerman, MD, an immunologist and professor of gastroenterology at Oxford, are researching CD8 T-cells, which are abundant in the gut of celiac disease patients even when they are on the gluten-free diet, through a Beyond Celiac Established Investigator grant awarded in 2019. They were among a group of Beyond Celiac-funded researchers who talked about their work at the summit. The summit also included panels that addressed pediatric clinic trials and diversity in celiac disease in clinical trial recruitment.
Iain Croall, PhD, of the University of Sheffield, UK, outlined previous research into the gut brain connection that forms the basis of the new study funded through a Beyond Celiac Established Investigator Award. It was awarded to Nigel Hoggard, MD, also a Sheffield scientist, and Croall in 2021.
Work on four studies was presented to a variety of stakeholders in celiac disease, including clinicians, academic researchers, pharmaceutical company representatives and those with celiac disease, made up the summit audience. (See part 2 for details on presentations by Marisa Gallant Stahl, MD, of Children’s Hospital Colorado, who received the 2019 SSCD/Beyond Celiac Early Career Investigator Award, and Jocelyn Silvester, MD, director of research at the Celiac Disease Program at Children’s Hospital, recipient of the 2019 Pilot and Feasibility Award.)
CD8 Killer T-cells go after stressed cells in the gut with blunt force, Fitzpatrick explained, but another part of the response involves what he called “an elite special force,” with highly targeted tools that recognize very specific antigens.
In their research at Oxford, Klenerman and Fitzpatrick are looking for answers to questions about what the CD8 T-cells are doing in celiac disease, what kind of CD8 T-Cells are found in celiac disease and how these cells are using highly targeted receptors in response to gluten. They are investigating these issues in both adults and children using single cell RNA sequencing of biopsy tissue.
Early findings of their study show that in those who have celiac disease the gut is permanently altered, that the cells lining the gut, called epithelial cells, are less differentiated and are busy dividing. These cells also express different genes, partly in response to chemical messages, which are normally seen in viral infections. The epithelial cells play a role in presenting proteins to other cells, including the CD8 T-cells.
“We are looking at what genes cell populations are expressing and what they are doing in different disease states,” Fitzpatrick said.
Additionally, the study has found that cells in those who have celiac disease have not developed all the machinery to properly absorb nutrients in the gut.
The CD8 Killer T-cells are tissue resident cells, which serve as the memory population in the gut, where they sit like sentinels, Fitzpatrick said. He said this can best be described by the song “Hotel California” by the Eagles. “You can check out, but you can never leave.”
“They are long lived cells sitting there, but they have lost their hotel key card,” he explained. “They can’t escape and go back to the blood. It’s these cells that play a key role in celiac disease.”
Some of these CD8 T-cells are radically increased in proportion in both active and treated celiac disease when compared to controls who do not have celiac disease. They also express different genes in both active and treated celiac disease compared to controls. The gene associated with activation and inflammation give researchers insight into different pathways that potentially could be targeted for new therapies for celiac disease, Fitzpatrick said.
The research he and Klenerman are working on is designed to try to figure out “who is talking to who in the gut,” he noted, and where these interactions are happening.
“We think these interactions will bear fruit in understanding celiac disease immunology and the CD8 T-cell response,” he said.
The immune process that occurs in celiac disease is the same as that seen in seen in the response to viral infection.
Klenerman likened the immune system to a party being at a large English country estate, where invited guests are allowed in, but gate crashers are kept out. “The immune system distinguishes between what is invited and what is not,” he said. There are a number of barriers, include the “guard dog” innate immune system, which destroys viruses directly and then calls for security. “Gluten should not require a guard dog response,” he said, though this is what happens in celiac disease.
Killer cells, such as the CD8 T-cell are part of the security team that also includes helper cells and antibody cells. Collectively, they make up the adaptive immune system. Killer cells go “room to room” as they examine every cell and specifically address the invader, stopping the process of viral spread. But in celiac disease the hypothesis is that this process is out of tune, according to Klenerman.
After killer cells identify an invader, they retain a long-term memory of it and are posed to go on the offensive when they see it again.
“This is the natural process for generating immune response to anything,” Klenerman said. “All the tools we have used to understand how we generate these against different viruses, how we generate vaccines, can very well now be applied to celiac disease to really push our understanding forward quickly.”
The processes triggered in the gut by gluten in those who have celiac disease can also affect the brain, resulting in neurological symptoms, Croall noted in his presentation. Previous research based on independent populations data has shown that brain and cognitive changes are detectable in those with celiac disease.
In his talk titled “Your brain on gluten,” Croall noted that references to connections between gluten and neurological symptoms in those who have celiac disease date as early as 1908. He outlined conditions that are triggered by gluten – gluten ataxia, which affects the brain but does not always involve that gastrointestinal system, celiac disease, in which gluten can cause gastrointestinal and neurological symptoms, and dermatitis herpetiformis, which is the skin manifestation of celiac disease.
In the UK, National Institute for Health and Care Excellence (NICE) guidelines say that celiac disease involves a number of non-gastrointestinal symptoms and those who have unexplained neurological symptoms should be tested for the condition. However, there are still diagnostic delays often resulting in permanent neurological disability, Croall quoted a 2019 study as concluding. These delays are traced to variations in reported prevalence and poor understanding of the use of serological testing, the study says.
“There are a couple of points [the study] really nailed,” Croall said. “First, is the need to get the diagnoses correct because the brain does not recover from injury in the same way the gut can do…It’s important that people who would benefit from treatment, the gluten-free diet and so on, are identified at the earliest point that is possible.”
The second issue highlighted in the study conclusion is that the right way to identify neurological problems is not understood, Croall said. Sometimes neurological conditions are full blown, such as outright diagnosable ataxia or neuropathy, which are fairly progressed, but there is a large spectrum of neurological health before that, a whole range of things relevant to the brain and to the patient’s experience, he said.
Overall, previous research has shown that: brain and cognitive changes are detectable in patients with celiac disease; these patients may experience neurological symptoms including headache, brain fog, sensory symptoms and coordination problems mirroring more severe versions in gluten ataxia; a strict gluten-free diet slows or prevents progression of these problems, but additional, better-powered research is underway to properly evaluate this.
In their current research, Croall and Hoggard are combining clinical data, including brain scans and blood test results, from more than 1,000 people with celiac disease who have reported neurological problems with new cognitive, mood and quality of life measurements.
The study is seeking to determine whether and by how much the gluten-free diet halts the progression of neurological symptoms and what other factors determine how well a person progresses over time. The researchers are also looking for measurement of how neurological problems impact the quality of life of those with celiac disease and what new treatments might mean. Study participants are currently being mailed a questionnaire on diet and mood.
In their earlier research, Hoggard and Croall showed evidence from brains scans that people with celiac disease have a greater risk of damage to brain white matter, as well as worsened cognitive and mental health.