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INVESTIGATIVE REPORT Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Ex vivo Culture of Duodenal Biopsies from Patients with Dermatitis Herpetiformis Indicates that Transglutaminase 3 Antibody Production Occurs in the Gut
Minna HIETIKKO 1, Kaisa HERVONEN 1, 2, Tuire ILUS 1, 3, Teea SALMI 1, 2, Heini HUHTALA 4, Kaija LAURILA 1, Tiina RAUHAVIRTA 1, Timo REUNALA 1, 2, Katri KAUKINEN 1, 5 and Katri LINDFORS 1
1
Coeliac Disease Research Center, Faculty of Medicine and Life Sciences and 4 Faculty of Social Sciences, University of Tampere, Departments of 2 Dermatology, 3 Gastroenterology and Alimentary Tract Surgery, and 5 Internal Medicine, Tampere University Hospital, Tampere, Finland
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.
Key words: coeliac disease; dermatitis herpetiformis; transglutaminase; autoantibody.
Accepted Nov 24, 2017; Epub ahead of print Nov 28, 2017 Acta Derm Venereol 2018; 98: 366 – 372.
Corr: Katri Lindfors, Coeliac Disease Research Center, Faculty of Medicine and Life Sciences, PO Box 100, University of Tampere, FIN-33014, Tampere, Finland. E-mail: katri. lindfors @ uta. fi
Malabsorption, diarrhoea and other gastrointestinal complaints are classical symptoms of coeliac disease, a systemic autoimmune-mediated condition occurring in a subset of individuals carrying the susceptibility genotype, human leucocyte antigen( HLA)-DQ2 or-DQ8. Typically, in patients with coeliac disease the ingestion of gluten, which is present in wheat, rye and barley, induces gradual destruction of the small-intestinal mucosal architecture, leading eventually to villous atrophy and crypt hyperplasia, as well as chronic inflammation within the intestinal epithelium and in the lamina propria. Active coeliac disease is further characterized by circulating gluten-dependent IgA endomysial autoantibodies( EMA) known to target transglutaminase 2( TG2)( 1). In addition to being present in serum, the autoantibodies are bound to
TG2 in various tissues, including the small intestine( 2), which is where they are produced( 3 – 6).
Although classically associated with gastrointestinal symptoms, coeliac disease has a wide variety of extraintestinal manifestations. One of the best characterized of these is the cutaneous manifestation dermatitis herpetiformis( DH), a blistering autoimmune disorder characterized by granular IgA deposits in the papillary dermis( 7). Belonging to the same spectrum of gluten sensitivity disorders, DH and coeliac disease share similar genetic predisposition, HLA-DQ2 / 8, and these different disease phenotypes can occur in the same families( 8) and even in monozygous twins( 9). Moreover, it has been reported that coeliac disease with classic enteropathy may evolve over time into DH on a gluten-containing diet( 10, 11). The majority of patients with DH also show villous atrophy and crypt hyperplasia in the small intestine( 12), and the remainder at least have signs of inflammatory changes characteristic of coeliac disease( 13, 14). In addition, 70 – 80 % of patients with DH have TG2-targeting autoantibodies in the serum( 15) and small bowel mucosa( 16). However, instead of TG2, the pathognomonic dermal IgA targets transglutaminase 3( TG3), which is currently regarded as the main autoantigen in DH( 17). The majority of patients with DH also have specific TG3 antibodies in the circulation( 17, 18), which are also occasionally detected in the serum of patients with coeliac disease without skin symptoms( 19). In contrast to TG2 antibodies, however, the site of TG3 antibody formation is, thus far, unknown.
Coeliac disease and DH are both treated with a glutenfree diet, which results in alleviation of symptoms and recovery of the small intestinal mucosa. Dietary treatment also alleviates DH rash, albeit often relatively slowly, and hence patients with severe skin symptoms are also treated with dapsone medication at the beginning of the glutenfree diet. During treatment, TG2-specific antibodies disappear from the serum and, although more slowly, from the small-intestinal mucosa in both coeliac disease and DH( 20, 21). In DH, TG3-targeting antibodies also disappear from the serum concomitant with a gluten-free diet( 22).
Previous studies have demonstrated that intestinal TG2-targeting antibodies at different stages of coeliac disease can be assessed in the organ culture system of small-intestinal biopsies( 23 – 28). However, no studies are available for the TG3 antibody response and DH. The aim doi: 10.2340 / 00015555-2849 Acta Derm Venereol 2018; 98: 366 – 372
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica.