Dome Epithelium Research Articles

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.

Tumorigenesis: A hairy and nervous start.

Peterson et al. report that basal cell carcinomas primarily arise from stem cells within hair follicle and touch dome epithelia, and that cutaneous nerves promote tumorigenesis.

Basal Cell Carcinoma Preferentially Arises from Stem Cells within Hair Follicle and Mechanosensory Niches

Basal cell carcinoma (BCC) is characterized by frequent loss of PTCH1, leading to constitutive activation of the Hedgehog pathway. Although the requirement for Hedgehog in BCC is well established, the identity of disease-initiating cells and the compartments in which they reside remain controversial. By using several inducible Cre drivers to delete Ptch1 in different cell compartments in mice, we show here that multiple hair follicle stem cell populations readily develop BCC-like tumors. In contrast, stem cells within the interfollicular epidermis do not efficiently form tumors. Notably, we observed that innervated Gli1-expressing progenitors within mechanosensory touch dome epithelia are highly tumorigenic. Sensory nerves activate Hedgehog signaling in normal touch domes, while denervation attenuates touch dome-derived tumors. Together, our studies identify varying tumor susceptibilities among different stem cell populations in the skin, highlight touch dome epithelia as "hot spots" for tumor formation, and implicate cutaneous nerves as mediators of tumorigenesis.

Morphological variations of the vallate papillae in some mammalian species

The morpho-structural characteristics of the vallate papillae of the tongue of rat, dog, donkey and buffalo were investigated by macroscopy and their microstructure by light and scanning electron microscopy (SEM). The numbers of vallate papillae varied among the different species. In rat, a single vallate papilla surrounded by incomplete groove and an annular fold was observed. Taste buds were detected along the entire length of the medial and lateral groove epithelium, but not in the papillary dome. In dog, some papillae lacking the annular pad had irregular ridges and grooves toward the center of the papillary surface, while other papillae had small secondary papillary grooves arising from the center of the papilla. Taste buds were located in the medial and lateral epithelium of both primary and secondary grooves as well as in the dome epithelium. In donkey, two papillae were frequently observed around the midline of the tongue root, and an additional papilla was found occasionally in the middle and associated with secondary papilla. In buffalo, several papillae were relatively small and variable in shape. With SEM, small ridges and grooves were found in the papillae of donkey and buffalo. In both species, taste buds were constantly observed along the medial wall epithelium, but no taste buds were found in the lateral wall. We conclude that the vallate papillae exhibited peculiar characteristics, which are species specific and might have a correlation with the variable feeding habits among these animals.

The identification of intestinal M cells in the sacculus rotundus and appendix of the Angora rabbit

The present study was aimed at the immunohistochemical demonstration of M cells, found in the follicle-associated epithelium (FAE) of the sacculus rotundus (SR) and appendix of the Angora rabbit, using anti-vimentin primary antibodies, and at the determination of certain fine structural characteristics. Ten adult Angora rabbits constituted the material of the study. Immunohistochemical staining revealed that many cells composing the FAE, which covered the dome regions of the SR and appendix, reacted positively with vimentin. FAE contained two different types of vimentin-positive cells. The first type surrounded intraepithelial lymphocytes (IEL) with a basolateral invagination in the apex and periphery of the dome epithelium, whilst the second type consisted of columnar cells found in the FAE near crypts. The immunoreactivity of the cells found in the FAE covering the apex and periphery of the domes was observed particularly in the perinuclear cytoplasm and the cytoplasm surrounding the IEL. Electron microscopic examination demonstrated that the M cells found in the FAE covering the apex and periphery of the dome regions of the SR and appendix did not exhibit any microvilli on their apical surface. The FAE near crypts contained columnar cells, which resembled enterocytes. The apical membrane of these cells exhibited shorter and irregular microvilli, in contrast to neighbouring enterocytes. It was determined that M cells, found in the FAE of the SR and appendix in the Angora rabbit, displayed similarities in terms of localization and fine structure. This situation may be indicative of the two lymphoid structures with different localization having similar functional properties.

