Peyer’s patch B cells drive TG2 autoantibodies in celiac disease
“B-cell-directed therapies have not yet been explored for the treatment of celiac disease, but they might well be pursued in the future given their success for the other autoimmune diseases."
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09/23/2025
Investigators recently demonstrated that Peyer’s patch B cells can directly sample transglutaminase 2 from the gut lumen and may play a key role in driving autoantibody production in celiac disease, according to a study published in Gastroenterology.
Production of transglutaminase 2 (TG2) autoantibodies is a key characteristic of celiac disease. It is believed to result from TG2-specific B cells receiving help from gluten-specific CD4+ T cells in gut-associated lymphoid tissues (GALT). However, the location in the body where enzymatically active TG2 encounters gluten peptides is unknown.
To study celiac disease–relevant T-cell–B-cell interactions in GALT, M. Fleur du Pré, PhD, and co-authors developed a mouse model that expresses HLA-DQ2.5 to reproduce key features of celiac disease.
“Based on the observations that there are no signs of B-cell tolerance in transgenic mice expressing a celiac-patient derived anti-TG2 B-cell receptor, and that enterocytes contain abundant amounts of TG2 we proposed that pathogenic TG2-gluten enzyme-substrate complexes could be generated in the gut lumen and initiate an anti-TG2 antibody response in gut-associated lymphoid tissues (GALT),” wrote the investigators.
The mice received adoptive transfers of TG2-specific B cells and gluten-specific T cells and were orally immunized with an engineered antigen that combined B-cell and T-cell epitopes. To ensure effective delivery of gluten epitopes to TG2-specific B cells, the team used a “Troybody” strategy: an antibody targeting the TG2-specific B-cell receptor was modified to carry a deamidated gluten peptide recognized by T cells. This enabled the researchers to track immune activation and antibody production in response to TG2 and gluten.
Mice that received both TG2-specific B cells and gluten-specific T cells developed TG2-specific IgA in the gut and IgG in serum. TG2-specific B cells expanded in Peyer’s patches and mesenteric lymph nodes, which reflects human celiac disease patients, where TG2-specific plasma cells are abundant in small intestine mucosa.
“Having established a mouse model in which mice have anti-TG2 effector B cells in the gut and GALT, we next questioned whether TG2-specific B cells in the SED [subepithelial dome] area of PPs could take up TG2 antigen directly from the gut lumen,” wrote the investigators.
Using a ligated intestinal loop assay, the team introduced recombinant TG2 bound to a fluorescent inhibitor into the intestinal lumen of immunized mice. Microscopy showed that TG2-specific B cells in the SED of Peyer’s patches bound labeled TG2, whereas control reagents without a reactive group did not produce the same signal. The findings suggest that the TG2-specific B-cell receptor was required for antigen uptake.
“The model supports a mechanism in which TG2-gluten complexes formed in the gut lumen are taken up by TG2-specific B cells in GALT. We propose that this pathway plays an important role in driving the anti-TG2 IgA autoantibody response in patients with celiac disease,” the investigators wrote.
Limitations of the work acknowledged by the investigators include the fact that uptake of naturally occurring TG2–gluten complexes was not directly demonstrated, and the role of other antigen-presenting cells, such as dendritic cells, was not addressed. It is also uncertain whether TG2-specific B cells are positioned close to the gut lumen in human PPs. Additional studies are needed to confirm the relevance of the findings in patients.
Nevertheless, they still anticipate that the model could be beneficial for developing and testing new therapies for celiac disease. “B-cell-directed therapies have not yet been explored for the treatment of celiac disease, but they might well be pursued in the future given their success for the other autoimmune diseases. Another promising strategy to disrupt the crosstalk between TG2-specific B cells and gluten-specific T cells is inhibition of the TG2 enzyme,” concluded du Pré and colleagues.
The work was supported by the Research Council of Norway and the US National Institutes of Health. Ludvig M. Sollid disclosed consulting roles with Precigen Actobio, Sanofi, and Topas Therapeutics. Other authors reported no conflicts of interest.
Source: Gastroenterology
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The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.