Introduction
Coeliac disease is a unique and increasingly prevalent autoimmune disorder triggered by the ingestion of gluten in genetically susceptible individuals. Unlike many autoimmune diseases where the environmental trigger is unknown, coeliac disease has a clearly identified culprit: gluten proteins found in wheat, barley, and rye. However, the mere presence of gluten is not enough to cause disease. The pathogenesis involves a complex and highly specific interplay between gluten, the host’s own enzymes, and a targeted adaptive immune response that ultimately leads to inflammation and damage of the small intestine, known as villous atrophy. The diagram below, based on the work by Lindfors et al. (2019), provides a clear roadmap of this intricate process, which we will dissect in detail.
At its core, the adaptive immune response in coeliac disease is a case of mistaken identity and collateral damage, orchestrated by CD4+ T cells and B cells. This response is highly specific, depending on a crucial genetic predisposition—the presence of Human Leukocyte Antigen (HLA) variants HLA-DQ2 or HLA-DQ8, which are found in over 99% of individuals with the condition [1].
Step 1: Gluten Digestion and the Critical Role of TG2
The process begins in the lumen of the small intestine. When gluten is consumed, it is subjected to digestion by bodily proteases. However, gluten proteins are unusually rich in proline and glutamine residues, which makes them resistant to complete breakdown by gastric and pancreatic enzymes. This results in the persistence of long, partially digested gluten peptides that can cross the intestinal epithelium and enter the underlying tissue, the lamina propria [1].
Once in the lamina propria, these gluten peptides encounter a key enzyme: tissue transglutaminase (TG2). Under normal conditions, TG2 is involved in various cellular processes, but in the context of coeliac disease, it plays a pivotal pathogenic role. TG2 specifically targets certain glutamine residues within the gluten peptides and modifies them through a process called deamidation. This enzymatic reaction converts the neutral amino acid glutamine into the negatively charged glutamic acid [2]. This seemingly small chemical change has profound immunological consequences. The resulting deamidated gluten peptides now have a much higher affinity for the peptide-binding grooves of the specific HLA-DQ2 and HLA-DQ8 molecules.
The discovery of the remarkable concordance between TG2 specificity for gluten peptides and the high affinity of the resulting deamidated peptides for HLA-DQ2 (or –DQ8) inaugurated a fundamentally new chapter in our understanding of celiac disease pathogenesis [3].
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Step 2: Antigen Presentation and T Cell Activation
The deamidated gluten peptides are now perfectly shaped to be recognized by the immune system. Professional antigen-presenting cells (APCs), such as dendritic cells, located in the lamina propria, readily take up these modified peptides. Inside the APC, the deamidated peptide is loaded onto the HLA-DQ2 or HLA-DQ8 molecule and presented on the cell surface.
This HLA-peptide complex is the specific signal that activates anti-gluten CD4+ T cells. These T cells have T-cell receptors (TCRs) that are uniquely capable of recognizing the specific shape of the deamidated gluten peptide nestled within the HLA-DQ2/8 groove. This interaction is the central event that ignites the adaptive immune cascade. Upon activation, these CD4+ T cells begin to proliferate and orchestrate the subsequent inflammatory response.
Step 3: The Dual Role of B Cells and Antibody Production
The activated anti-gluten CD4+ T cells provide help to two distinct populations of B cells, leading to the production of the hallmark antibodies of coeliac disease.
1.Anti-Gluten B Cells: These B cells have B-cell receptors (BCRs) that can recognize and bind to gluten peptides. They internalize the gluten, process it, and present the deamidated peptides on their own HLA-DQ2/8 molecules. When an activated anti-gluten CD4+ T cell recognizes this complex on the B cell surface, it provides the necessary signal for the B cell to become a plasma cell and start producing anti-gluten antibodies.
2.Anti-TG2 B Cells: In a crucial break of self-tolerance, a similar process occurs with B cells that recognize TG2 itself as an antigen. It is believed that TG2 forms a stable complex with the gluten peptides it modifies. An anti-TG2 B cell can bind to the TG2 part of this complex, internalize the entire TG2-gluten package, and then present the deamidated gluten peptide on its HLA-DQ2/8 molecules. Again, an activated anti-gluten CD4+ T cell recognizes the gluten peptide and provides help, inadvertently driving the B cell to produce anti-TG2 antibodies. This explains why TG2, a host enzyme, becomes an autoantigen in the disease.
These newly differentiated plasma cells release large quantities of both gluten antibodies (e.g., anti-deamidated gliadin peptide, anti-DGP) and TG2 antibodies into the bloodstream and the gut tissue. The presence of these antibodies, particularly IgA-class anti-TG2, is a highly specific and sensitive marker used for diagnosing coeliac disease.
Step 4: The Inflammatory Cascade and Tissue Damage
The final consequence of this immune activation is tissue damage. The activated CD4+ T cells release a flood of pro-inflammatory cytokines, most notably Interferon-gamma (IFN-γ) and Interleukin-21 (IL-21). This cytokine storm promotes inflammation, activates other immune cells, and ultimately leads to the characteristic destruction of the intestinal villi (villous atrophy). This damage impairs the small intestine’s ability to absorb nutrients, leading to the wide range of clinical symptoms associated with coeliac disease.
Conclusion
The adaptive immune response in coeliac disease is a remarkable example of how a specific genetic background (HLA-DQ2/8) and an environmental trigger (gluten) can conspire to break immune tolerance. The process is critically dependent on the enzymatic activity of TG2, which modifies gluten into a highly immunogenic form. This leads to the activation of a cascade involving gluten-specific T cells, which in turn drive the production of both anti-gluten antibodies and, crucially, autoantibodies against TG2. The resulting inflammation is responsible for the debilitating intestinal damage that defines the disease. This detailed understanding of the pathogenesis has not only provided highly accurate diagnostic tools but also illuminates clear targets for the development of novel therapies beyond the current standard of a strict, lifelong gluten-free diet.
References
1.Sharma, N., et al. (2020). Pathogenesis of Celiac Disease and Other Gluten Related Disorders in Wheat and Strategies for Mitigating Them. Frontiers in Nutrition, 7, 6. https://doi.org/10.3389/fnut.2020.00006
2.Fleckenstein, B., et al. (2002). Gliadin T Cell Epitope Selection by Tissue Transglutaminase in Celiac Disease. Journal of Biological Chemistry, 277(37), 34109–34116. https://doi.org/10.1074/jbc.M204454200
3.Klöck, C., DiRaimondo, T. R., & Khosla, C. (2012). Role of Transglutaminase 2 in Celiac Disease Pathogenesis. Seminars in Immunopathology, 34(4), 513–522. https://doi.org/10.1007/s00281-012-0305-0
4.Lindfors, K., et al. (2019). Coeliac disease. Nature Reviews Disease Primers, 5(1), 3. https://doi.org/10.1038/s41572-018-0054-z