LECTURE

Pathogenesis of Gastritis in Ileitis-prone SAMP1/Yit Mice
Peter B. Ernst,1 Elizabeth B. Wiznerowicz,1 Sandford H. Feldman2 and Kenneth S. Tung3
1Department of Medicine, University of Virginia, Virginia, USA
2The Center for Comparative Medicine, University of Virginia, Virginia, USA
3Department of Pathology, University of Virginia, Virginia, USA(Received for publication on November 5, 2010)(Revised for publication on December 1, 2010)(Accepted for publication on December 16, 2010)

Inflammatory bowel disease is a chronic inflammatory disease of the gut which manifests as ulcerative
colitis or Crohn’s disease. One of the most studied animal models of spontaneous Crohn’s disease is thesenescence-accelerated mouse (SAMP1/Yit strain) model.1 In SAMP1/Yit mice, although many immunological responses are perturbed, some evidence suggests that the primary defect lies in the epithelial
cell barrier. In the process of studying epithelial permeability, we observed that the stomach in SAMP1/
Yit mice also had increased permeability. Upon further examination, these mice were shown to havemarked, chronic gastritis with focal to diffuse aggregates of mononuclear cells of mixed lineages. These
aggregates were located predominantly in the oxyntic mucosa, with occasional lesions in the forestomach but with relatively fewer cellular infiltrates in the antral mucosa. Real-time reverse transcription(RT) PCR showed an increase in several helper T cell (Th cell)-derived pro-inflammatory cytokines in
the gastric mucosa of SAMP1/Yit mice. However, many of the cells in the aggregates of SAMP1/Yit mice
were B cells. SAMP1/Yit B cells exacerbate ileitis when co-transferred into immunodeficient recipients. The gastritis also reflects a contribution by B cells. As SAMP1/Yit mice were derived from AKR
mice, we examined AKR mice and determined that they too have an increased occurrence of gastritis,
although they do not develop ileitis. B cells contributed to the gastric inflammation in these mice also.
Thus, SAMP1/Yit mice display gastritis as well as ileitis, and B cells appear to play a role in the pathogenesis of inflammation at both sites. This lecture will discuss some of the mechanisms that may accountfor these different manifestations of gastrointestinal disease. (Keio J Med 60 (2) : 65–68, June 2011)

Keywords: gastritis, ileitis, Crohn’s disease, B cell￼￼￼Introduction

eum, but in humans, the disease can arise virtually anywhere within the gastrointestinal tract.

The gastrointestinal tract faces the unique immunological challenge of coping with a dynamic and vast arrayof dietary and microbial antigens. Chronic inflammatory
disease of the intestine as well as the stomach of adults
and children2–4 arises in genetically susceptible individuals that fail to properly regulate host responses to theseluminal antigens. The importance of gastrointestinal infections in Japan is illustrated by the frequency of Helicobacter pylori infection5 and its key role in the pathogenesis of gastric cancer.6,7 Another example of chronic
inflammatory disease in the gut is inflammatory bowel
disease, which manifests as ulcerative colitis or Crohn’sdisease. Crohn’s disease tends to affect the terminal il-

Animal Models of Inflammatory Bowel Disease
For many years, it was believed that intestinal immune
responses were carefully regulated to prevent excessive
amounts of inflammation caused by luminal antigens.
This notion was confirmed when genetic engineering wasapplied broadly to manipulate gene expression in mice. It
quickly became apparent that disruption of several different genes leads to the development of colitis.8–10 It is
now appreciated that disrupting the expression of several genes encoding proteins that function in a related
signaling pathway often leads to disease. For example,

