Antibody Responses to Transglutaminase 3 in Dermatitis Herpetiformis: Lessons from Celiac Disease

Abstract

Dermatitis herpetiformis (DH) is the skin manifestation of celiac disease, presenting with a blistering rash typically on the knees, elbows, buttocks and scalp. In both DH and celiac disease, exposure to dietary gluten triggers a cascade of events resulting in the production of autoantibodies against the transglutaminase (TG) enzyme, mainly TG2 but often also TG3. The latter is considered to be the primary autoantigen in DH. The dynamics of the development of the TG2-targeted autoimmune response have been studied in depth in celiac disease, but the immunological process underlying DH pathophysiology is incompletely understood. Part of this process is the occurrence of granular deposits of IgA and TG3 in the perilesional skin. While this serves as the primary diagnostic finding in DH, the role of these immunocomplexes in the pathogenesis is unknown. Intriguingly, even though gluten-intolerance likely develops initially in a similar manner in both DH and celiac disease, after the onset of the disease, its manifestations differ widely.

Keywords: celiac disease; dermatitis herpetiformis; transglutaminase 3.

Figure 1

Known sites of human TG3 expression (left panel) and reported sites of immunological responses against TG3 (right panel) [15,16].

Figure 2

Epitope spreading from gliadin to TG2 or TG3. A simplified depiction of the suggested mechanism for epitope spreading during CeD and DH. B cells specific to TG2 and/or TG3 internalize and process gliadin–TG2 or –TG3 complexes through the endocytic pathway, leading to presentation of peptides on HLA II molecules. Gliadin-specific CD4+ T cells give survival signals to gliadin-presenting B cells, while TG2- or TG3-presenting B cells do not receive survival signals. Activated B cells class-switch into IgA and produce anti-TG2 or -TG3 antibodies. Created with BioRender.com.