Figure 1.
Generalized Schematic Depiction of the Parallels between Infectious Pathogen Transmission to a Susceptible Host via the Gut (Left Panel) and Celiac Sprue Pathogenesis in a Susceptible Individual (Right Panel)
Infectious pathogens (green rounded rectangle; left panel) replicate within a privileged niche in an infected individual, and are then transmitted, either directly or via a pathogen-bearing vector, to another susceptible host (white box; left panel). To infect this new host, the pathogen must evade host defenses, invade across host barriers into a privileged niche (pink box), and in some cases become activated to a virulent form. Damage is caused to the host by pathogen- and/or host-mediated processes, while replication within the infected host enables further transmission. Commensal microbes (yellow rounded rectangle) cannot access privileged niches and do not cause disease. Similarly, immunotoxic gluten peptides, clustered in proline/glutamine-rich regions of gluten proteins (protein depicted as yellow rectangle containing immunotoxic peptide in green, right panel), cause celiac sprue in susceptible individuals (white box; right panel) by evading gastrointestinal proteolysis, invading across the intestinal epithelium by unknown mechanisms, and, in some peptides, becoming activated by TG2 (represented by Q (glutamine) → E (glutamate) modification), resulting in a deleterious immune response. Most dietary proteins (yellow rectangle) are proteolyzed by gastrointestinal proteases and do not enact pathogenic effects. In contrast to infectious pathogens, gluten peptides have no replicative capacity within afflicted individuals. Instead, these immunotoxic peptides are propagated by grain cultivation and transmitted to celiac sprue patients via intentional or accidental ingestion in the course of their diet.
Table 1.
Selected Proline/Glutamine-Rich Repetitive Gluten Sequences Compared to Prion Oligopeptide Repeats
Figure 2.
Adaptive and Innate Immune Responses to Gluten in Celiac Sprue
Ingested gluten is digested to innocuous amino acids (yellow boxes) and proteolytically resistant, immunotoxic gluten peptides (green) in the small intestine. Immunogenic gluten peptides access the lamina propria by unknown mechanisms and are deamidated by TG2. These deamidated peptides are loaded onto HLA DQ2 (or DQ8) and presented on the surface of antigen-presenting cells (APC) to gluten-specific, DQ2-restricted CD4+ T cells in the lamina propria, causing their activation and clonal expansion. Activated T cells mediate the humoral response, by giving help to both gluten-specific and TG2-specific B cells, as well as the cell-mediated Th1 response, which, through the secretion of proinflammatory cytokines such as IFN-γ and TNF-α, disrupts tight junction integrity. In parallel, innate peptides act through unknown mechanisms as a stress signal toward enterocytes, inducing expression of MIC and IL-15. IL-15 promotes the infiltration of CD8+ IEL into the epithelium, and arms them with the NK receptor NKG2D. IL-15 may also influence the Th1 response. Intraepithelial lymphocytes bearing NKG2D target MIC-expressing enterocytes for killing via apoptosis, causing destruction of the epithelial layer, and villous flattening. The combination of enterocyte apoptosis and tight junction disruption renders the epithelium more permeable, thereby facilitating access of gluten and propagation of the disease. In the continued presence of dietary gluten, chronic inflammation persists, and, in a small percentage of patients, results in enteropathy-associated T cell lymphomas. TCR, T cell receptor.
Table 2.
Comparison of Celiac Sprue with Proposed Animal Models for Gluten Sensitivity
Figure 3.
Potential Therapies Targeting Each Stage of Celiac Disease Progression
Immunotoxic gluten peptides may be eliminated at the source through selection or engineering of non-toxic varieties of gluten-containing grains. Exposure to gluten peptides may be avoided by means of dietary abstention. Gluten peptides' proteolytic resistance may be countered via oral enzyme therapy with glutenases. Invasion of gluten peptides across the intestinal epithelium may be prevented by targeting mediators of epithelial permeability, such as proinflammatory cytokines IFN-γ and TNF-α. Pharmacological inhibition of TG2 represents a means of preventing the activation of native gluten peptides to their deamidated forms. Finally, the deleterious response to gluten peptides may be controlled by prophylactic vaccination, by blocking HLA DQ2-mediated presentation of gluten peptides, or by targeting the mediators of gluten-induced damage, such as IL-15 and NKG2D.