Abstract
Coeliac disease is a common small bowel enteropathy arising in genetically predisposed individuals and caused by ingestion of gluten in the diet. Great advances have been made in understanding the role of the adaptive immune system in response to gluten peptides. Despite detailed knowledge of these adaptive immune mechanisms, the complete series of pathogenic events responsible for development of the tissue lesion remains less certain. This review contributes to the field by discussing additional mechanisms which may also contribute to pathogenesis. These include the production of cytokines such as interleukin-15 by intestinal epithelial cells and local antigen presenting cells as a pivotal event in the disease process. A subset of unconventional T cells called gamma/delta T cells are also persistently expanded in the coeliac disease (CD) small intestinal epithelium and recent analysis has shown that these cells contribute to pathogenic inflammation. Other unconventional T cell subsets may play a local immunoregulatory role and require further study. It has also been suggested that, in addition to activation of pathogenic T helper cells by gluten peptides, other peptides may directly interact with the intestinal mucosa, further contributing to the disease process. We also discuss how myofibroblasts, a major source of tissue transglutaminase and metalloproteases, may play a key role in intestinal tissue remodeling. Contribution of each of these factors to pathogenesis is discussed to enhance our view of this complex disorder and to contribute to a wider understanding of chronic immune-mediated disease.
Highlights
Coeliac disease (CD) is a common inflammatory disorder of the small intestine resulting in malabsorption
It has long been observed that chronic immune activation by gluten in coeliac disease (CD) patients induces a permanent change in the intra-epithelial lymphocyte (IEL) compartment, characterized by an expanded and persistent presence of γ/δ IELs, which was recently verified using cell sequencing methodology [21,22,23]
Epithelial cells influence the behavior of many intestinal cell populations including innate lymphoid cells (ILC), neutrophils, basophils, macrophages, T cells and B cells through the production and release of a range of cytokines and chemokines including tumor necrosis factor alpha (TNF)α, interleukin (IL)-8, IL-18, IL-25, transforming growth factor (TGF)-β and B cell activating factor [66, 68]
Summary
Coeliac disease (CD) is a common inflammatory disorder of the small intestine resulting in malabsorption. It has long been observed that chronic immune activation by gluten in CD patients induces a permanent change in the intra-epithelial lymphocyte (IEL) compartment, characterized by an expanded and persistent presence of γ/δ IELs, which was recently verified using cell sequencing methodology [21,22,23]. Many studies report that innate immune components such as neutrophils [31], eosinophils [32,33,34], mast cells [35, 36] and complement proteins [37] are activated in the disease process and potentially contribute to disease pathogenesis Consideration of this information may lead to a more comprehensive understanding of CD pathology. While I-FABP is expressed in fully differentiated enterocytes in homeostasis, it appears earlier in crypt enterocytes when enteropathy is present [64]
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