Reprint requests to: Peter B Ernst, DVM, PhD, Department of Medicine, University of Virginia, Box 8000708, Charlottesville, VA 22908 -0708,
USA, E-mail: pernst@virginia.edu
Copyright © 2011 by The Keio Journal of Medicine.
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Ernst PB, et al: Gastritis in SAMP1/Yit Mice66

deficiencies in Il-10,10 its receptor11 or downstream signaling molecules12 all result in colitis. Il-10 receptors arebroadly expressed in cells in the gut13,14 and contribute toanti-inflammatory responses. It is intellectually satisfying that an entire pathway related to a receptor, its ligand
and signaling molecules all contribute to the control ofhost responses. However, there are many gene knockout
models that target unrelated pathways that still result in
the development of intestinal inflammation. For example,
mutations affecting the epithelial cell barrier,15 nerves,16
and innate and adaptive responses17,18 can all lead to colitis. These observations speak to the diverse aspects of thehost response that contribute to the optimal control of thehost response to luminal antigens.
While the appearance of intestinal inflammation invarious mouse models differs, most of this inflammation
is focused in the colon and, in general, provide a bettermodel of ulcerative colitis than Crohn’s disease.19 In somemouse models, such as the Il-10 knockout mouse, inflammation of the small intestine has been observed10 in addition to the more common colitis. Two other models, theSAMP1/Yit1,20 mouse and the TNF∆ARE21, 22 mouse, develop inflammation in the terminal ileum rather that thecolon and thus are often preferred as a model with whichto study Crohn’s disease.
The Role of the Microbiome in Gastrointestinal ￼￼￼
Inflammation
While luminal antigens, particularly microbes, havelong been believed to be factors that trigger or ameliorate disease, direct evidence supporting this notion has
emerged with the use of gnotobiotic mice. When colitisprone mice are housed in germ-free conditions, almost allof the strains remain healthy.2 For example, germ-free Il10-deficient mice do not develop disease.23 Using germfree mice, it is possible to identify a single species, or alimited numbers of species, as triggers of gastroentericdisease. While the intestinal microbe Helicobacter hepaticus can exacerbate disease in Il-10-deficient mice,24
it was insufficient to trigger colitis in germ-free mice.23
In fact, in wildtype mice, H. hepaticus induces a regulatory helper T cell that prevents inflammation by thisorganism.25 While some bacteria may promote disease26
and others attenuate it,27 in general, colitis that occurs
in various knockout mice results from an inappropriate
intestinal immune and inflammatory response to the normal gastrointestinal microbiome that is usually not pathogenic in wildtype mice. This is consistent with the factthat so many genetically engineered mice develop colitis
spontaneously without any intentional manipulation of
their microbiome.

Characterization of the SAMP1/Yit Mouse as ￼￼￼a Model of Crohn’s Disease
Senescence-accelerated mouse (SAM) strains wereoriginally derived from AKR mice.28 One of thesestrains, the SAMP1/Yit mouse, was subsequently shownto have many manifestations resembling human Crohn’sdisease, including discontinuous and transmural chronic
inflammation of the terminal ileum and, in some cases,
perianal fistulae.1,20,29 Other studies have shown that ileitis is associated with pro-inflammatory cytokine production – Th1 responses in younger mice20 but also Th2
cytokines,30 particularly as the mice mature.31
Extraintestinal Manifestations in ￼￼￼
the SAMP1/Yit Mouse
Although many immunological responses are perturbed in the SAMP1/Yit mouse, some evidence suggests that the primary defect lies in the epithelial cellbarrier. In the process of studying intestinal epithelial
permeability,32 we showed that the stomach in SAMP1/
Yit mice also has a disrupted epithelial cell barrier function.33 Upon further examination, it became obvious thatthe permeability defect in the SAMP1/Yit stomach was
associated with marked gastritis (Ernst et al, manuscript
in preparation). The histological changes include focal todiffuse aggregates of mononuclear cells of different lineages, including CD3+ T cells and B220+ B cells. These
aggregates are located predominantly in the oxyntic mucosa with occasional lesions in the forestomach, but withfewer cellular infiltrates in the antral mucosa. Inflammation in the oxyntic mucosa mimics that in the gerbil model of H. pylori-induced gastritis and parietal cell atrophy.6
Infiltration with polymorphonuclear cells (including
neutrophils) was remarkably modest. Realtime RT PCR
shows an increase in many of the pro-inflammatory Th
cell-derived cytokines in the gastric mucosa of SAMP1/
Yit mice (Ernst et al, manuscript in preparation).
The majority of cells in the gastric aggregates of
SAMP1/Yit mice are B cells. As SAMP1/Yit mice arederived from AKR mice, we examined AKR mice anddetermined that they too have significant gastritis. B cells
also contribute to the gastric inflammation in AKR mice.
B cells appear to have pathogenic roles in multiple tissues. The recruitment of B cells exacerbates inflammation in the ileum34; this recruitment is dependent on beta
7 integrin.35 The role of these B cells in the pathogenesisof ileitis is not entirely clear. It has been suggested that
B cells from SAMP1/Yit mice express glucocorticoid-induced TNFR-related protein (GITR) ligand which, whenengaged into its receptor GITR, decreases the functionof regulatory helper T cells.34 Interestingly, B cells in
SAMP1/Yit mice produce less Il-10 and TGF-β,36 which
may affect their function and favor a role in the pathogenesis of inflammation. Thus, it is possible that the B

