A novel blood test offering the potential for earlier and less invasive diagnosis of celiac disease is on the horizon, thanks to advances in high-throughput T-cell receptor (TCR) sequencing. Researchers have identified shared immune signatures in the blood of individuals with celiac disease that distinguish them from healthy controls, regardless of gluten intake.
Celiac disease (CD) is a chronic autoimmune disorder triggered by gluten in genetically susceptible individuals. Affecting roughly one percent of the global population, the condition damages the small intestine, leading to malabsorption and a range of gastrointestinal symptoms. However, recent screening studies suggest the actual prevalence may be significantly higher, potentially reaching three percent in certain populations, indicating a substantial number of undiagnosed cases.
Currently, diagnosis relies on serological testing followed by intestinal biopsy, considered the gold standard but an invasive procedure requiring patients to continue consuming gluten – a challenging and burdensome process. The new research, utilizing immune sequencing, aims to circumvent these limitations.
Researchers from Adaptive Biotechnologies, collaborating with Mayo Clinic and other institutions, discovered hundreds of shared, disease-associated TCRs enriched in patients with CD compared to healthy individuals. This discovery, currently available as a preprint, reveals patterns in the adaptive immune system that could allow clinicians to monitor the disease without resorting to invasive testing.
“By sequencing an individual’s TCR repertoire, we get a full, accurate picture of that person’s T cell response to disease antigens,” explained Rebecca Elyanow, Associate Principal Computational Biologist at Adaptive. Unlike traditional tests that capture a snapshot of antibodies or tissue changes, deep TCR sequencing provides a comprehensive view of the adaptive immune responses in celiac disease.
The study analyzed peripheral blood samples from over 1,600 biopsy-confirmed celiac disease patients, including those adhering to long-term gluten-free diets and compared them to over 1,100 healthy controls. The identified TCR signatures persisted even after gluten removal, suggesting the presence of long-lived memory T-cell populations.
“By taking this population scale, unbiased approach, we capture a broader set of CD-specific T cells that are gluten-specific, including those that might not bind to the set of known gluten antigens,” Elyanow said.
The concept of “public” TCRs, whereas seemingly counterintuitive given the vast diversity of the adaptive immune system, is rooted in biases in receptor generation, and selection. Shared TCRs can reflect common antigen exposures or underlying disease processes, making them valuable biomarkers. The researchers’ findings are compelling because the celiac-associated TCRs they identified are specifically enriched in patients and remain detectable even on a gluten-free diet.
“Our data demonstrates that these T cells are memory cells because they remain clonally expanded even after individuals have been on gluten-free diets for several years,” Elyanow explained. “That is why the public CD T-cell signature that we identified could be used to diagnose early onset of celiac disease.”
The potential for a non-invasive, blood-based diagnostic test is a significant advancement. The newly identified TCR signatures correlate with disease status and intestinal damage severity, suggesting TCR sequencing could serve as a sensitive biomarker of disease activity. “This is certainly our hope, particularly given that we only need a small amount of blood to detect these TCRs,” Elyanow said. “Our data indicate that TCR sequencing could potentially be used as a non-invasive option to quantify and longitudinally monitor the level of these disease-specific TCRs.” However, she noted that further studies correlating TCR dynamics with biopsy results over time are needed to fully validate this application.
Beyond diagnosis, TCR profiling could also be a valuable tool in clinical trials and disease monitoring. As new therapies for CD are developed, tracking changes in disease-associated T cell populations could provide insights into treatment efficacy before clinical symptoms change. “Many pharma and biotech companies are already using our TCR sequencing assay in clinical trials to understand patients’ T-cell responses before and after therapy,” Elyanow said. “As drugs currently under development for celiac disease turn into available, our CD T cell signature could be used to monitor treatment response by measuring the reduction or elimination of these pathogenic T cells.”
The approach extends beyond celiac disease, with similar TCR-based methods showing promise in other autoimmune disorders. The apply of immune repertoire signatures as diagnostic and prognostic biomarkers is gaining traction across various fields.
