Driel* Abstract A Convenient Model of Severe, High Incidence Autoimmune Gastritis Caused by Polyclonal Effector T Cells and without Perturbation of Regulatory T Cells Eric Tu, Desmond K. Y. Ang, Thea V. Hogan¤a, Simon Read¤b, Cheryl P. Z. Chia, Paul A. Gleeson, Ian R. van Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia Autoimmune gastritis results from the breakdown of T cell tolerance to the gastric H+/K+ ATPase. The gastric H+/K+ ATPase is responsible for the acidification of gastric juice and consists of an a subunit (H/Ka) and a b subunit (H/Kb). Here we show that CD4+ T cells from H/Ka-deficient mice (H/Ka2/2) are highly pathogenic and autoimmune gastritis can be induced in sublethally irradiated wildtype mice by adoptive transfer of unfractionated CD4+ T cells from H/Ka2/2 mice. All recipient mice consistently developed the most severe form of autoimmune gastritis 8 weeks after the transfer, featuring hypertrophy of the gastric mucosa, complete depletion of the parietal and zymogenic cells, and presence of autoantibodies to H+/K+ ATPase in the serum. Furthermore, we demonstrated that the disease significantly affected stomach weight and stomach pH of recipient mice. Depletion of parietal cells in this disease model required the presence of both H/Ka and H/Kb since transfer of H/Ka2/2 CD4+ T cells did not result in depletion of parietal cells in H/Ka2/2 or H/Kb2/2 recipient mice. The consistency of disease severity, the use of polyclonal T cells and a specific T cell response to the gastric autoantigen make this an ideal disease model for the study of many aspects of organ-specific autoimmunity including prevention and treatment of the disease. Citation: Tu E, Ang DKY, Hogan TV, Read S, Chia CPZ, et al. (2011) A Convenient Model of Severe, High Incidence Autoimmune Gastritis Caused by Polyclonal Effector T Cells and without Perturbation of Regulatory T Cells. PLoS ONE 6(11): e27153. doi:10.1371/journal.pone.0027153 Editor: Ciriaco A. Piccirillo, McGill University Health Center, Canada Received January 21, 2011; Accepted October 11, 2011; Published November 9, 2011 Copyright: 2011 Tu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by research grants from the National Health and Medical Research Council of Australia and the University of Melbourne. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors can confirm that Simon Read was at The University of Melbourne when this study was completed and that Novo Nordisk is his current address. The authors have declared no competing interests exist. * E-mail: ivd@unimelb.edu.au ¤a Current address: MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom ¤b Current address: Novo Nordisk a/s, Ma˚løv, Denmark Introduction Autoimmune gastritis is an excellent system to investigate the loss of T cell tolerance to self-tissues since it is a well-characterised autoimmune disease with a known target antigen and the mouse model of the disease has many similarities to the human equivalent. Pernicious anemia, the end stage of autoimmune gastritis, has an estimated prevalence of 1.9% in Western adult population over the age of 60 years [1], which represents the commonest cause of vitamin B12 deficiency in the elderly [2]. Autoimmune gastritis features infiltration of mononuclear cells in the submucosa which extends into the gastric mucosa, the depletion of gastric parietal and zymogenic cells and hypertrophy of the gastric mucosa [1]. The target antigen in autoimmune gastritis has been identified as the gastric H+/K+ ATPase expressed by gastric parietal cells [3– 5]. The gastric H+/K+ ATPase is a membrane proton pump responsible for the acidification of gastric juice and it is a heterodimer that consists of a catalytic a subunit (H/Ka) and a glycoprotein b subunit (H/Kb). Previous studies have demon- strated that both H/Ka and H/Kb are targeted in autoimmune gastritis [4,6–8]. It is well documented that, in both mice and man, CD4+ T cells that recognise the gastric H+/K+ ATPase initiate autoimmune gastritis while CD8+ T cells and B cells are ineffective in doing so [7–17]. Nevertheless, following initiation of the disease, autoantibodies to the H+/K+ ATPase are produced and are a very useful diagnostic tool of the disease although they are not pathogenic [3,16,18]. BALB/c mice have been shown to be the most susceptible to lymphopenia-induced autoimmune gastritis with an incidence of 30–90% [19,20]. The disease can be induced by thymectomy of 3 day-old mice or adult thymectomy combined with a single dose of cyclophosphamide [19,21]. In spite of this, it is difficult to evaluate therapeutic effects of treatments given to thymectomised mice since a spectrum of disease severity from mild to severe is always observed and incidence is variable, thus large group sizes are required to test statistical significance. Furthermore, the surgery involved and post-operative maintenance of animals is technically demanding. Autoimmune gastritis can also be induced in BALB/c mice by immunisation with purified gastric H+/K+ ATPase [5]. However, the disease is reversible after cessation of immunisation and has a low severity. Transfer of BALB/c T cells depleted of regulatory T (Treg) cells into athymic recipient mice causes severe autoimmune gastritis [15]. It is therefore impossible to dissect the relationship between autoreactive T cells and Treg cells during the disease development in this setting since Treg cells are absent. PLoS ONE | www.plosone.org 1 November 2011 | Volume 6 | Issue 11 | e27153