Keio J Med 2011; 60 (2): 65–68

cell defect(s) in SAMP1/Yit mice affects their regulatory
function; these defective B cells could contribute directly
to inflammation, perhaps through the production of antibodies leading to immune complex-mediated damage.
In the original description of the disease in SAMP1/Yit
mice, the authors reported “no significant extraintestinal
manifestations” detected in the stomach, liver, spleen,
thymus and various lymph nodes.20 Subsequently, it became clear that these mice also have some skin lesions aswell as mononuclear cell aggregates in their livers,1 and,based on our studies, gastritis. There are several possible
explanations for this discrepancy. First, there could be genetic drift between strains housed at different institutions.
While possible, this seems unlikely since SNP analysis of
the founding and current strains at our institution appear
genetically identical (Drs. Jesus Rivera-Nieves and M.
McDuffie, personal communication). Moreover, SAMP1/
Yit mice were originally derived from AKR mice,28
which also develop gastritis. Thus, the tendency to develop gastritis may lie in the AKR background that is embedded in SAMP1/Yit mice. Another interesting avenue
to explore is the role of epigenetic control of the disease.
The inability to detect gastritis previously could havebeen due to differences in the microbiome in the micenow compared to the initial studies. This is indeed possible because bacteria can at least exacerbate and/or hasten
the onset of lesions in SAMP1/Yit mice. In other cases,
the presence of certain bacterial species can attenuate theileitis.37–39 (It should be noted that, in view of the presence of gastritis, the effects of inflammation on gastricpH may favor the ability of probiotics to be protective,
and, in turn, these bacteria may not necessarily colonize
human Crohn’s disease patients that have normal gastric acid.) Importantly, histological review of stomachs
from germ-free mice shows occasional evidence of theaggregates that are typical of this form of gastritis (unpublished observation 2005), and inflammatory changes
are also found in the ileum.40 Thus, inflammation in thegastrointestinal tract of SAMP1/Yit mice is not entirely
dependent on a full microbiome, although it is exacerbated by the presence of microbial communities. It is possible that dietary antigens or microbial products withinmouse chow were sufficient to trigger these lesions; however, further study is required. A very likely factor in the
failure to recognize gastritis in SAMP1/Yit mice previously is that many scientists reviewing histology in murine models may not have a complete awareness of someof the subtle aspects of comparative pathology. Thus, they
may have simply failed to recognize gastritis in these animals, especially if they were being compared with AKR,
which also have gastritis.
Summary
In summary, the SAMP1/Yit mouse continues to provide an interesting model for studying the pathogenesis of67

inflammatory diseases. However, disease in these mice is
not limited to the ileum but is also manifest broadly in theskin, liver and, in particular, the stomach. How these lesions relate to each other and whether they reflect a common mechanism related to the pathogenesis of Crohn’sdisease remains unclear. It is more likely that they differ
significantly in their tissue-specific pathogenesis, but distinct pro-inflammatory mechanisms may emerge due ageneral defect in SAMP1/Yit mice.
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