The precipitating factor in coeliac disease.

In recent years, remarkable progress has been made in the elucidation of cereal protein structure and its relation to coeliac toxicity. Gluten proteins of wheat can be classified according to their primary structure into high-, medium- and low-molecular-weight (HMW, MMW, LMW) groups. Each of these groups contains two or three different protein types having partly homologous, partly unique, structural elements: chi- and gamma-type HMW subunits of glutenin (HMW group), omega 5 and omega 1,2-type gliadins (MMW group) and alpha-type gliadins, gamma-type gliadins and LMW subunits of glutenin (LMW group). Numerous proteins from the same type do exist with only a few modifications of the amino-acid sequence. The structure of the HMW and LMW group proteins can be divided into three and five domains, respectively. Most typical for each type and unique for cereals are the glutamine- and proline-rich domains containing repetitive sequences (HMW group: domain B; LMW group: domain I). omega-type gliadins consist almost entirely of repetitive sequences. Rye and barley, closely related to wheat, have protein types homologous to those of wheat. Early investigations showed that wheat gluten and, in particular, the alcohol-soluble gliadin fraction contained the factor toxic for coeliac patients. Equivalent protein fractions of rye, barley and probably oats were also considered to be toxic. The effects of toxic proteins were not destroyed by digestion with pepsin, trypsin and pancreatin. In-vivo (instillation) testing established the toxicity of alpha-type gliadins, and in-vitro (organ culture) testing of gliadin peptides demonstrated that the N-terminal region (domain I) of alpha-type gliadins is involved in activating coeliac disease. The longest sequences common for toxic peptides were found to be -Pro-Ser-Gln-Gln- and -Gln-Gln-Gln-Pro-. Various in-vitro tests and two in-vivo studies on synthetic peptides support the importance of one or both of these sequences. They do not occur in non-toxic food proteins and are characterized by their ability to form a beta-turn conformation. Although these sequences are probably not sufficient for toxicity in themselves, and other amino-acid residues are additionally required, they could serve as the starting point for further investigation.