Celiac disease is caused by a selective lack of T cell tolerance for gluten. It is known that the enzyme tissue transglutaminase (tTG) is involved in the generation of T cell stimulatory gluten peptides through deamidation of glutamine, the most abundant amino acid in gluten. Only particular glutamine residues, however, are modified by tTG. Here we provide evidence that the spacing between glutamine and proline, the second most abundant amino acid in gluten, plays an essential role in the specificity of deamidation. On the basis of this, algorithms were designed and used to successfully predict novel T cell stimulatory peptides in gluten. Strikingly, these algorithms identified many similar peptides in the gluten-like hordeins from barley and secalins from rye but not in the avenins from oats. The avenins contain significantly lower percentages of proline residues, which offers a likely explanation for the lack of toxicity of oats. Thus, the unique amino acid composition of gluten and related proteins in barley and rye favors the generation of toxic T cell stimulatory gluten peptides by tTG. This provides a rationale for the observation that celiac disease patients are intolerant to these cereal proteins but not to other common food proteins.

Terpenoids have diverse bioecological roles in all kingdoms of life. Here we discuss the evolution and ecological functions of microbial terpenoids and their possible applications.

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Recent research has implicated a large number of gluten-derived peptides in the pathogenesis of celiac disease, a preponderantly HLA-DQ2-associated disorder. Current evidence indicates that the core of some of those peptides is ten amino acids long, while HLA class II normally accommodates nine amino acids in the binding groove. We have now investigated this in detail, using gluten-specific T-cell clones, HLA-DQ2-specific peptide-binding assays and molecular modelling. T-cell recognition of both a gamma-gliadin peptide and a low-molecular-weight glutenin peptide was found to be strictly dependent on a ten-amino acids-long peptide. Subsequent peptide-binding studies indicated that the glutenin peptide bound in a conventional p1/p9 register, with an additional proline at p-1. Testing of substitution analogues demonstrated that the nature of the amino acid at p-1 strongly influenced T-cell recognition of the peptide. Moreover, molecular modelling confirmed that the glutenin peptide binds in a p1/p9 register, and that the proline at p-1 points upward towards the T-cell receptor. Database searches indicate that a large number of potential T-cell stimulatory gluten peptides with an additional proline at relative position p-1 exist, suggesting that the recognition of other gluten peptides may depend on this proline as well. This knowledge may be of importance for the identification of additional T-cell stimulatory gluten peptides and the design of a peptide-based, tolerance-inducing therapy.