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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 .