Pathophysiology of Celiac Disease

Koning, Frits

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/01.mpg.0000450391.46027.48
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ABSTRACT: Celiac disease (CD) is strongly associated with HLA-DQ2 and HLA-DQ8, HLA-class II molecules that present antigen-derived peptides to CD4 T cells. Indeed, proinflammatory CD4 T cells specific for gluten-derived peptides bound to HLA-DQ2 or HLA-DQ8 are present in the lamina propria of patients, and not found in nonceliac controls. While gluten peptides bind poorly to HLA-DQ2/8, modification by tissue tranglutaminase converts the neutral amino acid glutamine into glutamic acid, introducing a negative charge that allows high affinity binding. Thus, the association between CD and HLA-DQ2/8 is well understood. What is less clear is why only a small minority of HLA-DQ2/8 positive individuals develops CD, why disease can develop at any stage in life and present with highly variable symptoms. I discuss this in the framework of the multiple hit model: next to genetic predisposition, multiple other factors—some extrinsic, some intrinsic—can favour or protect from disease development.

Author Information

Address correspondence and reprint requests to Frits Koning, Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands (e-mail:

Article Outline

Celiac disease (CD) is a chronic inflammatory disease of the small intestine (1,2). It can develop at any point in time during life in genetically susceptible individuals upon ingestion of wheat gluten and related cereal proteins. It is a frequent disorder affecting approximately 1 in a 100 in the Western Hemisphere but the symptoms associated are highly variable among patients. Ultimately CD can lead to serious complications, including lymphoma in a small subset of adult patients. The disease goes in remission when patients are put on a gluten free diet, which is currently the only available treatment. In approximately 50% of patients on a gluten-free diet signs of inflammation persist, most likely due to (inadvertent) gluten exposure.

CD shares important features with other autoimmune diseases like type 1 diabetes mellitus and rheumatoid arthritis: it is chronic, multifactorial, with a female to male ratio of roughly 2 to 1. These diseases all have a strong HLA-association, indicative of the involvement of the adaptive immune system and the presence of autoantibodies is characteristic (1,2). There is accumulating evidence that a series of events is required to develop chronic multifactorial diseases and that with each event it becomes less likely that the process can be reversed to a “not-at-risk phenotype.” Such “multiple hit models,” schematically depicted in Figure 1, provide a logical explanation for the observation that only a small fraction of individuals that express the relevant disease predisposing HLA-molecules develop particular autoimmune diseases: in most individuals not all required “events” occur and/or occur in the right order so disease will not develop. In the case of celiac disease (CD) the HLA association is extraordinarily strong: approximately 95% of the patients express HLA-DQ2 and the remainder is mostly HLA-DQ8 positive (1,2). Nevertheless, although some 40% of the population in the Western world expresses one or both of these HLA-DQ alleles, only 1% of the population develops CD. In the multiple hit model the mere presence of the disease-associated HLA-DQ molecules is a necessary but by itself insufficient prerequisite for disease development. In the absence of additional predisposing factors and/or insults disease will never develop. Moreover, the multiple hit model may explain why not all patients are equally affected: when not all “events” occur, disease may be less severe. Only a small minority of patients eventually develops refractory CD (RCD), a potentially fatal complication of CD and probably caused by prolonged inflammatory conditions in the intestine due to gluten consumption that ultimately leads to malignant transformation.

