Celiac disease: pathogenesis of a model immunogenetic disease

Abstract

Celiac disease is characterized by small-intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals in response to the dietary ingestion of wheat gluten and similar proteins in barley and rye. Disease pathogenesis involves interactions among environmental, genetic, and immunological factors. Although celiac disease is predicted by screening studies to affect approximately 1% of the population of the United States and is seen both in children and in adults, 10%-15% or fewer of these individuals have been diagnosed and treated. This article focuses on the role of adaptive and innate immune mechanisms in the pathogenesis of celiac disease and how current concepts of immunopathogenesis might provide alternative approaches for treating celiac disease.

Figure 1. Small-intestinal mucosal biopsy.

(A and B) Small-intestinal mucosal biopsy viewed through a dissecting microscope. The normal biopsy (A) shows numerous surface villi, whereas a biopsy from an individual with CD and total villous atrophy shows, in place of the villi, numerous surface openings to underlying crypts and surface ridges (B). (C) H&E-stained section of a normal small-intestinal mucosal biopsy. Original magnification, ×400. (D) H&E-stained section of a small-intestinal mucosal biopsy from an individual with CD and total villous atrophy. Original magnification, ×400. All panels reprinted with from Gastroenterology (1) with permission from the American Gastroenterological Association.

Figure 2. Taxonomy of some dietary grains.

Wheat, barley, and rye, which contain the CD-activating proteins gluten, hordein, and secalin, respectively, are derived from the Triticeae tribe of the grass (Gramineae) family. In contrast, oats, which contain few CD-activating proteins, are more distantly related, as are rice, maize, sorghum, millet, Job’s tears, and tef.

Figure 3. Venn diagram depicting the distribution of HLA-DQ2 and HLA-DQ8 in the general population and in CD.

The MHC class II heterodimers HLA-DQ2 and HLA-DQ8 are commonly expressed by the general population of the United States. With few, if any, exceptions, patients with CD carry the HLA-DQ alleles HLA-DQB1*02 and HLA-DQA1*05, which encode the HLA-DQ2 heterodimer, or HLA-DQB1*0302 and HLA-DQA1*03, which encode the HLA-DQ8 heterodimer.

Figure 4. Two ways to inherit the HLA-DQ2 heterodimer associated with CD.

DR17 haplotypes (formerly termed DR3) carry in cis (that is, on the same chromosome) the HLA-DQ alleles HLA-DQB1*0201, which encodes a β chain, and HLA-DQA1*05, which encodes an α chain. The β and α chains form an HLA-DQ2 heterodimer that is associated with CD. DR7 haplotypes carry the very closely related HLA-DQB1*0202 allele on 1 chromosome. If the other chromosome carries a DR11, DR12, or DR13 (formerly termed DR5) haplotype that has the HLA-DQA1*05 allele, the β and α chains encoded by those alleles can pair in the cell and form the CD-associated HLA-DQ2 heterodimer. If an individual is homozygous for DR17, or heterozygous for DR17/DR7, 100% or 50%, respectively, of their HLA-DQ molecules are presumed to be the CD-associated HLA-DQ2 heterodimer.

Figure 5. Pathogenesis of CD.

This schematic divides the pathogenesis of CD into 3 major series of events: luminal and early mucosal events; the activation of pathogenic CD4⁺ T cells; and the subsequent events leading to tissue damage. During the luminal and early mucosal events, key features include the ingestion of “gluten” by a genetically susceptible individual. “Gluten” is not fully digested because of its high proline content, and this gives rise to a number of large undigested “gluten” peptides. The peptides cross the epithelial barrier to the lamina propria and encounter tissue TGase and APCs that express HLA-DQ2 or HLA-DQ8 heterodimers that are ideally suited to bind proline-rich peptides containing negatively charged glutamic acid residues as a result of glutamine deamidation by tissue TGase. In a further series of events, the APCs present some of these peptides to HLA-DQ2– and HLA-DQ8–restricted populations of CD4⁺ T cells that become activated and release mediators that ultimately lead to tissue damage. There are still many unknowns. These include the mechanism by which “gluten” peptides cross the epithelial cell barrier, the role of innate immunity and IELs in both the early and the late phases of CD pathogenesis, the role of IL-15 and type I IFNs in disease pathogenesis, the underlying basis for the release of tissue TGase that leads to deamidation of gluten peptides, and the sequence of, and relationship between, CD4⁺ T cell responses and the responses of the IEL population.