Celiac Disease: Molecular Basis

Abstract

Celiac disease (CD) is an inflammatory and multifactorial disorder triggered by cereal gluten in genetically predisposed individuals. CD has several clinical and histological forms characterised by different grade of small intestinal inflammation. Several studies have demonstrated the key role of adaptive CD4+ T lymphocytes in gluten‐dependent enteropathy, although it has been clear that the intraepithelial CD8+ T lymphocytes of innate immunity, highly infiltrating CD mucosa, are pivotal in the induction of intestinal mucosa alteration and malfunction. Recent evidences also highlighted how adaptive CD8+ T lymphocytes restricted by HLA class I molecules contribute to the enterocytes damage through a TCR‐dependent cytotoxic activity. The recent findings on the involvement of HLA class I genes in CD susceptibility are also discussed.

Key Concepts

  • Celiac disease is an immune‐mediated disorder triggered by dietary gluten.
  • Enteropathy is the main form of celiac disease, but extra‐intestinal manifestations are also frequent.
  • Celiac disease has autoimmune features characterised by the production of antitissue transglutaminase antibodies, with high diagnostic relevance.
  • Gluten‐reactive CD4+ T cells are key players as pathogenic T helper cells.
  • Cytotoxic CD8+ T cells, of both innate and adaptive branches, are involved in the intestinal villous atrophy.
  • The current therapy is the avoidance of gluten from the diet.

Keywords: celiac disease; gluten; autoimmunity; cytotoxic CD8+ T lymphocytes; HLA class I

Figure 1. Role of CD8 T cells in celiac disease. A hallmark of CD intestinal biopsies is a massive infiltration of the epithelium and lamina propria by CD8+ T lymphocytes, of either TCRαβ+ and TCRγδ+ lineages. Gliadin peptides are able to activate both intraepithelial lymphocytes (IELs), in particular CD8+ TCRαβ+ lymphocyte bearing the CD94 receptor (NKT cells), and lamina propria CD8+TCRαβ+ lymphocytes of the adaptive immunity. Several gluten peptides (as p123–132) are able to bind to HLA‐class I molecules (in particular to HLA‐A1, A2 and B8) expressed on the surface of both dendritic cells and epithelial cells, and are specifically recognised by CD8+TCRαβ+ in the lamina propria. Once activated by the MHC/gluten‐peptide complexes, CD8 T cells acquire the capacity to lyse the target cells, including enterocytes. On the other hand, peptides such as 31–43 or 31–55 of α‐gliadin stimulate enterocyte to produce IL15 that, in turn, induces the autocrine overexpression of stress molecules MICA and MICB. In addition, IL15 upregulates on T cells the NKG2C/D activating NK receptor, while, in normal condition, IELs express inhibitory NK receptors NKG2A. The interaction between MICA and MICB on enterocytes and NKG2D expressed on CD8+ T cells mediates the enterocyte death and tissue damage.
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Picascia, Stefania, Camarca, Alessandra, and Gianfrani, Carmen(Jan 2018) Celiac Disease: Molecular Basis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027650]