Under physiological conditions the gut associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens1,2. A notable counter-example is celiac disease, where genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T cell and antibody responses against dietary gluten, a protein present in wheat3. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, was shown to play a critical role in the induction of intestinal regulatory responses4–6. We found that in conjunction with IL-15, a cytokine greatly upregulated in the gut of celiac disease patients, retinoic acid rapidly activated dendritic cells to induce JNK phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings unveil an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.

In response to the suggestion that an increase in the incidence of celiac disease might be attributable to an increase in the gluten content of wheat resulting from wheat breeding, a survey of data from the 20th and 21st centuries for the United States was carried out. The results do not support the likelihood that wheat breeding has increased the protein content (proportional to gluten content) of wheat in the United States. Possible roles for changes in the per capita consumption of wheat flour and the use of vital gluten as a food additive are discussed.

Both high-and low-molecular-weight glutenin subunits (LMW-GSThe glutenin fraction of the gluten proteins is primarily responsible for the viscoelastic properties of wheat (Triticum aestivum L.) flour doughs. It consists of various types of protein subunits that are linked together by intermolecular disulfide bonds. These form a polymeric mixture that has a broad molecular-weight distribution, with component polymers ranging from the dimeric forms with molecular weights as low as 60,000, to polymers containing many subunits with molecular weights in the millions (for review, see Kasarda, 1989; Wrigley, 1996). Variations in the types and amounts of subunits correlate with quality variations among wheat cultivars, probably by affecting the molecular-weight distribution of the glutenin polymers (Gupta et al., 1993(Gupta et al., , 1995. There are two main types of subunits, the HMW-GS and the LMW-GS, with the former having been much more extensively characterized than the latter.Difficulties in characterization of LMW-GS arose because they derive from many more genes than HMW-GS and because the subunits are somewhat insoluble after reduction of the intermolecular disulfide bonds (which is necessary for their purification, but which also breaks down intramolecular disulfide bonds to expose buried hydrophobic regions). Until recently, almost all attempts at cloning lmw-gs genes led to DNA sequences corresponding to similar protein products that are not representative of the major LMW-GS types; almost all had the apparent N-terminal sequence METSCIPGL-, relatively low molecular weights of about 35,000 or less, and a total of eight Cys residues, including the Cys at position 5 (for review, see Shewry and Tatham, 1997; Cassidy et al., 1998).In contrast to the apparently single type (with very minor variations) of the LMW-GS indicated by the DNA sequencing, two main types of LMW-GS have been defined on the basis of N-terminal amino acid sequences: the LMW-s and LMW-m types, with the former starting with the sequence SHIPGL-, and the latter represented by the METSHIPGL-, METSRIPGL-, or METSCIPGL-N-terminal sequences (Kasarda et al., 1988; Tao and Kasarda, 1989; Lew et al., 1992). The LMW-s types are predominant. They also tend to have higher molecular weights, in the approximate range of 35,000 to 45,000 relative to the LMW-m types, which seem to fall into the wider molecular-weight range of about 30,000 to 45,000 (Lew et al., 1992). In bread wheat cultivars, the LMW-m type with the METSHIPGLsequence was the next most abundant type of LMW-GS, followed by the METSRIPGL-type, whereas the METSCIPGL-N-terminal sequence, typical of the cloned sequences, appeared to be somewhat rare among the types defined by direct protein sequencing (Lew et al., 1992). Both LMW-s and LMW-m types are coded by genes present at the complex Glu-3 loci (Glu-A3, Glu-B3, and Glu-D3 in hexaploid wheat). Only partial sequence information has been available for the LMW-s types because 1