Endodermal Origin of Bladder Trigone Inferred From Mesenchymal-Epithelial Interaction

In the classic view of bladder development the trigone originates from the mesoderm derived wolffian ducts while the remainder of the bladder originates from the endoderm derived urogenital sinus. Recent molecular developmental studies have questioned the veracity of this received wisdom, suggesting an endodermal origin for the trigone. To shed further light on this issue we observed mesenchymal-epithelial interactions between trigone epithelium and fetal urogenital sinus mesenchyma to infer the trigonal germ layer of origin. Mouse trigone epithelium was recombined with fetal rat urogenital sinus mesenchyma in tissue recombinant grafts that were placed beneath the renal capsule of athymic mouse hosts. Grafts were harvested at 4 weeks. Control grafts with bladder dome and ureteral epithelium were also examined. Tissues were evaluated with hematoxylin and eosin, and Hoechst dye 33258 to confirm cell species origin. Immunohistochemistry was done with androgen receptor, broad spectrum uroplakin, dorsolateral prostate secretions and seminal vesicle secretions to differentiate prostatic and seminal vesicle differentiation. Grafts of mouse trigone epithelium with fetal rat urogenital sinus mesenchyma yielded epithelial tissue that stained for dorsolateral prostate secretions but not for seminal vesicle secretions. Control grafts of bladder dome epithelium yielded the expected endodermal prostate differentiation. Control grafts of ureteral epithelium yielded the expected mesodermal seminal vesicle differentiation. The consistent finding of prostatic epithelium in tissue recombinants of trigone epithelium and fetal urogenital sinus mesenchyma reinforces the hypothesis that the trigone is derived from the endoderm and not from the mesoderm, as commonly accepted.

Transcytosis of F4 fimbriae by villous and dome epithelia in F4-receptor positive pigs supports importance of receptor-dependent endocytosis in oral immunization strategies

Very few antigens have been described that induce an intestinal immunity when given orally. Our laboratory demonstrated that oral administration of isolated F4 (K88) fimbriae of Escherichia coli to F4-receptor positive (F4R +) pigs induces protective mucosal immunity against challenge infection. However, presence of F4-receptors (F4R) on villous enterocytes is a prerequisite for inducing the immune response, as no F4-specific antibody-secreting cells (ASC) can be induced in F4R − pigs. In this study, the in vivo binding of isolated F4 fimbriae (F4) to the gut epithelium was examined in F4R + and F4R − pigs. It was further investigated whether binding of F4 to the F4R results in endocytosis in and translocation across the gut epithelium using microscopy. F4 did not adhere to the intestinal epithelium of F4R − pigs, whereas it strongly adhered to the villous epithelium and the follicle-associated epithelium (FAE) of the jejunum and ileum of F4R + pigs. Following binding to F4R, F4 was endocytosed by villous enterocytes, follicle-associated enterocytes and M cells. Transcytosis of F4 across the epithelium resulted in the appearance of F4 in the lamina propria and dome region of the jejunal and ileal PP. This is the first study showing transcytosis of fimbriae across the gut epithelium. This receptor-dependent transcytosis can explain the success of F4 fimbriae as oral immunogen for inducing protective immunity in F4R + pigs strengthening the importance of receptor-dependent endocytosis and translocation in oral vaccine strategies. Further identification of the receptor responsible for this transport is in progress.

Characteristics of histological location of bursin in sacculus rotundus and gut-associated lymphoid tissues of rabbits

The distribution of bursin in sacculus rotundus and gut-associated lymphoid tissues was investigated in rabbit by immuno-histochemical staining method with anti-bursin monoclonal antibody (McAb)2F9-4. The results indicated that the appearance of the bursin-containing cells coincided with the morphodifferentiation and growth process in rabbit. Bursin immunized cells not only distributed in dome epithelium and mucosal epithelium, but also in follicular germinal center, dome, T-cell area, goblet cell, inter-epithelial lymphocyte and cap-zone of sacculus rotundus. This founding suggested that bursin-containing cells in sacculus rotundus might play an important role in intestinal mucosal immunity.

Lectin binding profile of the small intestine of five-week-old pigs in response to the use of chlortetracycline as a growth promotant and under gnotobiotic conditions1,2