In CD there is unique insight into what drives the disease once it has been initiated (1,2). In the affected individual, 4 well-defined components interact: gluten, tissue transglutaminase (TG2), HLA-DQ2/8 and T cells. Upon ingestion gluten is degraded into relatively large fragments due to the activity of the enzyme pepsin in the stomach. Such fragments may be further trimmed by enzymes in the small intestine but because of the proline-rich nature of gluten relatively large fragments persist. Some of these can bind with low affinity to the disease predisposing HLA-DQ2 or HLA-DQ8 molecules and T cells reactive to such DQ-peptide complexes have been found in patients with CD, although in low frequencies (3–8). Nevertheless, such T-cell responses, probably in conjunction with the induction of innate responses, could lead to tissue damage. This would lead to the release of the enzyme TG2, which in the calcium-rich extracellular environment can modify gluten peptides (9,10). The modification, termed deamidation, involves the conversion of the neutral amino acid glutamine into the negatively charged glutamic acid. As a result of this introduction of a negative charge such deamidated gluten peptides bind with much higher affinity to HLA-DQ2 or HLA-DQ8 because these HLA molecules prefer to bind peptides in which one or more negatively charged residues are present. Moreover, a large number of gluten peptides can be modified in this fashion, thus broadening and amplifying the gluten specific T-cell response in the lamina propria (Fig. 2). This response is characterized by the secretion of proinflammatory cytokines that drive the local inflammation, in particular IFNγ (1,2). More important, these results explain the well-established fact that CD almost exclusively develops in HLA-DQ2 and/or -DQ8 positive individuals (1,2,11).

The dominant role of HLA-DQ2 is further illustrated by the fact that individuals homozygous for HLA-DQ2 have an at least 5-fold higher risk to develop CD compared with individuals heterozygous for HLA-DQ2. We observed that the HLA-DQ2 gene dose has a strong quantitative effect on the magnitude of gluten-specific T-cell responses which correlated with the level of gluten peptide binding to antigen-presenting cells, providing a functional explanation for the HLA-DQ2 gene dose effect (12).

In all likelihood the gluten-specific T-cell response also drives the antibody response to both deamidated gluten and TG2, antibodies that nowadays are more or less routinely used in the diagnostic procedure. Clearly, the CD4 T-cell response to deamidated gluten bound to HLA-DQ2 and HLA-DQ8 would provide help for B cells producing antibodies to deamidated gluten. Because TG2 can cross-link itself to gluten, this would allow the uptake of such TG2-gluten complexes by B cells expressing immunoglobulin specific for TG2. Due to degradation of such TG2-gluten complexes in the endosomal-lysosomal compartment, gluten fragments would become available for binding to HLA-DQ2/8 which, once expressed on the cell surface of the B cells, would activate gluten-specific T cells, which in turn would provide help for the production of TG2 specific antibodies by the B cells.

Next to the T-cell response against gluten, activation of intraepithelial lymphocytes (IEL) takes place, most likely driven by an increase in local IL-15 production (13,14 and Fig. 2). This leads to an enhanced expression and functionality of the activating NKG2D receptor by the IEL and its ligand MICA on the epithelium and results in epithelial cell damage, a hallmark of CD (13,14). In addition, a functional interaction between the NK receptor CD94/NKG2C on IEL and the non-classical HLA-E molecule on epithelial cells contributes to the activation and proliferation of IEL (15). Thus, in CD patients IEL acquire characteristics of NK-cells and this contributes significantly to the disease pathogenesis.

Notwithstanding these major advances in our understanding of the molecular mechanisms underlying disease pathogenesis, there are still several outstanding issues that remain to be solved. In particular it is not known which innate events precede and initiate the development of gluten-specific T-cell responses. Moreover, it is unknown how the gluten-specific T-cell response in the lamina propria is linked to the inflammation present in the epithelium and if (preexisting) perturbations in the epithelium are required for the development of the inflammation. This is particularly relevant because it is well known that in patients on a gluten-free diet, the presence of intraepithelial lymphocytes remains elevated, indicative of epithelial disturbances. Thus, although gluten-specific T cells are central to disease development, the factors determining their generation, polarization and link with the inflammation in the epithelium remain largely unknown. To delineate these issues a detailed analysis of the properties of both lamina propria–derived gluten-specific T cells and intraepithelial lymphocytes is required in order to understand how these may interact. Although it is likely that this is at least partly due to a deregulated cytokine network, it is also conceivable that downstream cell–cell interactions can play a role, for example, through polarization of dendritic cells in the lamina propria or enterocytes in the epithelium. This issue is crucial for our understanding of not only disease development but also disease initiation. The latter is of particular importance because the elucidation of such a mechanism would provide crucial insight that can be exploited to prevent disease.

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