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, 10 (5), 842-50

Sensitization to and Challenge With Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis

Affiliations

Sensitization to and Challenge With Gliadin Induce Pancreatitis and Extrapancreatic Inflammation in HLA-DQ8 Mice: An Animal Model of Type 1 Autoimmune Pancreatitis

Sung-Hoon Moon et al. Gut Liver.

Abstract

Background/aims: The aim of this study was to establish a pathogenetic mechanism of pancreatitis in celiac disease and IgG4-related disease using gluten-sensitive human leukocyte antigen (HLA)-DQ8 transgenic mice.

Methods: Transgenic mice expressing HLA-DQ8 genes were utilized. Control mice were not sensitized but were fed gliadin-free rice cereal. Experimental groups consisted of gliadin-sensitized and gliadin-challenged mice; nonsensitized mice with cerulein hyperstimulation; and gliadin-sensitized and gliadinchallenged mice with cerulein hyperstimulation.

Results: Gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation showed significant inflammatory cell infiltrates, fibrosis and acinar atrophy compared with the control mice and the other experimental groups. The immunohistochemical analysis showed greater IgG1-positive plasma cells in the inflammatory infiltrates of gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation compared with the control mice and the other experimental groups. Gliadin-sensitized and gliadin-challenged mice with cerulein hyperstimulation or gliadin-sensitized and gliadinchallenged mice showed IgG1-stained inflammatory cell infiltrates in the extrapancreatic organs, including the bile ducts, salivary glands, kidneys, and lungs.

Conclusions: Gliadinsensitization and cerulein hyperstimulation of gluten-sensitive HLA-DQ8 transgenic mice resulted in pancreatitis and extrapancreatic inflammation. This animal model suggests that chronic gliadin ingestion in a susceptible individual with the HLA-DQ8 molecule may be associated with pancreatitis and extrapancreatic inflammation.

Keywords: Autoimmune diseases; Celiac disease; Pancreatitis.

Figures

Fig. 1
Fig. 1
Histology of the pancreas of C57BL/6 mice with or without intraperitoneal cerulein injection. No significant inflammation was observed in either the mock-treated (A) or the cerulein-injected (B) C57BL/6 mice (H&E stain, ×200).
Fig. 2
Fig. 2
Histology of the proximal small intestinal mucosa of human leukocyte antigen (HLA)-DQ8 mice. (A) Long villi are well-preserved in mice fed a gliadin-free diet. (B) Mild villous blunting and increased lymphoplasmacytic infiltration are observed in gliadin-sensitized and gliadin-challenged mice (H&E stain, ×200).
Fig. 3
Fig. 3
Semi-quantification of pancreatic inflammation. Human leukocyte antigen (HLA)-DQ8 mice with exposure to both gliadin and cerulein have significantly higher inflammation scores than those undergoing the mock treatment (*p=0.002), gliadin-only exposure (p=0.032), or cerulein-only exposure (p=0.049). No significant difference was observed between the gliadin-only treatment group and the cerulein-only treatment group (p=0.674).
Fig. 4
Fig. 4
Histology of the pancreases of human leukocyte antigen (HLA)-DQ8 mice with or without exposure to gliadin and/or cerulein. (A, B) Pancreases of gliadin-restricted mice look normal and do not exhibit IgG1-positive cells. (C, D) Pancreases of the gliadin-only group have inflammatory foci showing lymphoplasmacytic infiltration, fibrosis and lobular atrophy. Several IgG1-positive cells are observed. (E, F) Pancreases of the cerulein-only group exhibit focal mild inflammatory cell infiltration. Mild edema and fibrosis can also be seen, and there are several IgG1-positive cells. (G, H) Mice with exposure to both gliadin and cerulein show profound lymphoplasmacytic infiltration, acinar atrophy and storiform fibrosis. Many IgG1-positive plasma cells are observed, and certain acinar cells and stromal cells are stained by IgG1 (A, E: H&E stain, ×100; C, G: H&E stain, ×200; B, D, F, and G: IgG1, ×100).
Fig. 5
Fig. 5
Quantification of IgG1-positive plasma cells. Human leukocyte antigen (HLA)-DQ8 mice exposed to both gliadin and cerulein show a significantly higher number of IgG1-positive cells than the control, gliadin-only or cerulein-only mice (*p=0.021, p=0.034, and p=0.034). There is no significant difference between the gliadin-only and cerulein-only groups (p=0.513). HPF, high power field.
Fig. 6
Fig. 6
Serum IgG1 levels. Human leukocyte antigen (HLA)-DQ8 mice exposed to both gliadin and cerulein show a significantly higher level of serum IgG1 than control mice (*p=0.034). No differences are found among the control, gliadin-only, and cerulein-only groups (p=0.513 and p=0.513). C57BL/6 mice show lower levels of serum IgG1 than HLA-DQ8 mice regardless of cerulein injection (§p=0.116).
Fig. 7
Fig. 7
Histology of selected extrapancreatic organs in both the control and gliadin/cerulein double-exposed human leukocyte antigen (HLA)-DQ8 mice. The salivary glands (A), extrapancreatic bile ducts (C), kidneys (E) and lungs (G) of the control mice do not show significant inflammation. In the gliadin and cerulein double-exposed mice, marked lymphoplasmacytic infiltration and fibrosis are observed in the salivary glands (B), extrapancreatic bile ducts (D), and lungs (H). The kidney (F) is mildly involved (H&E stain, ×100).
Fig. 8
Fig. 8
IgG1 staining of selected extrapancreatic organs in both the control and gliadin/cerulein double-exposed human leukocyte antigen (HLA)-DQ8 mice. In the control mice, no IgG1-positive plasma cells are observed, although there is a degree of cross reactivity in the endothelial cells, distal renal tubules, and lung alveoli (A, C, E, and G). In double-exposed mice, many IgG1-positive plasma cells are shown in the salivary glands (B), extrapancreatic bile ducts (D), kidneys (F), and lungs (H) (IgG1, ×100).

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