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Toward a better understanding of celiac disease
pinpointed within each peptide. Quantification was achieved by calculating the shift of the centroid masses of the The kinetics of an enzyme reaction peptides’ isotopic envelopes after TG2 may help researchers figure out how treatment from the values obtained celiac disease (CD) develops. Siri before treatment. Dørum, Burkhard Fleckenstein, and The sequence context of glutamine colleagues at the University of Oslo residues was known to influence and Rikshospitalet University Hospital whether the residues would be deami(Norway) report in JPR (DOI 10.1021/ dated by TG2. However, the researchpr800960n) that they have applied a ers discovered that the quantitative MS method peptide length is also a and observed a positive key factor. The longer a correlation between the gliadin peptide is, the degree of deamidation more likely it is to have and the frequency with deamidated glutamines. which various epitopes Various gluten peptides are recognized by T cells with known epitopes of CD patients. were studied individually CD is a common diand in a mixture to degestive disease in which termine the degree of nutrients from food are deamidation. A 33-mer, not absorbed well. shorter R-gliadin pepPeople with the disease tides, and one peptide cannot tolerate gluten, from γ-gliadin were which is a mixture of deamidated quickly. The proteins found in wheat, Skip the bread. Researchers analyzed gluten peptides by MS to figure out rest of the peptides were barley, and rye. When a whether the rate of glutamine deamidation by TG2 plays a role in the recognition of these peptides by the immune systems of CD patients. only partially deamipatient consumes gluten, dated, even after a long an immune response ocincubation. “The results curs. Villisfingerlike proseem to correlate with the observed nize γ-gliadin epitopes. Many gliadin jections in the small intestine that are frequency of the T cell response in cepeptides can be deamidated, so why are responsible for nutrient liac disease patients,” says Dørum. The some peptides recognized more freabsorptionsdisappear. Currently, the 33-mer and the R-gliadin peptide were quently by T cells than others? “What only treatment is a change in diet to good TG2 substrates and were recogwas not known was how fast the avoid proteins that trigger the immune nized by T cells from almost all paepitopes were deamidated by TG2, and response. In most cases, a gluten-free tients. In comparison, the glutamines we were wondering what implications diet reverses the intestinal damage. of most γ-gliadin peptides were deamithis would have for the T cell responses So, how does gluten cause the imdated less often and were recognized in celiac disease,” explains Dørum. mune system to run amok? Some deless frequently by patient T cells. HowTo see whether the rate of TG2 details of this process are still unknown, ever, one γ-gliadin peptide was an examidation correlates with T cell recogbut a strong genetic association exists. ception. “The γ-II epitope is a very nition of gluten peptide epitopes in Most CD patients express the human good substrate for TG2 but is not often patients, the researchers turned to MS. leukocyte antigen (HLA) molecules recognized by T cells,” Dørum points Fleckenstein points out that the conDQ2 or DQ8, which are receptors on out. She explains that proteolytic staventional method of assaying deamidaantigen-presenting cells. When HLA bility may be an additional factor. “It is tion is to couple the transglutaminase DQ molecules bind to foreign antigens known that the γ-II epitope is part of a activity to another enzymatic reaction, or self-antigens, these antigens are pregluten fragment that is less stable comwhich releases ammonium. But this sented to T cells, which either promote pared with the 33-mer,” she states. approach is indirect. “If there are sevor suppress an immune response. After Although the scientists are not sureral peptides in a mixture, which may gluten has been digested into peptides, prised by their findings, they say that be of high complexity, one can only the enzyme transglutaminase 2 (TG2) these results fill in a large knowledge measure the sum of ammonium prodeamidates some of these peptides and gap. “This adds one more piece to the duction,” says Fleckenstein. However, converts certain glutamine residues to puzzle on epitope selection,” notes with MS, the modifications on each glutamic acid. This process introduces Dørum. peptide can be detected, and the locanegative charges, which increase the —Katie Cottingham tions of those modifications can be affinities of these peptides for DQ2 and SIRI DØRUM
DQ8, and an immune response is triggered. Most of the peptides, or epitopes, that T cells recognize in CD patients are derived from R- and γ-gliadins, which are gluten proteins. Some epitopes are better triggers of an immune response than others. For example, almost all patients have T cells that recognize R-gliadin epitopes, but few have T cells that recog-
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Journal of Proteome Research • Vol. 8, No. 4, 2009
10.1021/pr900075y
© 2009 American Chemical Society
