Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota - Key players in the pathogenesis of celiac disease

Abstract

Celiac disease (CD) is a chronic immune-mediated disorder triggered by the ingestion of gluten in genetically predisposed individuals. Before activating the immune system, gluten peptides are transferred by the epithelial barrier to the mucosal lamina propria, where they are deamidated by intestinal tissue transglutaminase 2. As a result, they strongly bind to human leucocyte antigens (HLAs), especially HLA-DQ2 and HLA-DQ8, expressed on antigen-presenting cells. This induces an inflammatory response, which results in small bowel enteropathy. Although gluten is the main external trigger activating both innate and adaptive (specific) immunity, its presence in the intestinal lumen does not fully explain CD pathogenesis. It has been hypothesized that an early disruption of the gut barrier in genetically susceptible individuals, which would result in an increased intestinal permeability, could precede the onset of gluten-induced immune events. The intestinal barrier is a complex functional structure, whose functioning is dependent on intestinal microbiota homeostasis, epithelial layer integrity, and the gut-associated lymphoid tissue with its intraepithelial lymphocytes (IELs). The aim of this paper was to review the current literature and summarize the role of the gut microbiota, epithelial cells and their intercellular junctions, and IELs in CD development.

Keywords: Celiac disease; Epithelium; Intestinal barrier; Intestinal microbiota; Intraepithelial lymphocytes.

Figure 1

Schematic illustration of the intestinal barrier. The three main components of the intestinal barrier: the microbiota; epithelium, with its specialized cells (goblet cells, Paneth cells and enterocytes), together with a layer of mucus; and gut-associated lymphoid tissue cells, including IELs and dendritic cells. AJ: Adherens junction; D: Desmosome; IEL: Intraepithelial lymphocyte; TJ: Tight junction.

Figure 2

Ultrastructure and corresponding schematic representation of intercellular junctions. Transmission electron microscopy (JEOL JEM-1011, Japan; × 60000) was used to show the ultrastructure of intercellular junctions in the human small intestine. The transmission electron micrograph comes from our own research. JAM: Junction adhesion molecule.

Figure 3

Schematic illustration of celiac disease pathogenesis. Microbiota dysbiosis activates innate immunity resulting in pro-inflammatory changes, which leads to IEL infiltration and epithelial barrier disruption. This ultimately results in an increased paracellular and transcellular transfer of immunogenic gluten peptides and activation of adaptive pro-inflammatory Th1/Th17 pathways, leading to villous atrophy and production of autoantibodies against intestinal TTG2. HLA: Human leucocyte antigen; IEL: Intraepithelial lymphocyte; IL: Interleukin; INF: Interferon; NOD: Nucleotide-binding oligomerization domain; Th: T helper; TLR: Toll-like receptor; TTG2: Tissue transglutaminase 2.

Figure 4

A schematic illustration of progressive histopathological changes in the small intestine according to the modified Marsh-Oberhuber grading scale. Type 0: Normal mucosa with IEL count < 25 per 100 enterocytes; Type 1: Normal mucosa with an increased IEL count; Types 2 and 3 show increased IEL counts and lymphocytes in the lamina propria. IELs are presented as black dots. IEL: Intraepithelial lymphocyte.