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Review
. 2017 Jan 14;3(2):150-162.
doi: 10.1016/j.jcmgh.2016.12.006. eCollection 2017 Mar.

Celiac Disease: Role of the Epithelial Barrier

Michael Schumann  1 , Britta Siegmund  2 , Jörg D Schulzke  3 , Michael Fromm  3
Affiliations
Review

Celiac Disease: Role of the Epithelial Barrier

Michael Schumann et al. Cell Mol Gastroenterol Hepatol. .

Abstract

In celiac disease (CD) a T-cell-mediated response to gluten is mounted in genetically predisposed individuals, resulting in a malabsorptive enteropathy histologically highlighted by villous atrophy and crypt hyperplasia. Recent data point to the epithelial layer as an under-rated hot spot in celiac pathophysiology to date. This overview summarizes current functional and genetic evidence on the role of the epithelial barrier in CD, consisting of the cell membranes and the apical junctional complex comprising sealing as well as ion and water channel-forming tight junction proteins and the adherens junction. Moreover, the underlying mechanisms are discussed, including apoptosis of intestinal epithelial cells, biology of intestinal stem cells, alterations in the apical junctional complex, transcytotic uptake of gluten peptides, and possible implications of a defective epithelial polarity. Current research is directed toward new treatment options for CD that are alternatives or complementary therapeutics to a gluten-free diet. Thus, strategies to target an altered epithelial barrier therapeutically also are discussed.

Keywords: Bmp, bone morphogenetic protein; CBC, crypt base columnar cell; CD, celiac disease; Celiac Sprue; EGF, epidermal growth factor; Epithelial Polarity; GFD, gluten-free diet; GI, gastrointestinal; GWAS, genome-wide association studies; Gluten-Sensitive Enteropathy; IEC, intestinal epithelial cell; IL, interleukin; MIC-A, major histocompatibility complex class I chain–related gene-A; Partitioning-Defective Proteins; SNP, single-nucleotide polymorphism; TJ, tight junction; Tight Junction; ZO, zonula occludens; aPKC, atypical protein kinase C; α-Gliadin 33mer.

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Figures

Figure 1
Figure 1
Binding of a gliadin epitope to the HLA complex. Gliadin fragments are deamidated by tissue transglutaminase (ie, a glutamine is transformed to a glutamate), thereby adding an additional negative charge to the epitope (blue circle). This facilitates binding to the DQ2 groove of the major histocompatibility complex molecule. Here, binding of the glia-α1 fragment to HLA-DQ2 is exemplified. However, this principle holds true for various oligopeptide sequences within α-, γ-, and ω-gliadin sequences, and also for binding to HLA-DQ8. Amino acids are shown in the 1-letter code with Q, glutamine and E, glutamate. The recognition motif of tissue transglutaminase within the unprocessed gliadin peptide (Q-X-P) is denoted in red letters. APC, antigen-presenting cell, P1…P9, binding positions within the DQ2 complex.
Figure 2
Figure 2
Crypt–villous axis of the small intestinal mucosa and alterations of the stem cell compartment found in celiac disease. For detailed explanations refer to the corresponding text. Altered signaling components relevant for celiac disease are highlighted in red, and those for Crohn's disease are shown in green. c-myc, Myc proto-oncogen; Mϕ, macrophage; SG, secretory granule; BMPR I and II, BMP receptor I and II; EZH22 and SUZ12, polycomb proteins (histone methyltransferases); ATG16L1, autophagy-related protein 16-1; TCF1, transcription factor-1; EGFR (erb-b), epidermal growth factor receptor; PI3K, phosphatidylinositol 3-kinase; β-cat, β-catenin.
Figure 3
Figure 3
Composition of the apical junction and localization of polarity complexes in epithelia. The apical junction comprises the TJ and the adherens junction. Main mammalian TJ proteins are claudin-1 to claudin-27, occludin, and JAM-A, and important AJ proteins are cadherin and nectin. Although the proteins featuring 4 transmembrane domains (claudins, occludin) define the paracellular barrier or channel function for solute and water diffusion, the single-spanning proteins (JAMs, catenin, nectin) provide a mechanical linkage between neighboring cells. Note that JAMs are considered TJ proteins but do not convey barrier function. Virtually all TJ and adherens junction proteins are linked via intracellular proteins (ZO-1, Par-3, catenin, rap1) either interacting as scaffolds with the actin cytoskeleton (grey dots) and/or as polarity complexes with the membranes of the apical (red) or basolateral (blue) cell side.
Figure 4
Figure 4
Distribution of TJ and polarity complex proteins in CD. (A) Confocal LSM recordings of ZO-1 and Par-3 fluorescence signals in control and CD small intestinal mucosae. ZO-1 and Par-3 signals spread out along the lateral membrane (small arrows). The diagrams in the right row present apical-to-basal signal profiles along lateral membranes as indicated by the long arrow in the laser scanning microscopy (LSM) figure. Scale means ±SEM, *P < .05. (B) Caco-2 cells were subjected to a combined calcium switch and biotin translocation experiment with transepithelial resistance (TER) being monitored throughout the experiment. Filters were biotinylated apically at the indicated time points to uncover local barrier defects and then immunostained (Par-3, red; claudin-5, green; biotin/streptavidin, white; and 4′,6-diamidino-2-phenylindole [DAPI], blue). Orthogonal views are presented to illustrate differences in apico–basal biotin passage associated with the integrity of the TJ expressing Par-3 and claudin-5. Before ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) treatment, biotin is excluded from the basal compartment. Biotin deposits appear underneath dysfunctional TJs in EGTA-treated cells (red arrows). After calcium replenishment the TJ partially is reorganized (ie, belt-like TJs impermeable for biotin are found next to disorganized TJ strands permeable for biotin as seen in the x-y-z collapsed stack projection; inserted panels, arrows).
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