Antibiotics have traditionally been used for growth promotion in the pork industry; however, their use in animal feed has recently been limited because of human health concerns. The intestinal microbiota plays an important role in mediating many physiological functions such as digestion and animal growth. It was hypothesized that use of antibiotics as growth promotants and subsequent variations in intestinal microbiota induce significant changes in the intestinal glycoconjugate composition, which ultimately affects animal growth and disease susceptibility. The aim of this study was to characterize the lectin binding profiles of the ileum of weanling pigs in response to the absence of intestinal microbiota and to the use of the antibiotic chlortetracycline as growth promotant. Eighteen half-sib piglets obtained by cesarean section were divided into 3 treatment groups (n = 6) and maintained as control, antibiotic-fed, and gnotobiotic piglets until 5 wk of age. The glycoconjugate composition of the ileal tissues was examined by lectin histochemistry. Lycopersicon esculentum lectin, Jacalin, Pisum sativum agglutinin, Lens culinaris agglutinin (LCA), and Sambucus nigra lectin showed significant differences (P < 0.05) in binding intensities on the dome and villous epithelium between the treatment groups. Griffonia simplicifolia lectin I, Glycine maxi agglutinin, and Arachis hypogea agglutinin exhibited differences (P < 0.05) between treatment groups in lectin binding on goblet cells. Triticum vulgaris agglutinin, Pisum sativum agglutinin, and LCA showed significant differences (P < 0.05) in binding intensities on dome, corona, and follicular regions of the ileum among treatment groups of animals. Overall, ileal tissues from gnotobiotic piglets expressed significantly weaker (P < 0.05) lectin binding for many lectins compared with control and antibiotic groups. This suggests that the intestinal microbiota plays an important role in the expression of sugar moieties in the intestine. Lectins LCA, Phaseolus vulgaris Leucoagglutinin, and Maackia amurensis lectin II showed significant differences (P < 0.05) in lectin bindings between control and antibiotic-fed piglets. This indicates that chlortetracycline as a growth promotant induces biologically relevant changes in the lectin binding profile of the ileum. These findings will help in further understanding the role of the gut microbiota and the mechanisms of action of antibiotics as growth promotants in pigs.

Antigen Transport into Peyer's Patches: Increased Uptake by Constant Numbers of M Cells

Membranous (M) cells are specialized epithelial cells of the Peyer's patches that sample antigens from the gut lumen, thereby enabling the host to respond immunologically. Recent studies suggest that this transport can be up-regulated within hours by de novo formation of M cells from enterocytes. To test this hypothesis, we used an in vivo model and induced the transcytosis of tracers in Peyer's patches by application of Streptococcus pneumoniae R36a into the gut lumen. Using cell-type-specific markers, we quantified M cells in the Peyer's patch domes, lymphocytes associated with M cells, and the transport rate for experimentally applied microbeads after 3 hours of exposure to R36a. The transport of latex microbeads was significantly increased by +131% in the R36a-treated patches as compared to buffer controls (P < 0.001). While in controls, each M cell was associated with 2.05 +/- 0.64 lymphocytes, a significant increase (+55.1%; P < 0.001) was determined in the R36a-treated patches. However, no statistical difference was detected in the percentage of M cells in the dome epithelia (46.0 +/- 4.6% versus 45.5 +/- 3.8%). It is concluded that bacteria-induced up-regulation of particle transport in Peyer's patch domes is due to an increased transport rate of the M cells, but not to a de novo formation of M cells. The data support the hypothesis that M cells represent a separate cell lineage that does not derive from enterocytes on the domes.

Expression of the IRTA1 receptor identifies intraepithelial and subepithelial marginal zone B cells of the mucosa-associated lymphoid tissue (MALT)

AbstractIRTA1 (immunoglobulin superfamily receptor translocation-associated 1) is a novel surface B-cell receptor related to Fc receptors, inhibitory receptor superfamily (IRS), and cell adhesion molecule (CAM) family members and we mapped for the first time its distribution in human lymphoid tissues, using newly generated specific antibodies. IRTA1 was selectively and consistently expressed by a B-cell population located underneath and within the tonsil epithelium and dome epithelium of Peyer patches (regarded as the anatomic equivalents of marginal zone). Similarly, in mucosa-associated lymphoid tissue (MALT) lymphomas IRTA1 was mainly expressed by tumor cells involved in lympho-epithelial lesions. In contrast, no or a low number of IRTA1+ cells was usually observed in the marginal zone of mesenteric lymph nodes and spleen. Interestingly, monocytoid B cells in reactive lymph nodes were strongly IRTA1+. Tonsil IRTA1+ cells expressed the memory B-cell marker CD27 but not mantle cell-, germinal center-, and plasma cell-associated molecules. Polymerase chain reaction (PCR) analysis of single tonsil IRTA1+ cells showed they represent a mixed B-cell population carrying mostly mutated, but also unmutated, IgV genes. The immunohistochemical finding in the tonsil epithelial areas of aggregates of IRTA1+ B cells closely adjacent to plasma cells surrounding small vessels suggests antigen-triggered in situ proliferation/differentiation of memory IRTA1+ cells into plasma cells. Collectively, these results suggest a role of IRTA1 in the immune function of B cells within epithelia. (Blood. 2003;102: 3684-3692)

