New Insights into the Pathogenesis of Celiac Disease

Abstract

Celiac disease (CD) is an autoimmune and multisystem gluten-related disorder that causes symptoms involving the gastrointestinal tract and other organs. Pathogenesis of CD is only partially known. It had been established that ingestion of gluten proteins present in wheat and other cereals are necessary for the disease and develops in individuals genetically predisposed carrying the DQ2 or DQ8 human leukocyte antigen haplotypes. In this review, we had pay specific attention on the last discoveries regarding the three cellular components mainly involved in the development and maintenance of CD: T-cells, B-cells, and microbioma. All of them had been showed critical for the interaction between inflammatory immune response and gluten peptides. Although the mechanisms of interaction among overall these components are not yet fully understood, recent proteomics and molecular studies had shed some lights in the pathogenic role of tissue transglutaminase 2 in CD and in the alteration of the intestinal barrier function induced by host microbiota.

Keywords: B-cell; celiac disease; immunoglobulin; microbioma; transglutaminase.

Figure 1

Gluten-specific CD4⁺ T-cells of patients affected by Celiac disease show an high production of interferon-gamma (IFN-γ) and a low production of Bach2. CD4⁺ T-cells proliferate and differentiate into various subtypes in response to antigen (Ag) stimulation and their microenvironment. IFN-γ is known to promote the differentiation of T-helper 1 (TH1) cells, inhibit the TH2 immune response and Treg survival, and activate the phagocytosis of macrophages, B-cell immunoglobulin class switching, and presentation of major histocompatibility complexes (MHCs). Bach2 expression is crucial for the development of Treg and for the germinal center formation, somatic hypermutation and class-switch recombination of immunoglobulins in B-cells; thus is an important key regulator in the maintenance of immune homeostasis.

Figure 2

Tissue transglutaminase 2 (TG2) enzymatic activity. TG2 is a ubiquitously expressed member of the TG family of enzymes that all catalyze Ca²⁺-dependent protein deamidation or transamidation (cross-linking) of glutamine residues.

Figure 3

Structural tissue transglutaminase 2 (TG2) conformation influences TG2 catalytic activity. TG2 activity is regulated in cells by reversible conformational changes of the catalytic core site of the protein. The catalytic cystein residue (SH) is part of the conserved motif that is required for the enzymatic activity. Spatial arrangement of the four domains in TG2 leads TG2 domains in an inactive closed compact form. The binding of Ca²⁺ to the catalytic domain of TG2 alters the protein to move domains 3 and 4 away from the catalytic domain, thus making the active site accessible (open, catalytically active). Oxidation of the open/active protein (at the cystein position) results in loss of TG2 activity (open, catalytically inactive form). Modified from PDB, Liu, S. Strop, P. X-ray crystallography structures of tissue transglutaminase.

Figure 4

A model to explain the gluten-dependent production of tissue transglutaminase 2 (TG2)-specific antibodies. (1) TG2-gliadin complexes are taken up by a TG2-specific B cell through B-cell receptor (BCR)-mediated endocytosis. BCR shows a restricted use of VH and VK chains of IgD+ istotype. Then, BCR-TG2 cross linked to gliadin peptides complexes are endocytosed and transported to the cellular endosomal compartment where gliadin peptide deaminated by TG2 enzyme were release to bind human leukocyte antigen (HLA)-DQ specific molecules for CD4⁺ T-cell presentation. (2) CD4⁺ T-cell-recognize gliadin peptide presented by HLA-DQ molecule through a specific T-cell receptor (TCR). Correct TCR-peptide interaction causes the signal for B-cell stimulation. (3) B-cell stimulation of IgD+ naïve B-cells leads to the induction of immunoglobulin (Ig) mutation and class switching. (4) Naïve B-cells differentiate in short-lived plasma cells (PCs) (preferentially) and long-lived PCs or memory B cells and release IgA+ and IgG+ TG2-specific antibodies.

Figure 5

Illustration of the 33-mer proteolytically resistant site presnt on α-gliain, showing the T-cells sites and the additional immune peptide overlapping the 33-mer peptide.