Missing Insight Into T and B Cell Responses in Dermatitis Herpetiformis

Abstract

Dermatitis herpetiformis is a cutaneous form of celiac disease manifesting as an itching rash typically on the elbows, knees and buttocks. It is driven by the ingestion of gluten-containing cereals and characterized by granular deposits of immunoglobulin A in the papillary dermis. These antibodies target transglutaminase (TG) 3 and in the majority of patients they are also found in circulation. The circulating antibodies disappear and skin symptoms resolve as a result of gluten-free diet but the cutaneous anti-TG3 IgA deposits may persist for several years. In dermatitis herpetiformis, plasma cells secreting antibodies against TG3 are located in the intestinal mucosa similarly to those producing TG2 antibodies characteristic for celiac disease. In fact, both TG2- and TG3-specific plasma cells and gluten responsive T cells are found in dermatitis herpetiformis patients but the interplay between these cell populations is unknown. The small bowel mucosal damage in celiac disease is believed to be mediated by co-operation of cytotoxic intraepithelial T cells and the inflammatory milieu contributed by gluten-reactive CD4+ T cells, whereas the skin lesions in dermatitis herpetiformis appear to be devoid of gluten reactive T cells. Thus, how celiac disease-type intestinal T and B cell responses develop into an autoimmune condition affecting the skin is still incompletely understood. Finally, the skin and small bowel lesions may reappear upon reintroduction of gluten in patients treated with gluten-free diet but virtually nothing is known about the long-lived B cell and memory T cell populations activating in response to dietary gluten in dermatitis herpetiformis.

Keywords: B cell; T cell; celiac disease; dermatitis herpetiformis; epitope spreading; transglutaminase.

Figure 1

Putative pathogenetic mechanisms of dermatitis herpetiformis. The early gluten-induced autoimmune response results in the production of autoantibodies targeting gluten-derived gliadin peptides and transglutaminase 2 (TG2) in the small bowel mucosa. Antibody specificity to transglutaminase 3 (TG3) may develop later by epitope spreading after initial autoreactivity against TG2. However, the dynamics of this processes are unknown. Immune responses are mediated by subtype 1 or 2 T helper cells. In the skin, IgA and TG3 form punctate structures, typically found in the dermal papillae. TG3 is endogenously produced in the upper layers of epidermis but may spontaneously diffuse towards dermis providing a possible explanation for the recruitment of autoantibodies into tissue bound immunocomplexes. Alternatively, IgA-TG3 immunocomplexes circulating free in dermatitis herpetiformis patient serum may bind to these sites. Tissue bound immunocomplexes attract neutrophil infiltration to dermal-epidermal junctions resulting in the cleavage of the basement membrane and finally in blister formation. The membrane cleavage is likely catalyzed by neutrophil secreted proteolytic enzymes targeting the fibrillar proteins of the basement membrane. αTG2/3, TG2/3 autoantibody, αGliadin, anti-gliadin antibody, APC, antigen presenting cell.