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Enzyme Reaction Promises Better Understanding of Celiac Disease
Celiac.com 04/10/2009 - According to the latest findings by a Norwegian research team, the inner workings of a particular enzymatic reaction is helping scientists figure out how celiac disease develops.
In the latest issue of the Journal of Proteome Research, doctors Siri Dørum, Burkhard Fleckenstein, and associates at Norway’s University of Oslo and Rikshospitalet University Hospital describe how they used a quantitative MS method to chart a significant association between the amount of deamidation and the rate at which various epitopes are recognized by T cells of people with celiac disease.
The team set out to determine whether the rate of TG2 deamidation correlates with T cell recognition of gluten peptide epitopes.
Celiac disease is a common digestive disorder, in which people suffer from an adverse reaction to gliadin proteins in the gluten of wheat, barley, and rye. When people with celiac disease eat gluten, an adverse immune reaction occurs, in which the intestinal villi, the finger-like projections that line the small intestine and serve to absorb nutrients, suffer damage and eventually flatten and disappear.
Currently, the only treatment is the adoption of a gluten-free diet that eliminates exposure to the proteins that trigger the immune response. In most cases, the gluten-free diet heals the intestinal damage.
So, how does gluten exposure cause this adverse immune system reaction? Much of this process remains a mystery, but there appears to be a strong genetic component. It is known that most people with celiac disease display the human leukocyte antigen (HLA) molecules DQ2 or DQ8, which function as receptors on antigen-presenting cells.
The standard method of measuring deamidation is to tie the transglutaminase activity to a secondary enzymatic reaction, which gives off ammonium. But this method is not direct, and if there are multiple peptides in a mixture, which may be highly complex, one can only assess the total production of ammonium.
By contrast, the MS method allows the detection of changes on each peptide, and allows the locations of those modifications to be pinpointed within each peptide.
The team achieved their results by measuring the centroid masses of the peptides’ isotopic envelopes before TG2 treatment, and comparing the results to the values obtained after TG2 treatment.
Depending on the sequence context, the glutamine residues were shown to influence the extent of residual deamidation by TG2. Additionally, they team revealed that peptide length also plays a key role in the process—the longer the given gliadin peptide, the more likely it is to have deamidated glutamines.
The team examined an array of gluten peptides with known epitopes, both individually and in mixture, to assess the degree of deamidation. A 33-mer, shorter α-gliadin peptides, and one peptide from γ-gliadin all showed rapid deamidation. The rest of the peptides showed only partial deamidation, even after a long period of incubation.
They observed that the frequency of the T cell response in celiac disease patients seems to be tied to the rate of peptide deamidation. T cells from nearly every patient recognized the 33-mer and the α-gliadin peptide, which also served as good TG2 substrates. In comparison, the glutamines of most γ-gliadin peptides were deamidated less often and were recognized less frequently by patient T cells.
However, one γ-gliadin peptide showed itself to be an exception. The γ-II epitope functions as an excellent substrate for TG2, but is poorly recognized by T cells. Another factor may be proteolytic stability, as it is understood that the γ-II epitope is part of a gluten fragment that is less stable than the 33-mer.
By analyzing gluten peptides using MS, researchers were able to figure out whether the rate of glutamine deamidation by TG2 impacts the recognition of these peptides by the immune systems of those with celiac disease.
J. Proteome Res., 2009, 8 (4), pp 1748–1755
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Jefferson Adams is a freelance writer living in San Francisco. His poems, essays and photographs have appeared in Antioch Review, Blue Mesa Review, CALIBAN, Hayden's Ferry Review, Huffington Post, the Mississippi Review, and Slate among others.
He is a member of both the National Writers Union, the International Federation of Journalists, and covers San Francisco Health News for Examiner.com.View all articles by Jefferson Adams
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