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PubMed1990

Paneth cells and adult coeliac disease.

The number of Paneth cells in patients suffering from coeliac disease was compared with the control group (without gastrointestinal trouble) in this study. Samples of the intestinal mucosa from the jejunum were obtained with a bioptic capsule. Semithin sections (0.5-1 microns) were stained with toluidine blue and photographed and 100 crypts of Lieberkühn were photographed in every section. Every crypt had to contain one Paneth cell at least. The Paneth cells were counted on an enlarger. Acidophil secretory granules in the apical parts of the cells were significant for their identification. The material consisted of 10 patients suffering from coeliac disease and 1 patient with dermatitis herpetiformis. The control group consisted of 5 persons. The results revealed a statistically significant increase in the number of Paneth cells for the patients suffering from coeliac disease and for the one with dermatitis herpetiformis.

Adolescent↗
PubMed1996

Paneth cell defensins: endogenous peptide components of intestinal host defense.

Paneth cells are epithelial granulocytes at the base of the crypts of Lieberkühn in the small intestine of many mammalian species. These secretory cells contribute to mucosal barrier function by the apical release of granules containing a variety of antimicrobial products, including peptides termed cryptdins, for crypt defensins. In mice, six Paneth cell defensins have been characterized at the peptide level that have potent antimicrobial activities equivalent to or greater than that of rabbit neutrophil defensin NP-1. Cryptdin peptides that differ only by single amino acid substitutions have been shown to exhibit a high degree of specificity against certain target microorganisms. Cryptdins are coded by separate, two-exon genes that are located on chromosome 8 in both mice and humans. Human Paneth cells contain high levels of two different defensin mRNAs, but in mice at least 19 cryptdin isoforms are predicted from cDNA sequencing data. The mouse cryptdin-4 gene is expressed with positional specificity along the longitudinal intestinal axis, and cryptdin genes are active in the intestinal epithelium prior to Paneth cell differentiation. Accordingly, Paneth cell defensins are early markers of crypt ontogeny and are therefore useful in studies of lineage determination in the intestinal epithelium. Because cryptdins mediate innate immunity in the hostile environment of the intestinal lumen, it should be of interest to define biochemical and biophysical attributes that adapt these peptides to barrier function of mucosal surfaces.

Amino Acid Sequence↗
PubMed1988

Atropine inhibits the degranulation of Paneth cells in ex-germ-free mice.

Previous studies have shown that the secretory products of Paneth cells contain antibacterial agents (lysozyme, IgA) that are affected by the bacterial milieu in the intestine. To investigate whether Paneth-cell secretion is controlled via cholinergic mechanisms, the ultrastructure of Paneth cells was studied in four animal groups: (1) germ-free (GF) control mice (Jcl: ICR [GN], male, 13 weeks old), (2) GF mice injected subcutaneously with atropine sulfate (200 mg/kg body weight, dissolved in physiological saline 20 mg/ml), (3) ex-GF mice inoculated with feces from specific-pathogen-free (SPF) mice, and (4) ex-GF mice injected with atropine and inoculated with feces from SPF mice. In ex-GF mice inoculated with feces, 70-90% of the Paneth cells showed fewer secretory granules than those from GF mice (p less than 0.01). Approximately 30% of the Paneth cells had a large vacuole (3-10 micron diameter) in the apical cytoplasm. Exocytosed electron-dense material from secretory granules was observed in a few crypt lumens. In ex-GF mice inoculated with feces and given atropine, about 90% of the Paneth cells contained numerous secretory granules, like those in GF control mice, but vacuolated Paneth cells and exocytotic figures were rare; thus the secretion of Paneth cells was blocked by atropine. It is therefore possible that the bacterial milieu in the intestine affects the secretory activity of Paneth cells via cholinergic mechanisms.

Animals↗
PubMed1994

Paneth cell differentiation in the developing intestine of normal and transgenic mice.

Paneth cells represent one of the four major epithelial lineages in the mouse small intestine. It is the only lineage that migrates downward from the stem-cell zone located in the lower portion of the crypt of Lieberkühn to the crypt base. Mature Paneth cells release growth factors, digestive enzymes, and antimicrobial peptides from their apical secretory granules. Some of these factors may affect the crypt stem cell, its transit-cell descendants, differentiating villus-associated epithelial lineages, and/or the gut microflora. We used single and multilabel immunocytochemical methods to study Paneth cell differentiation during and after completion of gut morphogenesis in normal, gnotobiotic, and transgenic mice as well as in intestinal isografts. This lineage emerges coincident with cytodifferentiation of the fetal small intestinal endoderm, formation of crypts from an intervillus epithelium, and establishment of a stem-cell hierarchy. The initial differentiation program involves sequential expression of cryptdins, a phospholipase A2 (enhancing factor), and lysozyme. A dramatic increase in Paneth cell number per crypt occurs during postnatal days 14-28, when crypts proliferate by fission. Accumulation of fucosylated and sialylated glycoconjugates during this period represents the final evolution of the lineage's differentiation program. Establishment of this lineage is not dependent upon instructive interactions from the microflora. Transgenic mice containing nucleotides -6500 to +34 of the Paneth cell-specific mouse cryptdin 2 gene linked to the human growth hormone gene beginning at its nucleotide +3 inappropriately express human growth hormone in a large population of proliferating and nonproliferating cells in the intervillus epithelium up to postnatal day 5. Transgene expression subsequently becomes restricted to the Paneth cell lineage in the developing crypt. Cryptdin 2 nucleotides -6500 to +34 should be a useful marker of crypt morphogenesis and a valuable tool for conducting gain-of-function or loss-of-function experiments in Paneth cells.

Animals↗
PubMed2002

Expression of calnexin reflects paneth cell differentiation and function.

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.

Adenoma↗
PubMed2005

Paneth cells and antibacterial host defense in neonatal small intestine.

Paneth cells are specialized epithelia in the small bowel that secrete antimicrobial proteins. Paneth cells are vital to the innate immunity of the small bowel in adult mammals, but their role during neonatal infection of the small bowel is not well established. Dithizone selectively damages Paneth cells, and when dithizone-treated newborn rats are infected enterally with Escherichia coli, the numbers of E. coli cells in their jejunal and ileal lavage fluid are significantly increased compared to controls. The data support that Paneth cells are necessary for neonatal antibacterial defense.

Animals↗
PubMed2001

Absence of group II phospholipase A2, a Paneth cell marker, from the epididymis.

Paneth cell-like metaplasia has been reported in the epithelium of the epididymis and prostatic adenocarcinomas. We studied the expression of group II phospholipase A2 (PLA2), a marker of Paneth cell differentiation, in six orchiectomy specimens with Paneth cell-like metaplasia. Both immunohistochemistry for group II PLA2 protein and in situ hybridization for the mRNA of group II PLA2 gave negative results in all six cases but positive reaction for lysozyme. The results show that the cells of the Paneth cell-like metaplasia are not true Paneth cells.

Biomarkers↗
PubMed1997

Paneth cells and innate immunity in the crypt microenvironment.

Paneth cells release granules into the lumen of the crypts of Lieberkuhn in the small intestine where their component proteins participate in mucosal immunity. The granules contain a number of proteins associated with roles in host defense, including lysozyme, secretory phospholipase A2, and alpha-defensins, termed cryptdins. Mouse cryptdins 1-6 and recombinant human Paneth cell alpha-defensin HD-5 are potent antimicrobial agents against certain microorganisms. As defensins, they kill microbes by disruption of the target cell membrane. The peptides are coded by individual, two-exon genes that map to homologous regions of chromosome 8 in mice and humans, and the differential expression of certain mouse cryptdin genes provides markers for studies of crypt ontogeny and epithelial cell differentiation and lineage determination. Neutrophil alpha-defensin peptides exhibit numerous biological activities in addition to antimicrobial function including regulation of cell volume, chemotaxis, mitogenicity, and inhibition of natural killer cell activity. When administered apically, mouse cryptdins 2 and 3 can reversibly stimulate human T-84 intestinal epithelial cells to secrete chloride ion, suggesting that alpha-defensins from Paneth cells also may be multifunctional. Thus, cryptdins and varied Paneth cell secretory products seem to contribute both to innate immunity of the crypt lumen and to defining the apical environment of neighboring cells.

Animals↗
PubMed2001

Identification of Paneth cells in pyloric glands associated with gastric and intestinal mixed-type intestinal metaplasia of the human stomach.

We have proposed that intestinal metaplasia (IM) of the human stomach be divided into two types on the basis of cell differentiation status: a gastric and intestinal (GI) mixed type and a solely intestinal (I) type. In the GI mixed type, gastric (foveolar epithelial and pyloric gland cells) and intestinal (goblet, intestinal absorptive, and Paneth cells) phenotype cells coexist in the same intestinalized gastric glands in various combinations and degrees. Consequently, intestinalized gastric glands are hybrids. Although we have described the rare appearance of Paneth-like cells in pyloric glands of GI mixed-type IM, the absence of an appropriate Paneth cell marker leaves room for doubt as to their true character. The purpose of this study was to clearly identify Paneth cells in pyloric glands in IM lesions using a new Paneth cell marker, a polyclonal antibody human defensin (HD)-5, raised against HD-5, which is included in granules of Paneth cells. A total of 105 gastric samples (4 biopsy and 101 surgical resected specimens) were examined. In only nine cases (8.6%), the antibody allowed demonstration of Paneth cells in pyloric glands in GI mixed-type IM, confirming our previous finding. Analysis of the proliferative cell (P) zone indicated that a common stem cell might generate both GI phenotype cells by upward and downward migration. No Paneth cells were found above the P zone. The results suggest that the stem cells show abnormal cell differentiation in IM lesions but preserve their normal direction of migration.

Adenocarcinoma↗
PubMed2005

Mouse paneth cell secretory responses to cell surface glycolipids of virulent and attenuated pathogenic bacteria.

Mouse Paneth cells respond to bacteria and bacterial cell surface antigens by discharging secretory granules into the lumen of small intestinal crypts (T. Ayabe et al., Nat. Immunol. 1:113-118, 2000). To investigate mechanisms regulating these responses, purified surface glycolipid molecules with known acyl chain modifications and attenuated properties were tested for the ability to stimulate Paneth cell secretion. The antigens included lipopolysaccharide (LPS) from wild-type and msbB-null Escherichia coli and phoP-null and phoP-constitutive Salmonella enterica serovar Typhimurium strains, as well as LPS, lipid A, and lipoteichoic acid from Pseudomonas aeruginosa and Listeria monocytogenes grown in Mg2+-limited media. Measurements of total secreted protein, secreted lysozyme, and the bactericidal peptide activities of collected secretions showed that the purified antigens elicited similar secretory responses from Paneth cells in mouse crypts ex vivo, regardless of glycolipid acyl chain modification. Despite their impaired Tlr4 pathway, Paneth cells in ex vivo C3H/HeJ mouse crypts released equivalent amounts of bactericidal peptide activity in response to purified bacterial antigens, including lipid A. Thus, mouse Paneth cells respond equivalently to purified bacterial cell envelope glycolipids, regardless of functional Tlr4, the structural properties of glycolipid acyl chains, or their association with virulence in humans.

Animals↗
PubMed2006

Paneth cells and the innate immune response.

PURPOSE OF REVIEW: To review recently published studies presenting novel and relevant information on Paneth cells and their function. RECENT FINDINGS: Paneth cells are secretory epithelial cells which are predominantly found in the small-intestinal crypts of Lieberkühn. Their most abundant products are alpha-defensins, which are endogenous antibiotics with activity against gram-negative and gram-positive bacteria, fungi, viruses and protozoa. The differentiation from stem-cell progenitors to Paneth cells is regulated by Wnt signalling via a complex gene programme, terminally including defensins. A disturbance of Paneth-cell differentiation and function may predispose to intestinal infections and appears to be a critical factor in the pathogenesis of ileal Crohn's disease, an inflammatory disease of the intestinal tract. SUMMARY: It is conceivable that these recent findings together with a better understanding of underlying mechanisms involved in the regulation and biology of Paneth cells will open up new therapeutic avenues for preventing infection as well as for causally treating inflammatory bowel diseases.

