Expression of Calnexin Reflects Paneth Cell Differentiation and Function

Abstract

SUMMARY:It has been suggested that the behavior and function of Paneth cells in metaplasia are different from those found in normal intestinal mucosa. In this study, we investigated whether calnexin, a protein involved in secretory pathways, might be associated with differentiation and function of Paneth cells in normal small intestine, in complete intestinal metaplasia of the stomach, and in Paneth cell-rich adenomas. Differentiation and function of Paneth cells was monitored by Ki67, lysozyme, and morphologic features. Using a newly established monoclonal antibody, we found that calnexin is regularly synthesized by Paneth cells of normal small intestine. In these cells, the staining intensity of calnexin was inversely correlated with their content of secretory granules (lysozyme). In contrast, Paneth cells of intestinal metaplasia and Paneth cell-rich adenomas showed a reduced immunostaining of both calnexin and lysozyme. Moreover, these Paneth cells synthesized the proliferation marker Ki67, a phenomenon that was never observed in Paneth cells of normal small intestine. In vitro experiments using CaCo2 cells showed that the expression of calnexin is not directly affected by the induction of mitosis. In conclusion, calnexin probably reflects the status of Paneth cell differentiation and function. The results do not necessarily indicate that calnexin has a function in Paneth cell proliferation. (Lab Invest 2002, 82:1647-1659.T he four principal epithelial cell types of the human small intestinal mucosa (absorptive, goblet, Paneth, and endocrine cells) derive from a multipotent stem cell located near the base of crypts of Lieberkühn. In contrast to absorptive and goblet cells, which migrate in approximately 5 days from the crypt depths to the surface, endocrine cells and Paneth cells differentiate during a downward migration to the base of crypts. Paneth cells reside there for approximately 20 days (Bry et al, 1994). Paneth cells are generally recognized in hematoxylin and eosinstained sections by their large eosinophilic apical secretory granules and their characteristic ultrastructural pattern (Otto, 1973). Functions that have been attributed to Paneth cells include modulation of the intestinal microflora and maintenance of the mucosal defense barrier through production and secretion of several antimicrobial peptides, such as lysozyme, secretory phospholipase A 2 , and ␣-defensins (Nevalainen et al, 1998;Ouellette, 1999;Ouellette and Bevins, 2001). In addition, Paneth cells can also produce further regulatory molecules including growth factors, suggesting that Paneth cells may regulate the proliferation and differentiation programs of epithelial cell lineages by short-circuit paracrine loops (Bry et al, 1994;Ganz, 2000).In humans, Paneth cell metaplasia is preferentially found in atrophic gastritis (Wong et al, 2000). Other nonmalignant pathologic conditions associated with Paneth cell metaplasia are diversion colitis, ulcerative colitis, and collagenous colitis (Goff et al, 1997;Shah et al, 1998;Stamp et al, ...

Metaplastic Paneth Cells in Extra-Intestinal Mucosal Niche Indicate a Link to Microbiome and Inflammation

“…Esophagus Conventional H&E staining Chen et al, 2015 H&E, light microscopy and electron microscopy Schreiber et al, 1978 H&E, periodic acid-Schiff/Alcian blue Takubo et al, 1995 H&E, Lendrum's Phyloxine-tartrazine stain Thompson et al, 1983 Stomach Periodic acid-Schiff/Alcian blue at pH 2.5 Abraham et al, 2003 H&E, Masson's Trichome, Lendrum's Phyloxine-tartrazine, Periodic acid-Schiff/Alcian blue at pH 2.5 and colloidal iron pH 1.9 staining Albedi et al, 1984 H&E, Periodic acid-Schiff/Alcian blue at pH 2.5, immunostaining for lysozyme Deveci and Deveci, 2004 Immunostaining for lysozyme Gassler et al, 2002 Conventional H&E staining Inada et al, 1997 H&E, Periodic acid-Schiff/Alcian blue at pH 2.5 and Electron microscopy Matsubara, 1977 Immunoelectron microscopy for lysozyme Ohtani and Sasano, 1988 Immunostaining for HD5 and HD6 Ostaff et al, 2015 Conventional H&E staining Rubio et al, 1987 Lysozyme immunostaining Rubio, 2012 Gallbladder Conventional H&E staining Albores-Saavedra et al, 1986 Conventional H&E staining Bae et al, 2002 Electron microscopy, H&E, Periodic acid-Schiff Laitio and Nevalainen, 1975 Conventional H&E staining Sakaki et al, 2000 Ovary Conventional H&E staining Alrajban et al, 2018 Conventional H&E staining Niemiec et al, 1989 Prostate Conventional H&E staining, immunostaining for lysozyme Frydman et al, 1992 Conventional H&E staining Adlakha and Bostwick, 1994 (Shen et al, 2005). Additionally, Paneth-like cells were reported in gastric adenomas and carcinomas (Heitz and Wegmann, 1980;Ito et al, 1986;Caruso et al, 1989;Rubio, 1989).…”

“…This represented one of the earliest attempts to distinguish intestinal resident cells vs. metaplastic Paneth cells. Gassler et al (2002) later reported that the expression of calnexin was inversely related to secretory lysozyme in Paneth cells of normal intestinal mucosa but became directly correlated to lysozyme in metaplastic Paneth cells in gastric mucosa. They further identified the expression of proliferative marker Ki67 in metaplastic Paneth cells but not in Paneth cells of normal small intestines.…”

“…They further identified the expression of proliferative marker Ki67 in metaplastic Paneth cells but not in Paneth cells of normal small intestines. These studies suggested that metaplastic Paneth cells may behave differently from normal Paneth cells (Gassler et al, 2002). However, detailed information at the molecular level is currently absent to distinguish normal from metaplastic Paneth cells.…”

Altered Distribution of Metaplastic Paneth, Gastrin and Pancreatic Acinar Cells in Atrophic Gastritic Mucosa with Endocrine Cell Lesions

“…Gassler et al (2002) reported Paneth cells of IMs in the gastric mucosa and Paneth cell-rich adenoma express the proliferation marker Ki67, a phenomenon that was never observed in Paneth cells of normal small intestine. Moreover, Wong et al (2000) emphasized that numerous Paneth cells and goblet cells in areas of intestinal metaplasia were in cell cycle; however, the endocrine cells were non-proliferative.…”

Reduced expression of members of the MHC-I antigen processing machinery in ethnic Uighur women with cervical cancer in the Xinjiang region of China

“…Calcium binding protein in the endoplasmic reticulum, cnx, is a molecular chaperone that helps with the correct folding of mhc class i molecules to form a functional dimer 35,36 . Reduced expression or absence of cnx may therefore lead to downregulation of mhc-i expression 37,38 .…”