Differential characteristics of microfold cells on the dome epithelium of porcine ileum

ABSTRACTThe monospecific antibody directed against cytokeratin 18 consistently immunostained microfold cells (M‐cells) in the ileum epithelium of pigs. In adult pigs, M‐cells were numerously distributed in the dome epithelium overlying Peyer's patches, especially in the crypt epithelium to the lower dome epithelium. The M‐cells presented in the crypt epithelium were mostly columnar in shape and showed a gradual transition from columnar cells to pocket‐like cells as they drew near the lower dome epithelium. In contrast, the M‐cells that were sporadically located in the villus epithelium were all columnar and similar to enterocytes in shape. In newborn pigs, a few M‐cells were observed only in the infant dome epithelium, which were all columnar resembling the enterocytes. Of the 19 lectins used, the dome epithelial cells were selectively stained by lectins from Ulex europaeus‐I and Anguuilla anguilla. Especially, the M‐cells were stained by lectin from Anguuilla anguilla although the intensity varied on individual pigs. Lymphoid follicles in the lamina propria were well developed in the adults compared to these in the newborns, and lymphoid cells were more populated in the lower part than the upper part of the dome. The present results provide available information to understand the differentiation and functional heterogeneity of porcine M‐cells.

Activated STAT4 and a functional role for IL-12 in human Peyer's patches.

T cells in the Peyer's patches (PP) of the human ileum are exposed to a myriad of dietary and bacterial Ags from the gut lumen. Recall proliferative responses to common dietary Ags are readily demonstrable by PP T cells from healthy individuals, and the cytokine response is dominated by IFN-gamma. Consistent with Th1 skewing, PP cells spontaneously secrete IL-12p70, and IL-12p40 protein can be visualized underneath the PP dome epithelium. In this study, we have analyzed IL-12 signaling in PP and investigated whether IL-12 plays a functional role. CD3+ T lymphocytes isolated from PP and adjacent ileal mucosa spontaneously secrete IFN-gamma with negligible IL-4 or IL-5. RNA transcripts for IL-12Rbeta2, the signaling component of the IL-12R, are present in purified CD4+ and CD8+ T PP lymphocytes. Active STAT4, a transcription factor essential for IL-12-mediated Th1 differentiation, is readily detectable in biopsies from PP and ileal mucosa and STAT4-DNA binding activity is demonstrable by EMSA. Nuclear proteins from CD3+ T PP lymphocytes contain STAT4 and T-bet, a transcription factor selectively expressed in Th1 cells. Stimulation of freshly isolated PP cells with staphylococcal enterotoxin B dramatically enhanced the production of IFN-gamma, an effect which was largely inhibited by neutralizing anti-IL-12 Ab. These data show that IL-12 in human PP is likely to be responsible for the Th1-dominated cytokine response of the human mucosal immune system.

Peyer's patches epithelium in the rat: a morphological, immunohistochemical, and morphometrical study.

The epithelial layer covering lymphoid follicles of Peyer's patches consists of cells with a different surface morphology. Some of these cells have been described as a distinct cytotype, the so-called M cells. In order to resolve the controversy on the specific morphological and biochemical markers of M cells, structural, ultrastructural, and morphometrical study of the epithelium covering the rat Peyer's patches were performed. Peyer's patches from healthy rats were processed for light microscopy, immunohistochemistry, in situ nick-end labeling (TUNEL), and scanning and transmission electron microscopy. A morphometric study was also performed to evaluate microvillus density, length, and number of lysosomes in different areas of the epithelium. Peyer's patches were covered by simple columnar/cubical dome epithelium (DE). Scarce goblet cells and a large number of enterocytes were observed. Ultrastructural observations revealed that the DE showed cells with different morphology. The density and length of microvilli and the lysosome number varied along the whole dome without significant differences. The DE cells characterized by short and disorganized microvilli appeared always in close spatial relationship with lymphocytes. In conclusion, the concept that distinct cell types (enterocytes and M cells) can be identified in the rat DE does not appear to be valid based on morphological criteria. It seems correct to consider that in rat Peyer's patches the presence of scarce goblet cells and a large number of enterocytes showing dynamic morphofunctional modifications is related to the functional state and/or to cell cycle.

