1. Overview and pathogenesis of celiac disease
Martin F. Kagnoff 
Gastroenterology 
Volume 128, Issue 4, Pages S10-S18 (April 2005)
DOI: /j.gastro
Copyright © 2005 American Gastroenterological Association Terms and Conditions

2. Figure 1
Small intestinal mucosal biopsy. Small intestinal mucosal biopsy viewed through a dissecting microscope (A and B). The normal biopsy (A) shows numerous surface villi, whereas a biopsy from an individual with celiac disease 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. Features include a crypt to villous ratio of approximately 4–5:1, columnar villous epithelial cells with basally oriented nuclei, a normal complement of intraepithelial lymphocytes (approximately 1 per 6–10 enterocytes) and a normal representation of lymphocytes and plasma cells in the lamina propria characteristic of the “physiologic” inflammation in normal small intestinal mucosa. (D) A small intestinal mucosal biopsy from an individual with celiac disease and total villous atrophy. Note the abnormal surface epithelial cells that are flattened rather than columnar, the complete loss of villi, marked lenghtening of the crypt compartment, the increase in intraepithelial lymphocytes, lymphocytes, and plasma cells in the lamina propria, and increased crypt miltoses.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

3. Figure 2
Spectrum of pathology and malabsorption in celiac disease. The extent of the mucosal abnormality can vary markedly in celiac disease. Consistent with this, the extent of nutrient malabsorption also varies from minimal to severe.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

4. Figure 3
Spectrum of symptoms in celiac disease. Consistent with the marked variability in the extent of disease, the spectrum of symptoms varies markedly in individuals with celiac disease.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

5. Figure 4
Taxonomy of some dietary grains. Wheat, barley, and rye, which contain gluten, hordein, and secalin, respectively, are derived from the Triticaeae tribe of the grass (Gramilneae) family. In contrast, oats, which contains few disease-activating proteins, is more distantly related as are rice, maize, sorghum, and millet.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

6. Figure 5
Proteins that activate celiac disease are rich in glutamine and proline residues. The proteins in wheat, rye, and barley that activate celiac disease are characterized by a high content of glutamine (Q) and proline (P) as seen in this example, which is the primary amino acid sequence of an α gliadin (A-gliadin). This is only one of many different α gliadins present in wheat.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

7. Figure 6
Venn diagram depicting the distribution of DQ2 and DQ8 in the general population and in celiac disease. HLA DQ2 and DQ8 are common in the general population, but, as shown, with few if any exceptions, patients with celiac disease carry the HLA class II alleles DQB1*02 and DQA1*05, which codes for the celiac disease-associated DQ heterodimer, or DQB1*0302 and DQA1*03, which codes for DQ8.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

8. Figure 7
Two ways to inherit the DQ2 heterodimer associated with celiac disease. DR17 haplotypes (formerly termed DR3) carry in cis (ie, on the same chromosome) the DQ alleles B1*0201, which encodes a β chain, and A1*05, which encodes an α chain. The β and α chain form a DQ heterodimer that is associated with celiac disease. DR7 haplotypes carry the very closely related DQB1*0202 allele on 1 chromosome. If the other chromosome carries a DR 11 or 12 haplotype (formerly termed DR5) that has the DQA1*05 allele, the β and α chains encoded by those alleles can pair in the cell and form the disease-associated DQ2 heterodimer. Please note that, if an individual is homozygous for DR17, or heterozygous for DR17/DR7, 100% and 50%, respectively, of their DQ molecules can be the celiac disease-associated HLA-DQ2.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

9. Figure 8
DQ2 heterodimers on the surface of antigen-presenting cells bind “gluten” peptides. HLA class II molecules that are expressed on the cell surface of antigen-presenting cells (eg, macrophages, dendritic cells, B cells) bind foreign peptides encountered extracellularly. DQ2 and DQ8 are well suited to bind peptides of “gluten,” particularly if they contain deamidated glutamine residues.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

10. Figure 9
Treatment of gluten peptides with tissue transglutaminase deamidates selected glutamine residues. Treatment of “gluten” peptides with tissue transglutaminase results in the conversion of glutamine (Q) residues with a neutral charge to glutamic acid (E) residues with a negative charge. This renders those peptides better binders to DQ2 or DQ8. Shown are examples of sites of glutamine deamidation that occur in 2 gluten peptides that can bind to DQ2 and a gluten peptide that can bind to DQ8.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

11. Figure 10
Gluten peptide binding in the peptide binding groove of a DQ2 heterodimer encoded by DQB1*02 and DQA1*05. Gluten peptides form left-handed polyproline II helixes that are a preferred conformation for binding in the peptide-binding groove of HLA class II molecules. Pockets at several positions in the peptide-binding groove of DQ2 and DQ8, in addition, have a preference for negatively charged residues such as those formed in gluten peptides when their neutral glutamines are deamidated to negatively charged glutamic acid. These features render the DQ2 heterodimer ideally suited for binding deamidated gluten peptides. In this Figure, a peptide of gluten is shown in the DQ2 peptide binding groove. DQ2 residues of the α and β chains that interact with the peptide are shown using a 3-letter amino acid code. Dotted lines represent hydrogen bonds. Reprinted with permission from Kim et al.41
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

12. Figure 11
MHC-peptide-T-cell interaction. A molecular basis for the activation of DQ-restricted T cells in the small intestinal mucosa in celiac disease. In this schematic ribbon representation of a DQ2 or DQ8 molecule on the surface of an antigen-presenting cell, a gluten peptide is represented in the peptide-binding groove. This complex is recognized by the T-cell receptor of DQ2 or DQ8-restricted CD4 T cells.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

13. Figure 12
Pathogenesis of celiac disease. This cartoon divides the pathogenesis of celiac disease into 3 major series of events: luminal and early mucosal events, activation of pathogenic CD4+ T cells, and 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 gain access across the epithelial barrier to the lamina propria where they encounter tissue transglutaminase and antigen-presenting cells that express DQ2 or DQ8 that are ideally suited to bind those deamidated proline-rich peptides. In a further series of events, the antigen-presenting cells present some of these peptides to DQ2 or DQ8 restricted populations of CD4+ T cells, which 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 barrier, the role of the intraepithelial lymphocytes in early and late disease pathogenesis, the role of IL-15 and type I interferons in disease pathogenesis, and the underlying basis for the release of tissue transglutaminase that leads to deamidation of gluten peptides.
Gastroenterology  , S10-S18DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions