Innate immune system: the no man’s land where discover new biomarkers for gluten-related-disorders

Celiac disease (CD) is now considered, more than a just gluten sensitivity enteropathy, a multiple and systemic immune-mediate disorder triggered by the ingestion of wheat gluten and related proteins. Following the discovery of a link between gluten and CD, it was demonstrated that gliadin, one of the two principal protein groups comprising gluten, plays a key role in CD pathogenesis. It has since become clear that the different and crucial roles of gliadin in CD result from its ability to activate multiple signalling pathways that modulate CD pathology and CD progression (1,2). It is well known that CD is strongly associated with specific human leukocyte antigen (HLA) class II genes, known as HLA-DQ2 and HLA-DQ8, located on chromosome 6p21 (3). Gliadin-specific T-cell responses have been found to be enhanced by the action of intestinal transglutaminases. The infiltration of T cells in the lamina propria of the active celiac lesion is dominated by CD4+ memory T cells (CD45RO+) bearing the α/β T-cell receptor (TCR) (4). The adaptive immune response is initiated by APCs, primarily dendritic cells (DCs) but also macrophages and B cell subsets, which present to T-cell antigenic fragments in complex with cell surface MHC class II molecules (4). However, it is now known that to induce sufficient adaptive immune responses, antigens have to be recognized in the context of an activated innate immune system (5). Activation of innate immunity has been associated with the presence of toxic p31–49 gliadin peptides. In epithelial cells (ECs) toxic glaidin peptides are internalized into early endosomes and lysosomial enzymes or cytosolic enzymes can degrade late endosomes and the peptides. In celiac disease, toxic p31–49 peptide accumulates in the early endosome (6). This event was found associated to an over reactive oxygen species (ROS) and transglutaminase 2 (TG2) production, which may cause a decrease of peroxisome proliferator-activated receptors (PPARs) and a consequent activation of the NF-kB pathway (7). Breaking immunological tolerance, gliadin peptides stimulate different type of cell, particularly dendritic cells (DCs), which results in leukocyte infiltration and inflammation of gut mucosa (8). Given their high plasticity and maturation ability in response to local danger signals derived from innate immunity, dendritic cells are key actors in the connection between innate immunity and adaptive immunity responses (8). In addition to their role as sentinels DCs also act as immune system sensors given their high expression of pattern recognition receptors, including Toll-like receptors (TLRs) (11). TLRs …