Animals↗
PubMed1969

The Paneth cell in disease.

A systematic study of the distribution of Paneth cells in disease of the small and large intestine is described. In disease of the small intestine and appendix there is usually a fall in the number of Paneth cells normally present. Occasionally, as in Crohn's disease, there may be proliferation. In disease of the colon the number of Paneth cells is unaltered in functional and developmental disorders and increased in the inflammatory and neoplastic diseases. It is suggested that the Paneth cell proliferation originates from stem cells in the colon. The significance of an increase in Paneth cells is discussed and it is suggested that in ulcerative colitis it may produce a self-perpetuating and destructive state.

Appendix↗
PubMed1984

Relation between the mucosal flora and Paneth cell population of human jejunum and ileum.

The Paneth cell population in surgically resected human jejunum and ileum was estimated using image analysis of the granule area in patients who had not received antibiotics. The mucosa was cultured aerobically and anaerobically. In the jejunum 22 samples were sterile and five yielded bacteria; in the ileum four were sterile and three were non-sterile. The mean Paneth cell granule area in the sterile jejunum was 122.7 +/- 37.2 micron2 and in the non-sterile samples 67.2 +/- 36.6 micron2 (p less than 0.006). The corresponding values for the ileum were 137.9 +/- 109.8 and 100.5 +/- 9.1 (NS). Thus an increase in the Paneth cell population may occur in response to changes in the intestinal luminal environment. Failure of this response and resultant Paneth cell deficiency may lead to bacterial overgrowth.

Aged↗
PubMed2004

Paneth cell granule depletion in the human small intestine under infective and nutritional stress.

Paneth cells are important contributors to the intestinal antimicrobial barrier through synthesis and release of antimicrobial peptides and proteins. Animal studies indicate that Paneth cell numbers, location and granule morphology are altered by infection and zinc status. We examined human tissue to determine whether Paneth cell numbers, distribution or granule morphology are altered in infective, inflammatory and nutritional disorders. Archival sections from infective disorders (giardiasis, cryptosporidiosis, HIV, helminth infection) were compared with active inflammatory conditions (coeliac, Crohn's and graft-versus-host diseases) and histologically normal tissues. A subset of tissues was studied by electron microscopy and TUNEL staining for apoptosis. Human defensin-5 (HD5) peptide and mRNA was analysed by immunohistochemistry, in situ hybridization and quantitative reverse transcription polymerase chain reaction. Sections from a tropical population cohort study were then analysed to determine the relationship of granule depletion to infection, nutritional status and plasma zinc concentration. In HIV-related cryptosporidiosis, but not other disorders, Paneth cells were reduced in number and markedly depleted of granules. Paneth cell granule depletion was associated with reduced HD5 immunoreactivity, but this was not due to apoptosis and there was no reduction in mRNA transcripts. In the tropical population studied, depletion of granules was associated with reduced body mass index, reduced plasma zinc levels and HIV infection. Paneth cell granules in human small intestine may be depleted in response to infective and nutritional stress. We postulate that this is one mechanism through which zinc status influences host susceptibility to intestinal infection.

AIDS-Related Opportunistic Infections↗
PubMed2004

The Paneth cell and the innate immune response.

