RT info:eu-repo/semantics/doctoralThesis
T1 Effect of the gluten-free diet on the intestinal and circulating immunome from patients with coeliac disease
A1 Fiz López, Aida
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Enfermedad celiíaca
K1 Coeliac disease
K1 Enfermedad celíaca
K1 Immunology
K1 Immunología
K1 Cytometry
K1 Citometría
K1 Gluten free diet
K1 Dieta sin gluten
K1 32 Ciencias Médicas
AB Introduction: Coeliac disease (CD) is an autoimmune disorder triggered by gluten ingestion in genetically predisposed individuals, primarily affecting the small intestine but with systemic implications. It leads to villous atrophy in the duodenum and involves intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL). CD is also linked to increased susceptibility to other autoimmune diseases and malignancies. A gluten-free diet (GFD) is the primary treatment, but adherence is challenging. Monitoring includes serological tests and detection of gluten immunogenic peptides in faeces. Hypothesis and Aim: It is hypothesized that persistent mucosal atrophy in CD patients, despite a GFD, may be linked to immune alterations in the mucosal and/or peripheral immune system. The aim of this thesis is to study the effect of a GFD on the phenotype and function of immune cells from the intestinal mucosa and peripheral blood in CD patients Material and Methods: The study characterized IEL throughout the human gastrointestinal tract (stomach, duodenum, ileum, and colon) and assessed their enrichment and cell culture. The effect of a GFD on the immunome was analyzed in duodenal LPL and peripheral blood mononuclear cells (PBMC) from non-celiac controls, newly diagnosed CD patients, and GFD-treated patients, categorized by symptom presence and villous atrophy was performed using top-of-the-art spectral and computational cytometry.  Cytokines in the duodenal microenvironment and plasma samples were also evaluated  Results: Significant immune shifts were observed in the gut, with Tγδ IEL expanding and classical T IEL decreasing, particularly in those with mucosal atrophy. Unexpectedly, IL-15R subunits were not significantly increased in IEL, but IL-15Rα expression was elevated in epithelial cells, suggesting a trans-presentation model where IL-15 is transferred from epithelial cells to IEL. NKG2D, an immune activation marker, was upregulated on T IEL, especially in patients with atrophy, suggesting its potential as an immune therapy target. Despite improvements in mucosal structure with GFD, persistent atrophy was observed in 68.4% of patients. Prolonged GFD use was linked to increased gut-homing markers (Integrins α4, β7, CCR9, CCR2) and inflammatory markers (CD2, CD38) in LPL. Symptomatic GFD-treated patients exhibited higher gut-homing markers in CD8 T cells and memory B cells, with reduced CXCR3 and CD38 expression in regulatory T cells. Cytokine analysis showed normalization of IL-18 and IL-12p70. Peripheral immune activation remained in newly diagnosed and GFD-treated patients with atrophy, indicating enhanced migration of immune cells to the intestine, contributing to ongoing mucosal damage.Discussion: Despite strict adherence to the GFD, many patients continue to exhibit villous atrophy and immune activation, suggesting unresolved chronic inflammation. This inflammation may be driven by factors such as dysbiosis or exposure to non-gluten dietary antigens, calling for a more comprehensive approach to treatment. The findings raise the question of whether persistent villous atrophy should be considered a marker of prolonged damage rather than a definitive sign of refractory coeliac disease (RCD). Personalized therapeutic strategies focusing on immune regulation, beyond gluten exclusion, are essential for better management of CD and improved long-term outcomes.Conclusions: Over half of CD patients show persistent villous atrophy despite GFD adherence. NKG2D expression on IEL is linked to atrophy, suggesting it as a target for immune therapies. IL-15 receptor expression is not increased in these lymphocytes, indicating other cytokines may play a role in their cytotoxicity. While the GFD restores immune balance in LPL, symptomatic patients exhibit increased gut-homing and inflammatory markers, which worsen over time. Atrophy and persistent symptoms correlate with peripheral immune activation, with increased inflammatory markers indicating unresolved chronic inflammation, potentially driven by dysbiosis or non-gluten dietary antigens.
YR 2025
FD 2025
LK https://uvadoc.uva.es/handle/10324/79453
UL https://uvadoc.uva.es/handle/10324/79453
LA eng
NO Escuela de Doctorado
DS UVaDOC
RD 08-nov-2025