Spontaneous development of pancreatitis in the MRL/Mp strain of mice in autoimmune mechanism

Abstract

MRL/Mp mice are known to have autoimmune disease-prone genetic background, which contributes to the development of a lethal autoimmune disease at an early age in association with the lymphoproliferative gene, lpr. In this study, we found that MRL/Mp mice, not bearing lpr (MRL/Mp-(+)/+), spontaneously developed pancreatitis at a late stage of life, which was histopathologically characterized by destruction of pancreatic acinar cells with mononuclear cell infiltration. In female 34-38-weeks-old mice the incidence of pancreatitis reached 74%, whereas the male mice developed the disease with a reduced incidence, at a later stage of life and with a reduced severity. Cell infiltrates in the affected lesions were composed predominantly of CD4+ cells and to lesser extent Mac-2+ macrophages. Adoptive transfer of the spleen cells obtained from pancreatitis-bearing female mice generated pancreatitis in female normal mice, but not in the male mice. Transfer of the serum of pancreatitis-bearing mice failed to induce any pancreatic lesions. These findings indicate that pancreatitis in MRL/Mp-(+)/+ mice may be mediated by cellular autoimmune mechanism. This may present a useful concept for analysis of the developmental mechanisms of human chronic pancreatitis in an aspect of autoimmunity.

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

“…Six-week-old female MRL/Mp mice were treated by i.p. injections with 100 mg polyinosinic-polycytidylic acid [poly (I:C); InvivoGen, San Diego, CA] twice a week for a total of 14 or 16 injections to induce experimental AIP (22,23). In some experiments, mice were treated with Ab against bone marrow stromal cell Ag 2 (100 mg, 120G8; Bioceros, Utrecht, the Netherlands) and Ab against IFN-ab receptor (100 mg, anti-type I IFN receptor [IFNAR] Ab, MAR1-5A3; BD Biosciences, San Jose, CA) (24) prior to each poly (I:C) injection to deplete pDCs and inhibit type I IFN-mediated signaling pathways, respectively.…”

“…Histopathological evaluation of pancreatic lesions was performed to assess the degree of inflammatory cell infiltration (22,23,27). Inflammatory infiltrates were scored as follows: 0, pancreas without mononuclear cell infiltration; 1, mononuclear cell aggregation and/or infiltration within the interstitium, with no parenchymal destruction; 2, focal parenchymal destruction with mononuclear cell infiltration; 3, diffuse parenchymal destruction but some intact parenchymal residue retained; and 4, almost all pancreatic tissue, except the pancreatic islets, destroyed or replaced with fibrosis or adipose tissue (22).…”

Assessment of the immunotoxic potential of trichloroethylene and perchloroethylene in rats following inhalation exposure

“…One study did report histopathological changes in the spleen following TCE vapor exposure at 500 ppm, while no changes were observed in thymus morphology at any concentration level (Kaneko et al, 2000). However, effects on the spleen in that study may be due to the mouse strain used (MRL-lpr/lpr), which is known to develop spontaneous autoimmune disease that can affect lymphoid tissues from 6 weeks-of-age (Murphy, 1981;Kanno et al, 1992;Ratkay et al, 1994). Another study reported significant decreases in thymus weight in B6C3F1 mice after 30 weeks of exposure to 1.4 and 14 ppm TCE in drinking water (Keil et al, 2009); however, this effect was not observed in a developmental immunotoxicology study with TCE in B6C3F1 mice conducted in the same lab at the same concentrations (Peden-Adams et al, 2006).…”

Toll-Like Receptor 3 Signaling Induces Chronic Pancreatitis through the Fas/Fas Ligand-Mediated Cytotoxicity

“…MRL/Mp mice spontaneously develop chronic pancreatitis at an older age, possibly due to an autoimmune mechanism, since the pancreatitis was successfully transferred to younger mice by the injection of splenocytes from the older mice (Kanno et al 1992), and poly I:C injection into younger MRL/Mp mice accelerates the development of pancreatitis (Qu et al 2002). Pancreatitis in these mice is histopathologically characterized by the severe infiltration of lymphocytes, plasma cells and macrophages into the pancreatic parenchyma.…”

“…Pancreatitis in these mice is histopathologically characterized by the severe infiltration of lymphocytes, plasma cells and macrophages into the pancreatic parenchyma. Such lesions are thought to be initiated by the accumulation of lymphoid cells into the periductular regions and then the ductular epithelial cells, followed by their destruction (Kanno et al 1992;Qu et al 2002), similar to autoimmune pancreatitis in human (Finkelberg et al 2006;Zandieh and Byrne 2007). This initial event in the pancreas leads to the destruction of pancreatic acini, associated with the formation of granulomatous lesions, with a partial regeneration of the ductules, thus showing so called "epithelial islands" (Okazaki et al 2008).…”