PURPOSE OF REVIEW: Innate immune defense of the small intestine is mediated in part by antimicrobial peptides and proteins secreted by Paneth cells, epithelial cells positioned at the base of the crypts of Lieberkuhn. Recent studies have yielded better understanding of the role that Paneth cells may play in host defense. Emerging data suggest that these cells may contribute to the pathophysiology of several human diseases. A wealth of data has also emerged on the regulatory pathways of Paneth cell functions and structure-function analysis on Paneth cell antimicrobials. This review discusses new reports in these areas. RECENT FINDINGS: Studies of transgenic and knockout mice have supported a pivotal role of Paneth cell defensins in protection from oral bacterial pathogens. Other studies suggest that Paneth cells may be the targets of virulence mechanisms of bacterial pathogens. New observations also suggest that Paneth cell dysfunction may contribute to the clinical phenotype of Crohn disease, necrotizing enterocolitis, and, perhaps, intestinal manifestations of cystic fibrosis. SUMMARY: Paneth cells are emerging as key mediators of innate host defense in the small intestine. The antimicrobial activity of Paneth cell secretory products on transient and resident microbes in the gut may have a profound influence on health. The possible role of Paneth cell dysfunction in human disease and a better understanding of Paneth cell regulatory pathways are areas poised for significant advances in the near future.

Journal Article↗
PubMed1991

Paneth cell degranulation and lysozyme secretion during acute equine alimentary laminitis.

The equine Paneth cell response to a shift in the microbial balance of the intestinal tract was studied by inducing an acute episode of alimentary laminitis in 6 mature ponies. The normal bacterial population of the gut was modified by administration of a carbohydrate-rich ration. During acute laminitis a dramatic degranulation of the Paneth cells occurred in the intestinal glands throughout the duodenum, jejunum, and ileum. Bacteriocidal lysozyme, which was immunohistochemically identified as a component of the Paneth cell secretory granule, was evident in the glandular lumina and in degranulated Paneth cells. These results indicate that lysozyme is secreted by the equine Paneth cell in an apparent attempt to regulate the changing microbial population induced by carbohydrate overload of the gut. From these observations, it is suggested that the Paneth cell plays a role in the mucosal defense system of the equine intestinal tract.

Animals↗
PubMed1992

Incidence of Paneth cells in minute tubular adenomas and adenocarcinomas of the large bowel.

This study attempted to demonstrate the incidence of Paneth cells within large bowel tubular adenoma and adenocarcinoma according to location and macroscopic appearance using minute tumors (up to 5 mm in size). We have shown that Paneth cells were sometimes seen in the early stage of the development of large bowel epithelial neoplasia. According to the macroscopic appearance (elevated or depressed type), in large bowel epithelial neoplasia, there was a statistical difference between the depressed type (32.5%, 14 of 40 cases) and the elevated type (16.6%, 24 of 145 cases) (Chi square analysis, p < 0.05) in the incidence of Paneth cells. Paneth cells were seen more frequently in adenocarcinoma (45.8%, 11 of 24 cases) than in tubular adenoma (16.8%, 27 of 161 cases), with a significant statistical difference (Chi square analysis, p < 0.01). According to location, in both tubular adenoma and adenocarcinoma, Paneth cells were more frequently observed in the proximal colon (tubular adenoma: p < 0.01, adenocarcinoma: p < 0.05, Chi square analysis).

Adenocarcinoma↗
PubMed1980

Ileal Paneth cells and IgA system in rats with severe zinc deficiency: an immunohistochemical and morphological study.

Morphological abnormalities in Paneth cells occur in patients with acrodermatitis enteropathica, a hereditary disease associated with zinc deficiency; furthermore, rat Paneth cells contain large amounts of zinc. This study was conducted to assess the effect of severe zinc deficiency in Sprague-Dawley rats on various parameters of Paneth cells. Morphology at both the light microscopical and ultrastructural levels, Paneth cell numbers per crypt and the intracellular distribution of lysozyme were not altered by zinc deficiency. A weak correlation (r = +0.38, P = 0.05) was noted between ileal zinc concentration and numbers of IgA-containing Paneth cells per crypt. These findings indicate that the morphological abnormalities noted in human Paneth cells in patients with acrodermatitis enteropathica cannot be reproduced by experimental severe zinc deficiency in rats. Furthermore, these generally negative findings suggest that the severe diarrhoea often associated with zinc deficiency is not attributable to abnormalities induced in Paneth cells by zinc deficiency.

Animals↗