Transglutaminases in autoimmune and inherited skin diseases: The phenomena of epitope spreading and functional compensation

Abstract

Transglutaminases (TGs) are structurally and functionally related enzymes that modify the post-translational structure and activity of proteins or peptides, and thus are able to turn on or switch off their function. Depending on location and activities, TGs are able to modify the signalling, the function and the fate of cells and extracellular connective tissues. Besides mouse models, human diseases enable us to appreciate the function of various TGs. In this study, skin diseases induced by genetic damages or autoimmune targeting of these enzymes will be discussed. TG1, TG3 and TG5 contribute to the cutaneous barrier and thus to the integrity and function of epidermis. TGM1 mutations related to autosomal recessive ichthyosis subtypes, TGM5 mutations to a mild epidermolysis bullosa phenotype and as novelty TGM3 mutation to uncombable hair syndrome will be discussed. Autoimmunity to TG2, TG3 and TG6 may develop in a few of those genetically determined individuals who lost tolerance to gluten, and manifest as coeliac disease, dermatitis herpetiformis or gluten-dependent neurological symptoms, respectively. These gluten responder diseases commonly occur in combination. In autoimmune diseases, the epitope spreading is remarkable, while in some inherited pathologies, a unique compensation of the lost enzyme function is noted. K E Y W O R D Sautosomal recessive ichthyosis, gluten-sensitive diseases, hair mutation, skin barrier defect, transglutaminases

Humoral Epitope Spreading in Autoimmune Bullous Diseases

“…Histologically DH, such as other subepidermal autoimmune diseases, presents subepidermal blisters neutrophil and eosinophil infiltration and granular IgA deposition in the dermal papilla by DIF. DH patients show circulating IgA to TG3, which is the pivotal autoantigen ( 212 , 213 ). In most of DH patients, IgA to TG2 are detected, indicating an underlying, usually latent or mild celiac disease (CD) ( 212 , 213 ).…”

LEKTI domains D6, D7 and D8+9 serve as substrates for transglutaminase 1: implications for targeted therapy of Netherton syndrome

“…TGs are Ca 2+ ‐dependent enzymes catalysing an irreversible crosslink of specific substrates forming a covalent isopeptide bond, in which a primary amine residue becomes attached to a glutamine acceptor . Three of the eight known TG isozymes are involved in formation of the CE: TG1, TG3 and TG5 crosslink proteins such as profilaggrin, involucrin, loricrin, trichohyalin and small proline‐rich proteins, representing constitutive components of the CE . TG1 specifically crosslinks sphingolipids, namely ceramides, to the protein envelope to achieve the linkage with the lipid envelope …”

Dermatitis Herpetiformis and Celiac Disease Increase the Risk of Bullous Pemphigoid

“…Epitope spreading has been reported to occur often during the first 3 months after a diagnosis of BP and is associated with disease severity (Di Zenzo et al, 2011). Epitope spreading has also been hypothesized to explain the onset of DH in patients with CD (Kárpáti et al, 2018). With regard to the present study, epitope spreading is a possible immunomechanism driving the association between DH and BP, but unfortunately, because this was a registry-based study, we had no access to the DIF findings or serum samples of the DH patients who developed BP subsequently and, therefore, we were unable to confirm or disprove this hypothesis.…”