Dear Sir,
In issue 41, Alaedini and Green provided a review of autoantibodies in celiac disease [Citation1]. In particular, they considered anti-transglutaminase 2 (TG2) antibodies, directed against the autoantigen tissue TG and whether these antibodies may play a role in the pathogenesis of celiac disease. The authors conclude “the available evidence suggests that they (the antibodies) have the potential to have a pathogenic contribution”. For the reasons outlined below, I believe that, instead, the available evidence provides little support for this view.
Firstly, Alaedini and Green cite research showing that anti-TG2 antibodies interfere with the bioactivity of the TG enzyme and thus may detrimentally affect its role in cell differentiation through reducing its catalysing ability [Citation2]. However, this is not well-proven and other studies have shown that when bound by anti-TG2 antibodies, the TG2 enzyme retains a significant level of residual activity and allows catalysis to occur [Citation3].
Indeed, the immunogenic epitopes of TG2 that the autoantibodies bind to have been identified and do not include the active site [Citation4]. Instead, the antibodies were directed against domains in the N and C terminal regions. Furthermore, the notion of anti-TG2 antibodies inhibiting the enzyme is contrary to the proven role of TG in bringing about the celiac immune reaction through deamidation of gliadin.
Secondly, Alaedini and Green describe how TG2 plays a role in activating TGF-β, which is involved in differentiation of epithelial cells. They propose “the production of antibodies (against TG2) might have deleterious effects on cell differentiation, contributing to the mucosal transformation in celiac disease”. The role of TG2 in catalysing the release of TGF-β from its latent complex is well recognised [Citation5] but, whether or not this process contributes to the formation of celiac lesions is unclear. Indeed, research has demonstrated an increase in TGF-β levels in celiac disease, which runs counter to the inhibitory antibody theory [Citation6].
Finally, there is a well-supported consensus that the immune reaction in celiac disease is primarily Th1 in nature. This includes IFN-γ and IL-15 upregulation, and culminates in lymphocyte infiltration, matrix metalloproteinases activation and enterocyte apoptosis [Citation7,Citation8,Citation9,Citation10]. These mechanisms account for the typical appearance of the celiac small intestine: flat atrophied villi and hyperplastic crypts.
The Th1 response is unlikely to be compatible with autoantibodies against TG2 being the primary cause of mucosal damage. If anti-TG2 antibodies do have a causal pathogenic role in celiac disease (which at present is poorly supported), this must be shown to be integrated with the Th1 mechanisms described above.
References
- Alaedini A, Green PHR. Autoantibodies in celiac disease. Autoimmunity 2008; 41: 19–26
- Esposito C, et al. Anti-tissue transglutaminase antibodies from coeliac patients inhibit transglutaminase activity both in vitro and in situ. Gut 2002; 51: 177–181
- Dieterich W, et al. Autoantibodies of patients with coeliac disease are insufficient to block tissue transglutaminase activity. Gut 2003; 52: 1562–1566
- Seissler J, et al. Autoantibodies from patients with coeliac disease recognise distinct functional domains of the autoantigen tissue transglutaminase. Clin Exp Immunol 2001; 125: 216–221
- Nunes I, et al. Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol 1997; 136: 1151–1163
- Hansson T, et al. Transforming growth factor-beta and tissue transglutaminase expression in the small intestine of children with coeliac disease. Scand J Immunol 2002; 56: 530–537
- Nilsen EM, et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon γ. Gut 1995; 37: 766–776
- Mention J, et al. Interleukin 15: A key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 2003; 125: 730–745
- Daum S, et al. Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibition of metalloproteinase-1 in intestinal biopsy specimens from patients with coeliac disease. Gut 1999; 44: 17–25
- Moss SF, et al. Increased small intestinal apoptosis in coeliac disease. Gut 1996; 39: 811–817