Journal of Hepatology and Gastrointestinal disorders
Open Access

The Gut Barrier in Celiac Disease: Mechanisms of Intestinal Permeability and Immune Activation

Ellie Litwin^{* *}Correspondence: Ellie Litwin, Department of Gastroenterology, University of Dhaka, Dhaka, Bangladesh, Email:

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About the Study

Celiac disease is an autoimmune disorder characterized by an inappropriate immune response to gluten, a protein found in wheat, barley, and rye. This immune system dysregulation is a complex interplay between genetic predisposition, environmental factors, and immunological pathways. The immune system in celiac disease fails to differentiate between harmful pathogens and harmless dietary proteins. This aberration is rooted in genetic predisposition, particularly the presence of human leukocyte antigen-DQ2 (HLA-DQ2) or HLADQ8 molecules, which are encoded by the HLA class II genes. These molecules are expressed on the surface of antigenpresenting cells and are central to the recognition of gluten peptides. The genetic component is necessary but not sufficient for disease development, indicating that environmental factors and additional genetic modifiers also contribute to immune dysregulation.

The immune response to gluten involves both the innate and adaptive arms of the immune system. When gluten-containing food is ingested, it is partially digested in the gastrointestinal tract, leading to the formation of gluten peptides. These peptides are resistant to complete degradation due to their high proline and glutamine content, allowing them to persist and interact with the immune system. The enzyme tissue Trans Glutaminase (tTG) modifies these peptides by deamidating specific glutamine residues, converting them into negatively charged glutamate residues. This modification increases the binding affinity of gluten peptides to HLA-DQ2 or HLA-DQ8 molecules, facilitating their presentation to CD4⁺ T cells.

The activation of gluten-specific CD4⁺ T cells is a symbol of celiac disease. These T cells reside in the lamina propria of the small intestine and recognize deamidated gluten peptides presented by HLA-DQ2 or HLA-DQ8. Upon activation, these T cells proliferate and secrete pro-inflammatory cytokines, including Interferon-gamma (IFN-γ), which contributes to tissue damage and inflammation. The activation of CD4⁺ T cells is a critical event in the immune response, as it leads to the activation of other immune cells, amplifying the inflammatory response.

One of the most unique characteristics of celiac disease is the production of autoantibodies, particularly anti-tTG antibodies. These autoantibodies are generated due to the unique communication among gluten-specific T cells and B cells that recognize tTG as an auto antigen. The formation of immune complexes between gluten peptides and tTG facilitates the uptake and presentation of these complexes to T cells, resulting in B cell activation and antibody production. The presence of anti-tTG antibodies is a symbol of celiac disease and serves as a diagnostic marker. However, the precise role of these autoantibodies in tissue damage remains a topic of investigation.

The innate immune system also plays an important role in the pathogenesis of celiac disease. Gluten peptides can directly activate innate immune cells, such as epithelial cells and dendritic cells, leading to the release of pro-inflammatory cytokines and chemokines. One such peptide, gliadin, has been shown to induce the production of Inter Leukin-15 (IL-15) by intestinal epithelial cells. IL-15 is a potent cytokine that drives the activation and proliferation of Intra Epithelial Lymphocytes (IELs), a subset of immune cells located within the intestinal epithelium. IELs are cytotoxic and contribute to epithelial cell damage, leading to villous atrophy and the characteristic histological changes observed in celiac disease. The dysregulated immune response in celiac disease is not limited to the gut. Systemic manifestations, such as dermatitis herpetiformis and neurological symptoms, indicate that the immune system's aberrant activation extends beyond the intestine. This systemic involvement highlights the complex interplay between the immune system and gluten, emphasizing the need for a comprehensive understanding of immune dysregulation.

Regulatory mechanisms that usually maintain immune homeostasis are impaired in celiac disease. Regulatory T cells (Tregs), which play a critical role in suppressing excessive immune responses, are functionally deficient in individuals with celiac disease. The impaired function of Tregs allows for unchecked inflammation and contributes to the perpetuation of the immune response against gluten. Additionally, the gut microbiota, which plays an important role in immune regulation, is altered in individuals with celiac disease. Dysbiosis, characterized by an imbalance in microbial composition, may exacerbate immune dysregulation by influencing the development and function of immune cells. The chronic inflammation in celiac disease leads to structural changes in the small intestine, including villous atrophy and crypt hyperplasia.

These changes are managed by the continuous activation of immune cells and the release of pro-inflammatory mediators. The resulting tissue damage impairs nutrient absorption, leading to the clinical symptoms of malabsorption and nutritional deficiencies.