From the Guidelines
The primary immunological mechanism leading to villus atrophy in celiac disease is an autoimmune reaction involving type 2 transglutaminase (TG2), triggered by gluten peptides in genetically susceptible individuals, particularly those with HLA-DQ2 or HLA-DQ8 molecules. This reaction is characterized by the deamidation of gliadin fractions, which increases their immunogenicity and facilitates binding to HLA-DQ2 or HLA-DQ8 molecules, leading to the activation of CD4+ T cells and the release of pro-inflammatory cytokines 1. The resulting inflammation and tissue injury cause crypt hyperplasia and villous atrophy, which are hallmark features of celiac disease. Key steps in this process include:
- The ingestion of gluten, which is partially digested into peptides that cross the intestinal epithelium
- The deamidation of these peptides by tissue transglutaminase (tTG), which increases their binding affinity to HLA-DQ2 or HLA-DQ8 molecules
- The activation of CD4+ T cells, which release pro-inflammatory cytokines, such as interferon-gamma
- The stimulation of matrix metalloproteinases and other enzymes that damage the intestinal epithelium
- The activation of intraepithelial lymphocytes, which directly kill enterocytes through various mechanisms. The evidence from the study published in Nature Reviews Gastroenterology and Hepatology in 2024 1 supports this mechanism, highlighting the importance of gluten avoidance in managing celiac disease.
From the Research
Primary Immunological Mechanism Leading to Villus Atrophy in Celiac Disease
The primary immunological mechanism leading to villus atrophy in celiac disease involves:
- Activation of gluten-specific CD4+ T cells expressing T cell receptors that recognize gluten peptides presented in the context of HLA-DQ2 and DQ8 2
- Binding of gluten peptides to HLA-DQ2 and/or DQ8 molecules on antigen-presenting cells, which triggers a T cell-driven small intestinal inflammation 3, 4
- Modification of gluten peptides by tissue transglutaminase (tTG), which enhances their immunostimulatory effect and leads to the activation of gluten-reactive T cells 4
- Release of tTG from cells during inflammation, which also serves as a target autoantigen in the immune response 4
Key Factors Involved in the Immunological Mechanism
- HLA-DQ2 and/or DQ8 haplotype, which is expressed by genetically susceptible individuals 3, 4, 5
- Gluten peptides, which are efficiently presented by celiac disease-specific HLA-DQ2- and HLA-DQ8-positive antigen-presenting cells to CD4(+) T-cells 4
- Tissue transglutaminase (tTG), which plays a crucial role in the pathogenesis of celiac disease by modifying gluten peptides and serving as a target autoantigen 4, 5
Consequences of the Immunological Mechanism
- Villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis, which are the histological hallmarks of celiac disease 3, 4
- Malabsorption of nutrients, including iron, which can lead to anemia and other complications 6
- Increased risk of autoimmune diseases, osteoporosis, and intestinal T cell lymphoma in untreated celiac disease 3