While the central role of an adaptive, T cell-mediated immune response to certain
gluten peptides in
celiac disease is well established, the innate immune response to wheat
proteins remains less well defined. We identified wheat
amylase trypsin inhibitors (ATIs), but not
gluten, as major stimulators of innate immune cells (dendritic cells>macrophages>monocytes), while intestinal epithelial cells were nonresponsive. ATIs bind to and activate the CD14-MD2
toll-like receptor 4 (TLR4) complex. This activation occurs both in vitro and in vivo after oral ingestion of purified ATIs or
gluten, which is usually enriched in ATIs. Wheat ATIs represent a family of up to 17
proteins with molecular weights of around 15 kDa and a variable primary but conserved secondary structure characterized by 5 intrachain
disulfide bonds and alpha helices. They mostly form di- and tetramers that appear to equally activate TLR4. Relevant
biological activity is confined to ATIs in
gluten-containing cereals, while
gluten-free cereals display no or minimal activities. ATIs represent up to 4% of total wheat
protein and are highly resistant to intestinal
proteases. In line with their dose-dependent function as co-stimulatory molecules in adaptive immunity of
celiac disease, they appear to play a role in promoting other immune-mediated diseases within and outside the GI tract. Thus, ATIs may be prime candidates of severe forms of non-celiac
gluten (wheat) sensitivity.