Celiac Disease - NIH Consensus Development Program - National ...

susceptibility (e.g., DR17 homozygous individuals who carry DQB1*02 and DQA1*05 in cis onboth chromosomes have a greater risk of disease). (11) CD is concordant in approximately70 percent of monozygotic twin pairs and approximately 30–40 percent of HLA identicalsiblings, and it has been estimated that HLA class II genes are responsible for about 40 percentof the genetic contribution to disease. (12) There is no clear definition of what other genescontribute to disease or how they do so, although linkage studies suggest disease-associatedgenes in a region of chromosome 5 and perhaps a region on chromosome 19 in somepopulations. (13)What is the link between the DQ2 and DQ8 heterodimer, the disease activating peptidesand T-cell-activated immune injury. CD4 + T-cell populations that recognize putative diseaseactivating peptides are present in the intestinal mucosa of CD patients. Moreover, these peptidesbind more efficiently in the peptide binding groove of the DQ2 or DQ8 heterodimer whenspecific glutamine residues are deamidated to negatively-charged glutamic acid by tissuetransglutaminase. (14,15) Nonetheless, a broad array of peptides derived from gliadins, glutenins,hordeins, and secalins likely can activate disease (16,17) and their deamidation does not appear to bean absolute requirement, at least for initiating this disease. (17)In summary, significant progress has been made at the protein, genetic and immunologiclevel in understanding the pathogenesis of CD. However, significant questions have not beenanswered and a great deal remains to be discovered regarding early luminal events that effectdisease susceptibility and pathogenesis, the more complex and perhaps subtle genetic factors andmechanisms that enhance disease susceptibility, and the pathways involved in the mucosal entryand processing of disease activating peptides and the activation of T-cells and other cells thatlead to the immune tissue injury.References1. Hoffenberg EJ, MacKenzie T, Barriga KJ, et al. A prospective study of the incidence ofchildhood celiac disease. J Pediatr. 2003;143:308–314.2. Maki M, Mustalahti K, Kokkonen J, et al. Prevalence of Celiac disease among children inFinland. N Engl J Med. 2003;348:2517–2524.3. Kagnoff MF. Celiac disease pathogenesis: the plot thickens. Gastroenterology.2002;123:939–943.4. Van de Wal Y, Kooy YM, Van Veelen P, et al. Glutenin is involved in the gluten-drivenmucosal T cell response. Eur J Immunol. 1999;29:3133–3139.5. Molberg O, Solheim Flaete N, Jensen T, et al. Intestinal T-cell responses to highmolecular-weightglutenins in celiac disease. Gastroenterology. 2003;125:337–344.6. Hausch F, Shan L, Santiago NA, Gray GM, Khosla C. Intestinal digestive resistance ofimmunodominant gliadin peptides. Am J Physiol Gastrointest Liver Physiol.2002;283:G996–G1003.20