Image source: Verdu Lab.

Intestinal epithelial cells express major histocompatibility complex class II genes

Celiac disease affects approximately 1% of the global population and is an immune-mediated condition driven by gluten in genetically predisposed individuals. The disease is characterized by damage to the small intestinal mucosa, with blunting of the villi, and infiltration of immune cells. The persistent immune response is directed against gluten peptides, and requires individuals carry the HLA-DQ2.5 and/or -DQ8 alleles. The only current available treatment for celiac disease is a life-long, strict gluten-free diet, which is very restrictive and not always effective.

In celiac disease, professional antigen-presenting cells (APCs), such as dendritic cells, B cells, and plasma cells, express major histocompatibility complex (MHC) class II molecules encoded by the HLA-DQ2 or -DQ8 alleles, which bind deamidated gluten peptides and present them to CD4+ T cells in the lamina propria of the intestine1,2. Because intestinal epithelial cells (IECs) are the first line of cells in contact with the gut luminal content, it has long been suspected that they could, under certain circumstances, take up an antigen-presenting role.

Previous studies have indicated that IECs can constitutively express MHC class II molecules, which are upregulated under proinflammatory conditions3-5. Whether IECs can function as APCs in celiac disease, presenting gluten peptides to underlying CD4+ T cells via MHC class II molecules remained unclear. This study demonstrated elevated MHC class II expression in epithelial cells from duodenal biopsies from patients with active celiac disease compared with those with celiac disease treated with a gluten-free diet, implying that disease activity is associated with epithelial MHC class II expression. The study further confirmed that the HLA-DQ molecule of MHC class II, which is associated with CeD (DQ2 and or DQ8), is expressed in biopsies from patients with celiac disease6.

 

The involvement of intestinal epithelial cells in gluten peptides presentation to CD4+ T cells open new potential therapeutic targets in celiac disease

The role of IECs in the activation of CD4+ T cells is difficult to decipher in human biopsies because immune cell activation could originate from the epithelium or the very well-known professional APCs in the tissue. Therefore, a multidisciplinary team of engineers and health sciences researchers at McMaster University, Canada, in collaboration with researchers in Argentina, Australia and the USA, developed an ex vivo “isolated gut epithelium” model in the form of “humanized organoid monolayers.”

The epithelium was “humanized” as it was derived from the small intestine of transgenic mice expressing the celiac disease risk allele: DQ2.5, providing a controlled model for studying a specific IEC role in celiac disease. This “DQ2”-only expressing organoid monolayer upregulated this type of MHC class II after various inflammatory stimuli were applied. More importantly, when the organoid monolayer was exposed to gluten and CD4+ T cells were subsequently added to the system, these immune cells proliferated and released proinflammatory cytokines, which are implicated in celiac disease6.

“These findings reveal a novel role for IECs in the immune response in celiac disease, challenging the traditional view that gluten antigen presentation is limited to professional APCs inside the intestinal tissue”, says Sara Rahmani, first author of the study.

 

Gut opportunistic pathogens can degrade gluten and lead to peptides that influence intestinal epithelial cells-T-cell interactions

Not all patients that have risk genes and consume gluten develop celiac disease, and thus additional factors are suspected to play a role, including microbial triggers. Therefore, this study also explored the impact of microbial interactions on the T-cell response induced by the organoid DQ2-expressing monolayer. Pseudomonas aeruginosa is an opportunistic pathogen producing “elastase-like” enzymes, that can metabolize gluten into highly immunogenic peptides7. In the new study, Rahmani et al. demonstrated that gluten metabolized by P. aeruginosa indeed exacerbated CD4+ T cell activation in DQ2-expressing monolayers. This finding further supports the hypothesis that gut microbes are additional modulators of inflammation in celiac disease, through a variety of mechanisms, including modulation of epithelial antigen presentation8,9.

Overall, this study provides compelling evidence that IECs, traditionally considered passive barriers or targets of immune-mediated damage, actively contribute to the immune response in celiac disease by presenting gluten peptides to CD4+ T cells. This discovery opens new avenues for therapeutic intervention, suggesting that targeting MHC class II expression on IECs or disrupting gluten peptide presentation in this compartment could prevent or decrease inflammation in celiac disease. Given that IECs are the first cells to encounter dietary antigens, this study may have broader implications for other diseases associated with MHC class II, such as type 1 diabetes, according to the authors.

 

References:

  1. Iversen R, Roy B, Stamnaes J, et al. Efficient T cell-B cell collaboration guides autoantibody epitope bias and onset of celiac disease. PNAS. 2019; 116(30):15134-15139. doi: 10.1073/pnas.1901561116.
  2. Høydahl LS, Richter L, Frick R, et al. Plasma cells are the most abundant gluten peptide MHC-expressing cells in inflamed intestinal tissues from patients with celiac disease. Gastroenterology. 2019; 156(5):1428-1439.e10. doi: 10.1053/j.gastro.2018.12.013.
  3. Marley NJ, Macartney JC, Ciclitira PJ. HLA-DR, DP and DQ expression in the small intestine of patients with coeliac disease. Clin Exp Immunol. 1987; 70(2):386-393.
  4. Heuberger CE, Janney A, Ilott N, et al. MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T-cell responses. Mucosal Immunol. 2024; 17(3):416-430. doi: 10.1016/j.mucimm.2023.05.001.
  5. Malik A, Sharma D, Aguirre-Gamboa R, et al. Epithelial IFN g signalling and compartmentalized antigen presentation orchestrate gut immunity. Nature. 2023; 623(7989):1044-1052. doi: 10.1038/s41586-023-06721-1.
  6. Rahmani S, Galipeau HJ, Clarizio AV, et al. Gluten-dependent activation of CD4+T cells by MHC class II-expressing epithelium. Gastroenterology. 2024; doi: 10.1053/j.gastro.2024.07.008.
  7. Caminero A, Galipeau HJ, McCarville JL, et al. Duodenal bacteria from patients with celiac disease and healthy subjects distinctly affect gluten breakdown and immunogenicity. Gastroenterology. 2016; 151(4):670-683. doi: 10.1053/j.gastro.2016.06.041.
  8. Galipeau HJ, Hinterleitner R, Leonard MM, et al. Non-host factors influencing onset and severity of celiac disease. Gastroenterology. 2024; 167(1):34-50. doi: 10.1053/j.gastro.2024.01.030.
  9. Verdu EF, Schuppan D. Co-factors, microbes, and immunogenetics in celiac disease to guide novel approaches for diagnosis and treatment. Gastroenterology. 2021; 161(5):1395-1411.e4. doi: 10.1053/j.gastro.2021.08.016.