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Coeliac disease and dermatitis herpetiformis (DH) are characterized by autoantibodies targeting transglutaminase (TG)2 and TG3, respectively. Previous studies show that TG2 antibodies are produced in the gut and can be assessed in organ culture of small-intestinal biopsies from patients with coeliac disease. Thus far, no studies have investigated TG3 antibodies in organ culture of biopsies from patients with DH, or exploited the method in DH. The aim of this study was to investigate TG3 and TG2 antibody responses in serum and small-intestinal biopsies from patients with DH with active disease, and from those in remission. The majority of patients with DH were negative for both serum and organ culture medium TG2-targeting antibodies. Surprisingly, patients with active DH secreted TG3 antibodies into the culture medium despite seronegativity. In patients secreting high levels of TG3 antibodies into the culture medium, we also detected TG3-antibody-positive cells in the small-intestinal mucosa. These findings suggest that TG3 antibodies can be investigated in the organ culture system and that their secretion occurs in the small intestine, especially in active DH.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of celiac disease causing an itchy, blistering rash. Granular IgA deposits in the skin are pathognomonic for DH, and the treatment of choice is a lifelong gluten-free diet (GFD). Preliminary evidence suggests that there are patients with DH who redevelop gluten tolerance after adherence to a GFD treatment. To evaluate this, we performed a 12-month gluten challenge with skin and small-bowel mucosal biopsy samples in 19 patients with DH who had adhered to a GFD for a mean of 23 years. Prechallenge biopsy was negative for skin IgA and transglutaminase 3 deposits in 16 patients (84%) and indicated normal villous height-to-crypt depth ratios in the small bowel mucosa in all 19 patients. The gluten challenge caused a relapse of the rash in 15 patients (79%) in a mean of 5.6 months; of these 15 patients, 13 had skin IgA and transglutaminase 3 deposits, and 12 had small-bowel villous atrophy. In addition, three patients without rash or immune deposits in the skin developed villous atrophy, whereas one patient persisted without any signs of relapse. In conclusion, 95% of the patients with DH were unable to tolerate gluten even after long-term adherence to a GFD. Therefore, lifelong GFD treatment remains justified in all patients with DH.

Dermatitis herpetiformis (DH) is an itchy, blistering skin disease characterised by the deposition of granular immunoglobulin A (IgA) in the papillary dermis. It is regarded as the cutaneous manifestation of coeliac disease, an autoimmune-mediated condition affecting the small intestine. In addition to skin symptoms, DH patients have mostly subclinical small-intestinal villous atrophy and crypt hyperplasia or at least coeliac-type inflammatory changes. Moreover, DH patients have specific antibodies targeting epidermal transglutaminase (a.k.a. transglutaminase 3, TG3), the dominant autoantigen in DH 1. This article is protected by copyright. All rights reserved.

Celiac disease is a common inflammatory disorder with a prevalence of 1–2 % in which a distinct dietary wheat, rye, and barley component, gluten, induces small-bowel mucosal villous atrophy, crypt hyperplasia, and inflammation. The small-bowel mucosal damage can be reversed by a strict lifelong gluten-free diet, which is currently the only effective treatment for the condition. A key player in the pathogenetic process leading to the enteropathy is played by a protein called transglutaminase 2 (TG2), which is able to enzymatically modify gluten-derived gliadin peptides. The TG2-catalyzed deamidation of the gliadin peptides results in their increased binding affinity to the disease-predisposing human leukocyte antigen (HLA) DQ2 and DQ8 molecules, thus enabling a strong immune response to be launched. Blocking the enzymatic activity of TG2 has thus been suggested as a suitable novel pharmacological approach to treat celiac disease. By virtue of its transamidation capacity, TG2 is also able to cross-link gliadin peptides to itself, this resulting in the generation of TG2-gliadin peptide complexes whose presence might provide an explanation for the generation of the TG2 autoantibodies characteristic of celiac disease. Due to their excellent specificity for the disorder, the TG2-targeted autoantibodies are widely used in the diagnostics as a first-line test to select patients for gastrointestinal endoscopy. More recently, it has come to be appreciated that these autoantibodies and also the TG2-specific B cells might play an active role in the disease pathogenesis. In this review, we assess the role of TG2, TG2-specific B cells, and autoantibodies in celiac disease.