Carbohydrate expression in the intestinal mucosa.

The understanding of mechanisms responsible for alterations in mucin synthesis and secretions is essential in elucidating the aetiology of intestinal disorders. The existence of distinct mucins and M-cell transport mechanisms, and their beneficial effects, have long been recognised. Since nutritional and bacterial factors alter the mucin characteristics and are relevant to planning preventative strategies for intestinal diseases, the studies described in this monograph were designed to test the hypothesis that mucin composition and endocrine status of the intestinal tract are altered by dietary constituents and microbial flora. A study of gut-associated lymphoid tissue (GALT) was undertaken to test the hypothesis that lymphocyte-epithelial interactions influence the glycosylation of cells overlying Peyer's patches. The effects of diet and microbial flora were analysed by comparing the data from male Wistar germ-free rats, with conventional or human flora. Such rats were fed either a commercial diet, containing crude fibre, or a purified diet. Bone marrow transfers from syngeneic Balb/c mice to severe combined immunodeficient (SCID) mice were made to induce the formation of GALT. A comparison was made of the glycoconjugate profile of Peyer's patches in the guts of mice and humans. The results of the study showed that feeding a fibre-rich diet to germ-free rats resulted in increased villus-crypt lengths, decreased carboxylated mucin content of goblet cells, increased N-acetylglucosamine and sialic acid residues in the surface goblet cells, and a reduction in the number of endocrine cells in the small intestine. The lectin markers revealed M-cell development in the dome epithelium of the reconstituted SCID mice. Mouse M cells were labelled by fucose-specific lectins but in human Peyer's patches no distinct M-cell-staining pattern was observed. (1) the interactions between diet and flora alter the mucosal architecture and the activity of endocrine cells; (2) the dietary changes are influential in modifying the epithelial mucin predominantly in the small intestine while the microbial flora influences the mucosal architecture predominantly in the large intestine; (3) the use of bone marrow transplantation from syngeneic mice into SCID mice along with lectin markers for M cells can be used to study the histogenesis of Peyer's patches; (4) the distinct differences between mouse and human Peyer's patches suggest that when considering cell surface glycoconjugates as target molecules appropriate lectin should be used for each species. A future challenge in intestinal epithelial cell biology is identifying the nature and distribution of cell surface receptors for specific dietary components and bacteria.

Human Peyer's patch T cells are sensitized to dietary antigen and display a Th cell type 1 cytokine profile.

Animal studies have demonstrated that feeding Ags induces regulatory (Th2, Th3) cells in Peyer's patches (PP), which migrate to the periphery and produce immunomodulatory cytokines such as IL-4, IL-10, or TGF-beta. In this work we have attempted to extend this paradigm to man by analyzing the response of human PP T cells to in vitro challenge with the common dietary Ag beta-lactoglobulin (betalg) of cow's milk. PP T cells stimulated with betalg showed enhanced proliferation compared with blood T cells from the same patient. Increased expression of CD25 and the Th1-associated chemokine receptor CCR5 was also seen on CD4(+) and CD8(+) PP T cells, but not blood T cells, stimulated with betalg. By enzyme-linked immunospot assay and RT-PCR, the PP T cell recall response to betalg and casein was dominated by IFN-gamma, with negligible IL-4, IL-5, IL-10, or TGF-beta. To help explain the PP T cell response to betalg, we examined IL-12 expression. Both IL-12p40 and -p35 transcripts were abundantly expressed in PP, but not in adjacent normal ileal mucosa. Immunoreactive IL-12p40-containing cells were present below the PP dome epithelium. Furthermore, in culture, PP, but not paired PBMC, spontaneously released IL-12p70. These results suggest that the human response to oral Ags in the gut may be different from that in rodents.

Uptake and transport of intestinal macromolecules and microorganisms by M cells in Peyer's patches— a personal and historical perspective

Dr Kenzaburo Kumagai identified dome epithelium of in- testinal lymphoid tissues as a site of uptake for mycobacteria in 1922, but he saw this only as a possible initiation point for intestinal tuberculosis and abandoned even that premise as non-specific, after finding that sheep red blood cells were also taken up. When development of ultrastructural tech- niques in 1972 permitted identification of M cells with phagocytic capabilities, harboring migrating lymphoid cells in the specialized epithelium over Peyer's patches, these patches remained anatomic curiosities with no recognized physiologic role. These structural observations of M cells and of intestinal lymphoid tissues stimulated functional, struc- tural and molecular biologic investigations which now pro- vide the basis for many of our current concepts of mucosal immunology and the roles of M cells in initiation of defen- sive immune responses.

