Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders
Highlights
► PTMs play a critical role in the pathogenesis of celiac disease. ► PTMs select T-cell epitopes and TCR repertoire, and determine HLA association. ► Conditions driving activation of enzymes mediating PTMs also mature APC allowing expansion of autoreactive T cells. ► The redox status of the tissue plays a role in TG2 activation. ► PTMs and HLA association can be used to identify disease relevant antigens.
Introduction
As a model, celiac disease is conducive to study as the tissue targeted by the immune process is easily accessible and the onset of pathogenesis can be controlled by the administration of gluten. The links between the causative antigen, the HLA molecules required for pathogenesis, and the enzyme involved in posttranslational modification (PTM) have been extensively analyzed. The notion that observations made in the celiac disease model may help gain insights into the role of PTM and the basis for association with particular MHC molecules in other autoimmune disorders serves as the foundation for this paper. Even though the causative antigen in celiac disease is foreign, we will argue that observations of celiac disease are relevant to autoimmunity. The reasoning is based on genetic observations demonstrating sharing of a large number of susceptibility loci between various autoimmune disorders and celiac disease [1]. Moreover, key features of the pathogenesis of celiac disease, as summarized in Figure 1, are shared with other autoimmune disorders, notably with rheumatoid arthritis.
Section snippets
HLA and non-HLA genes predisposing to celiac disease
Celiac disease has a strong HLA association with HLA-DQ2.5 (DQA1*05,DQB1*02) encoded in cis or trans and with HLA-DQ8 (DQ*03,DQB1*03:02). The very few celiac disease patients who do not carry HLA-DQ2.5 or HLA-DQ8, carry HLA-DQ molecules with one but not both of the DQA1*05 or DQB1*02 alleles found in HLA-DQ2.5, that is, HLA-DQ7 (DQA1*05, DQB1*03:01) or HLA-DQ2.2 (DQA1*02:01,DQB1*02) [2]. HLA in celiac disease is a necessary, but not sufficient factor for disease development. Most individuals
Enzymatic mechanism of transglutaminase 2
Transglutaminase 2 (TG2) belongs to a family of enzymes which are involved in crosslinking reactions [5]. The enzyme is targeting specific glutamine residues of polypeptides. As a first step in the enzymatic reaction, the glutamine residue makes a thiolester bond to the active site cysteine of TG2. This enzyme-substrate intermediate then reacts with a primary amine group, such as a lysine residue, and an isopeptide bonded covalent crosslink is formed in a process termed transamidation.
Regulation of TG2 activity by environmental factors
TG2 is ubiquitously present in tissues. There is evidence that most extracellular TG2 is inactive under normal physiological conditions, but abundant TG2 activity can be detected in vitro around the wound in a cultured fibroblast scratch assay and in vivo by stimulation with the toll-like receptor 3 ligand, polyinosinic–polycytidylic acid (poly(I:C)) [8••]. TG2 is rapidly inactivated in the extracellular environment by oxidation through formation of a disulphide bond between two vicinal
Gluten T-cell epitopes
More than 15 different wheat gluten T-cell epitopes recognized in the context of HLA-DQ2.5 or HLA-DQ8 have been identified over the last 15 years. Recently epitopes from barley and rye were also characterized [11•]. The great majority of these T-cell epitopes contain glutamine residues that are targeted by TG2 and converted into glutamate residues by a deamidation reaction. In general T cells of celiac disease patients recognize deamidated epitopes with greater efficiency than native ones. This
Factors determining the selection of gluten T-cell epitopes
Despite the existence of many gluten epitopes by T cells of celiac disease patients, available data suggest that selection of these epitopes is anything but a random process. Gluten proteins are extremely heterogenous. They group into families of gliadins and glutenins, and in a single wheat cultivar several hundred distinct gluten proteins each of more than 200 residues are expressed. In addition there is variation between various cultivars. Many different sequences are thus represented in
Effect of gluten peptide deamidation for the generation of stable peptide-MHC complexes
Studies on the differential risk of HLA-DQ2.5 and HLA-DQ2.2 for celiac disease highlighted the importance of stable peptide-MHC complexes for generating in vivo T-cell responses to gluten. It may well be that a major effect of deamidation in vivo also relates to peptide-MHC stability. The off-rate of a naturally occurring 33-mer fragment of digested gliadin was found to increase sevenfold upon deamidation [30]. Similar differences between native and deamidated peptides were observed for an
The impact of gluten deamidation on T-cell recognition
In addition to playing a critical role by allowing the generation of gluten peptides bound more avidly by MHC and hence the selection of T-cell epitopes, deamidation may also be involved in defining the T-cell receptor (TCR) repertoire that is selected in the response to gluten. In particular, this may be the case for HLA-DQ8, which can promote a response of similar amplitude to native and deamidated gluten peptide through the recruitment of T cells that have a negative charge in their TCR.
Conclusion: relevance to other autoimmune disorders
The ability of PTMs to cause break of tolerance has been widely suggested [32, 33], the idea being that, given the correct MHC context, the creation of neoepitopes would allow for the recruitment of T cells that have not been negatively selected in the thymus (Figure 3). It is important to point out that creation of neoepitopes in the absence of inflammation would probably lead to peripheral tolerance to the neoantigen, because they would be presented by resting immature antigen-presenting
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Funding by the Research Council of Norway, the European Research Council, the South-Eastern Norway Regional Health Authority (to L.M.S.) and National Institutes of Health (grant R01 DK-67180 to B.J.) is acknowledged. We thank V. Abadie for discussion and preparation of the figures, and B. Sally and H. Fehlner-Peach for critical reading of the manuscript.
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