Pathophysiology of celiac disease

Abstract

Celiac disease results from the interplay of genetic, environmental, and immunologic factors. An understanding of the pathophysiology of celiac disease, in which the trigger (wheat, rye, and barley) is known, will undoubtedly reveal basic mechanisms that underlie other autoimmune diseases (eg, type 1 diabetes) that share many common pathogenic perturbations. This review describes seminal findings in each of the 3 domains of the pathogenesis of celiac disease, namely genetics, environmental triggers, and immune dysregulation, with a focus on newer areas of investigation such as non-HLA genetic variants, the intestinal microbiome, and the role of the innate immune system.

Figure 1. Factors involved in celiac disease pathophysiology

Celiac disease is thought to arise from the interplay of genetic, environmental and immunological factors. This review highlights seminal findings in each of these domains.

Figure 2. Class II HLA-DQ

The genes encoding for HLA molecules are found in the major histocompatibility (MHC) complex on chromosome 6. HLA molecules involved in celiac disease are encoded in a region known as class II; by genes known as -DQ (other class II genes include -DR and –DP). Class II HLA-DQ genes encode for α- and β-chains that are associated as heterodimers on the surface of antigen presenting cells and form a cleft that binds antigens. HLA-DQA1 genes code for two α-chains (α₁ & α₂) and HLA-DQB1 genes code for two β-chains (β₁ & β₂).

Figure 3. HLA configurations in celiac disease. A) HLA-DQ2 homozygotes, heterozygotes and half-heterodimers, and B) HLA-DQ8 homozygotes, heterozygotes and DQ8/DQ2

Red boxes denote the DQA1 gene encoding the alpha-chain and orange boxes denote the DQB1 gene encoding the beta-chain (see figure 2). Shown in the boxes are the specific alleles for each gene. Current WHO nomenclatures uses an asterix followed by the allele group (e.g., 05), a colon then the protein group (e.g., 01). An empty box refers to other HLA alleles not associated with celiac disease. Shown below the genes are the isoforms. †cis acting (i.e. on the same chromosome); ††trans acting (i.e. on opposite chromosomes); ††† risk of celiac disease for DQ2 half heterodimers is lower than the general population especially individuals carrying only DQA1*05 (ref 15)

Figure 3. HLA configurations in celiac disease. A) HLA-DQ2 homozygotes, heterozygotes and half-heterodimers, and B) HLA-DQ8 homozygotes, heterozygotes and DQ8/DQ2

Red boxes denote the DQA1 gene encoding the alpha-chain and orange boxes denote the DQB1 gene encoding the beta-chain (see figure 2). Shown in the boxes are the specific alleles for each gene. Current WHO nomenclatures uses an asterix followed by the allele group (e.g., 05), a colon then the protein group (e.g., 01). An empty box refers to other HLA alleles not associated with celiac disease. Shown below the genes are the isoforms. †cis acting (i.e. on the same chromosome); ††trans acting (i.e. on opposite chromosomes); ††† risk of celiac disease for DQ2 half heterodimers is lower than the general population especially individuals carrying only DQA1*05 (ref 15)

Figure 4. Clinical application of HLA testing

HLA testing should be considered for screening, disease exclusion or to support a diagnosis. Testing is unaffected by a gluten-free diet. Providers should ensure that both DQ2 alpha and beta chains are tested. If a patient carries HLA-DQ2 or –DQ8, they carry a risk factor (or varying magnitude) for celiac disease and additional work-up should be considered. Individuals carrying HLA-DQ2 half-heterodimers, are also at risk for celiac disease (albeit substantially lower than other HLA-DQ2 and –DQ8 positive patients). If HLA-DQ2 and –DQ8 are not present, then celiac disease risk is highly unlikely and antibody screening is not necessary.

Figure 5. MHC class II-gluten peptide complexes

MHC class II molecules HLA-DQ2 and –DQ8 preferentially bind a glutamate residue of the gluten peptide at position 6 and position 1/9 respectively. This binding is enhanced by a negatively charged glutamate and positively charged pocket of the HLA molecule.

Figure 6. Enrichment analysis of non-HLA genes associated with celiac disease

We used GeneTrail to test for enrichment of functional annotations among non-HLA genes associated with celiac disease from genome-wide association studies published through 2012. In this graph is shown the fold enrichment (y-axis) and significantly enriched biological functions (x-axis). Background expectations were based on all human genes. P-values were calculated using a hypergeometric distribution using the approach by Benjamini & Hochberg to control the false discovery rate. P-values for enrichment shown here ranged from 4.8 × 10⁻² to 3.2 × 10⁻¹¹.

Figure 7. Divergence of oats from wheat, rye and barley

Wheat, rye, barley and oats belong to the same grain family (Poaceae) and subfamily (Pooideae). However, they belong to distinct tribes: wheat, rye and barley (Triticeae) and oats (Avenae). The prolamins from the triticeae tribe are immunogenic and contribute to celiac disease, while avenins from pure, uncontaminated oats are safe for the vast majority of celiac patients.

Figure 8. Active and inactive states of tissue transglutaminase (tTG2)

tTG2 is active in an open conformation in a reduced state. In presence of GTP and in the absence of Ca2⁺ (i.e. intracellular environment), tTG2 is in a reduced, closed state and the enzyme is inactive. Upon release to the extracellular environment with low GTP and high Ca2⁺, tTG2 takes on an open conformation and is active. Usually oxidizing conditions in the extracellular environment render tTG2 inactivated in its open conformation by the formation of a disulphide bond between two vicinal cysteine residues in the enzyme. Upon creation of reducing conditions (i.e. inflammation), the disulphide bond is reduced and the enzyme can again take an active open conformation.

Figure 9. Immune dysregulation in celiac disease

a) In health, gluten is tolerated in the presence of anti-gluten Foxp³⁺ regulatory T cells. Moreover, intraepithelial lymphocytes (IELs) express inhibitory natural killer (NK) receptors that prevent uncontrolled T cell activation. b) With inflammation (e.g., celiac disease shown here) or infection, HLA-DQ2 or –DQ8 bind gluten on antigen presenting cells and present to T cells leading to an anti-gluten T cell response which release IFN-γ and possibly IL-21 leading to epithelial damage. The upregulation of IL-15 and IFN-α in the lamina propria induce dendritic cells to acquire a pro-inflammatory phenotype. The innate immune system is also dyregulated in celiac disease in that IELs undergo reprogramming to acquire a natural killer phenotype characterized by upregulation of NKG2D and CD94/NKG2C receptors that recognize MICA, MICB and HLA-E on epithelial cells mediating tissue damage. IL-15 upregulates NK receptors and promotes T-cell receptor independent killing as well as blocking Foxp³⁺ regulatory T cell action on IELs. Finally, the humoral immune system produces gluten-specific antibodies that mediate systemic manifestations notably dermatitis herpetiformis.