Murine experimental autoimmune gastritis models refractive to development of intrinsic factor autoantibodies, cobalamin deficiency and pernicious anemia
Introduction
Cobalamin (vitamin B12) deficiency is a common cause of macrocytic anemia and has been implicated in a spectrum of neuropsychiatric disorders [1]. Pernicious anemia is generally the cause of cobalamin deficiency in Western populations with an incidence of around 1.9% in persons over 60 years of age [2]. Human autoimmune gastritis (type A chronic atrophic gastritis) is considered the underlying pathological lesion of pernicious anemia [3], [4]. The gastric lesion, confined to the fundus and body of the stomach, is characterized by an inflammatory infiltrate within the gastric mucosa, and the loss of parietal and zymogenic cells from gastric glands [4]. Most patients with pernicious anemia have circulating autoantibodies reactive to ATP4 (the proton pump), present on and in parietal cells (∼ 85%) and to intrinsic factor (∼ 60%) [5]. Intrinsic factor, secreted by stomach parietal cells in humans, promotes absorption of cobalamin in the ileum via a specific receptor-mediated endocytosis [6].
There have been many reports on murine experimental autoimmune gastritis (EAG) models arguing their relevance to the study of human autoimmune gastritis (AIG) and pernicious anemia [7], [8]. The histopathological features of gastric lesions in patients with chronic atrophic gastritis and murine EAG are similar [9], [10]. It is also well documented that all murine EAG models can result in the development of circulating antibodies reactive to parietal cells and the proton pump (ATP4A and B). However, there are no reports as to whether murine EAG results in circulating antibodies reactive to intrinsic factor, or the development of a cobalamin deficiency and subsequent macrocytic anemia.
Here we report on the incidence of circulating antibodies reactive to intrinsic factor, levels of cobalamin in blood and evidence of anemia in mice subjected to the immunization (imm:EAG), neonatal thymectomy (nTx:EAG) and a transgenic model carrying a granulocyte macrophage colony stimulating factor (GMCSF) transgene whose expression is controlled by the ATP4 β subunit promoter (PC-GMCSF:EAG).
Section snippets
Mice
BALB/cCrSlc mice were immunized intraperitoneally at 24 h, 72 h and between 20 to 21 days after birth with 7.5 μg crude gastric membranes [11] (n = 39). Neonatal thymectomy (nTx) (n = 59) was performed on 3-day old BALB/cCrSlc mice under cold anesthesia, as previously described in Alderuccio et al. [12]. Transgenic PC-GMCSF mice were identified by PCR of genomic DNA isolated from tails, using the method previously described by Biondo et al. [13] (n = 31). In addition, normal age matched BALB/cCrSlc
EAG model cohorts
Three disparate models, that utilize alternative modes of EAG induction, were selected for use in this study (Fig. 1a). The most popularly exploited neonatal thymectomy model (nTx:EAG) generates a state of transient lymphopenia [20]; the non-lymphopenic immunization model (imm:EAG) exploits gastric ATP4 in the absence of adjuvant as an immunogen breaking tolerance [11], [21], [22]; and the transgenic model utilizes a granulocyte macrophage colony stimulating factor (GMCSF) transgene whose
Discussion
The first reports of animal models (canine) to investigate autoimmune gastritis date back to the early sixties [23]. Current mouse models, utilizing the inbred BALB/c strain and neonatal thymectomy, were initiated by work of Ansar and Penhale [24]. Decades later researchers in this field have developed and exploited lymphopenic, non-lymphopenic, transgenic, spontaneous and infectious agent experimental gastritis models for the study of human organ-specific autoimmune disease [8]. In the case of
Acknowledgments
D.L.V.G was supported by a NH&MRC Biomedical (Dora Lush) Research Scholarship. The authors would like to acknowledge the assistance of: Damian McVeigh of the Alfred Pathology Service for interpretation of blood films; Ms Valentina Dubljevic for assistance with the M(H)6mrGIF construct and Mr. Michael Bailey, Monash University Department of Epidemiology and Preventive Medicine for statistical analysis.
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Current address: Centre for Animal Biotechnology, Department of Veterinary Science, The University of Melbourne, Parkville, Victoria 3010, Australia.