Transglutaminase 2-specific coeliac disease autoantibodies induce morphological changes and signs of inflammation in the small-bowel mucosa of mice

Abstract

Coeliac disease is hallmarked by an abnormal immune reaction against ingested wheat-, rye-and barleyderived gluten and the presence of transglutaminase 2 (TG2)-targeted autoantibodies. The small-bowel mucosal damage characteristic of the disorder develops gradually from normal villus morphology to inflammation and finally to villus atrophy with crypt hyperplasia. Patients with early-stage coeliac disease have TG2-autoantibodies present in serum and small-intestinal mucosa and they may already suffer from abdominal symptoms before the development of villus atrophy. Previously we have shown that intraperitoneal injections of coeliac patient-derived sera or purified immunoglobulin fraction into mice induce a condition mimicking early-stage coeliac disease. In the current study, we sought to establish whether recombinantly produced patient-derived TG2-targeted autoantibodies are by themselves sufficient for the development of such an experimentally induced condition in immune-compromised mice. Interestingly, mice injected with coeliac patient TG2-antibodies had altered small-intestinal mucosal morphology, increased lamina propria cellular infiltration and disease-specific autoantibodies deposited in the small bowel, but did not evince clinical features of the disease. Thus, coeliac patient-derived TG2-specific autoantibodies seem to be sufficient for the induction of subtle small-bowel mucosal alterations in mice, but the development of clinical features probably requires additional factors such as other antibody populations relevant in coeliac disease.

Injection of prototypic celiac anti-transglutaminase 2 antibodies in mice does not cause enteropathy

“…If anti-TG2 antibodies were pathogenic, the duration of exposure necessary to develop enteropathy would be unknown. Minor effects were reported already on day eight in the studies by Kalliokoski et al [ 15 , 16 ]. Enteropathy is usually detectable in celiac patients after two weeks of gluten challenge.…”

“…When generating an anti-TG2 response in vivo by immunizing with TG2 [ 13 ] or expression of mini-antibodies using virus vectors [ 14 ], no significant pathology was observed. Kalliokoski et al injected celiac IgA-deficient serum, total IgG or recombinant monoclonal anti-TG2 mini-antibodies [ 15 , 16 ]. They observed minor histologic changes and in one study minor clinical effects.…”

Review article: Diagnosis of coeliac disease: a perspective on current and future approaches

“…Evidence for TG2 being the primary driver of autoimmunity in CD, however, is unconvincing with inconsistent reports of TG2‐specific CD4+ T cells 43,109,114,115 . Similarly, evidence for TG2 IgA causing pathology relevant to CD is weak 116,117 . Instead, B cells, plasma cells and TG2 IgA in CD are thought to arise from transamidation of gluten peptides to lysine residues in TG2 87 .…”

Interplay between Type 2 Transglutaminase (TG2), Gliadin Peptide 31-43 and Anti-TG2 Antibodies in Celiac Disease

“…In an endothelial cell model, celiac antibodies significantly modify the expression profile of genes involved in angiogenesis regulation and induce several defects in cell adhesion and polarization [58,59]. In a mouse model, the intraperitoneal injection of anti-TG2 antibodies causes an alteration in the smallintestinal mucosal morphology and an increased cellular infiltration in the lamina propria [60]. The general idea that emerges from all these studies, performed in in vitro and in vivo models, is that antibodies to TG2 could have a role in CD pathogenesis as they are able to reproduce several features of CD intestinal mucosa, such as enhanced proliferation and reduced differentiation, altered permeability, cell architecture modification, etc.…”