The Development of M Cells in Peyer's Patches Is Restricted to Specialized Dome-Associated Crypts

It is controversial whether the membranous (M) cells of the Peyer's patches represent a separate cell line or develop from enterocytes under the influence of lymphocytes on the domes. To answer this question, the crypts that produce the dome epithelial cells were studied and the distribution of M cells over the domes was determined in mice. The Ulex europaeus agglutinin was used to detect M cells in mouse Peyer's patches. Confocal microscopy with lectin-gold labeling on ultrathin sections, scanning electron microscopy, and laminin immuno-histochemistry were combined to characterize the cellular composition and the structure of the dome-associated crypts and the dome epithelium. In addition, the sites of lymphocyte invasion into the dome epithelium were studied after removal of the epithelium using scanning electron microscopy. The domes of Peyer's patches were supplied with epithelial cells that derived from two types of crypt: specialized dome-associated crypts and ordinary crypts differing not only in shape, size, and cellular composition but also in the presence of M cell precursors. When epithelial cells derived from ordinary crypts entered the domes, they formed converging radial strips devoid of M cells. In contrast to the M cells, the sites where lymphocytes invaded the dome epithelium were not arranged in radial strips, but randomly distributed over the domes. M cell development is restricted to specialized dome-associated crypts. Only dome epithelial cells that derive from these specialized crypts differentiate into M cells. It is concluded that M cells represent a separate cell line that is induced in the dome-associated crypts by still unknown, probably diffusible lymphoid factors.

Lectin histochemistry reveals the appearance of M-cells in Peyer's patches of SCID mice after syngeneic normal bone marrow transplantation.

Peyer's patches in the intestinal mucosa are characterized by the presence of several lymphatic follicles and interfollicular T-cell regions. Luminal antigens are transported across the intestinal epithelium to stimulate the Peyer's patch pre-B-cells in the follicles that proliferate and migrate to distant sites. Evidence suggests that antigen priming of B-lymphocytes is responsible for the number and location of Peyer's patches during postnatal life, but little is known about the histogenesis of Peyer's patches and their overlying membranous (M) cells. To examine whether T- and B-lymphocytes in Peyer's patches have an influence on M-cell generation, we studied the development of Peyer's patches and M-cells in severe combined immunodeficient (SCID) mice reconstituted with bone marrow cells from normal syngeneic mice. Our experiments demonstrate that the donor bone marrow cells in the host scid mice repopulate to form single (primary) follicles and aggregates of lymphoid nodules, the Peyer's patches. Use of the lectins Anguilla anguilla (AAA) and Ulex europaeus I (UEA-I) as positive markers of mouse Peyer's patch M-cells revealed that M-cells develop in the dome epithelium overlying the single primary follicles and Peyer's patches of reconstituted scid mice. This experimental system therefore allows the study of the histogenesis of Peyer's patches and M-cells.

The role of M cells in the protection of mucosal membranes.

The mucosa-associated lymphoid tissues continuously take up antigenic matter from the lumen to generate immune responses or to maintain immune tolerance. This antigen sampling is performed by highly specialised epithelial cells, the membranous (M) cells of the dome epithelia. M cells possess a unique ultrastructure and lie in close contact to lymphoid cells. They endocytose soluble and solid substances, including entire microorganisms, at their apical membrane, transport these in vesicles to their basolateral membrane and exocytose them to the intercellular space. This review summarises the structural and functional peculiarities of M cells in different species and at the different sites of lymphoid tissue along the digestive and respiratory tracts. Specialisations of M cells for antigen uptake and transport comprise the composition of their apical membrane and its glycocalyx, a modified cytoskeleton as compared to enterocytes and a pocket-like invagination of the basolateral membrane populated by lymphocytes and macrophages. Besides ultrastructural characteristics, histochemical markers are listed that are currently available for detecting M cells by light microscopy. The origin, differentiation and distribution of M cells and other epithelial cell types of the dome epithelium are outlined. As M cells are used as entry sites by various pathogens and, in the future, might be employed for the oral application of vaccines and drugs, the clinical relevance of M cells in health and disease is discussed.