Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders

Posttranslational modification (PTM) of antigen is a way to break T-cell tolerance to self-antigens and promote autoimmunity. However, the precise mechanisms by which modifications would facilitate autoimmune T-cell responses and how they relate to particular autoimmune-associated MHC molecules remain elusive. Celiac disease is a T-cell mediated enteropathy with a strong HLA association where the immune response is directed mainly against deamidated cereal gluten peptides that have been modified by the enzyme transglutaminase 2. The disease is further characterized by autoantibodies to transglutaminase 2 that have extraordinary high disease specificity and sensitivity. There have been important advances in the knowledge of celiac disease pathogenesis, and these insights may be applicable to other autoimmune disorders where PTM plays a role. This insight gives clues for understanding the involvement of PTMs in other autoimmune diseases.

► 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.