The human glands of Moll are specialized apocrine glands located at the margin of the eyelids (Vaughan and Asbury, 1980;Fawcett, 1994).Ikeda (1953) analyzed the glands of Moll in humans and other mammalian species quantitatively and could show that in human eyelids the glands of Moll are found all along the rim of the upper and lower eyelid with a small increase in number in the middle part of the upper eyelid and in the lateral region of the lower lid. Comparing the number of glands in humans to that of other mammalian species (e.g., pig, cow, horse, dog), Ikeda found that the glands of Moll are relatively rare in humans and an unidentified monkey species. An early and detailed morphologic description of these specialized glands was provided bySattler (1877), whereasKölliker (1850) and Moll (1857) were the first to mention "sweat glands with a duct that runs into a hair follicle" (Kölliker) and "a strange form of sweat glands at this position of the body" (Moll). Histologically, the glands of Moll closely resemble other apocrine glands. An apocrine glandular unit is composed of two parts: a proximal coiled glandular (secretory) portion and a duct portion, the main part of which runs straight through the dermis. Apocrine glandular cells are characterized in the active state as tall cells showing apical protrusions that are pinched off as blebs in the lumen. Inactive glandular cells are flat without protrusions (Montagna et al, 1992). The terms active and inactive are usually based on morphologic criteria (Schaffer, 1940), which, however, can be correlated with functional criteria (Welsch et al, 1998). In general, apocrine glands begin to function at puberty in apocrine areas of the body – the axilla, external female genitalia, inguinal, perianal, periumbilical, and periareolar regions, and, rarely, face, scalp, and breast. Apocrine glands in unusual locations are the glands of Moll of the eyelids and the ceruminous glands in the external ear canal. Interestingly, apocrine glandular cells in the ear canal already contain secretory granules within their cytoplasm in the fetus (Requena et al, 1998).Sattler (1877) found that the glands of Moll are fully developed in infants.
What is the function of these glands in the eyelid? Does their secretory product form part of the tear film? This film comprises three layers: the superficial lipid layer produced by the sebaceous glands of Meibom and Zeis, the middle aqueous layer derived from the major lacrimal glands and the accessory lacrimal glands of Krause and Wolfring, and the inner mucinous layer predominantly from the goblet cells of the conjunctiva (Argueso and Gipson, 2001). So far, a contribution to the tear film from the glands of Moll and from the surface epithelium is not mentionend in the literature.
The nature and function of the secretions of the glands of Moll is unknown (Fawcett, 1994). More attention has been paid to their involvement in pathologic conditions, and there are a number of tumors and apocrine gland cysts (apocrine hidrocystomas) (Combemale et al, 1997) derived from the gland of Moll. Examples of the eyelid tumors of apocrine origin are papillary oncocytoma (Rodgers et al, 1988), papillary cystadenoma (Sacks et al, 1987), signet ring carcinoma (Jakobiec et al, 1983), and syringocystadenoma papilliferum (Jakobiec et al, 1981). Because of the significance of these glands in pathology we have tried to characterize the secretory components (SC) of the apocrine glandular cells in the human eyelid by histochemical and immunohistochemical means to determine the probable physiologic function of this specialized gland.
Materials and methods
Tissue and patients
We obtained human eyelids from eight persons, five males and three females (age of the patients 60, 67, 69, 72, 77, 81, 87 y). In accordance with The Helsinki Principles, all patients have been consulted in respect of our intention to study the human glands of Moll. All patients have agreed that the excised parts of their eyelids can be used for the scientific investigation on the glands of Moll. In one case an upper and lower lid was obtained from a cadaver (75 y old) and removed about 4 h after death. All other material derived from surgical procedures for ectropion (six cases) or for basal cell carcinoma (one case). In these only tissue from the lower eyelid was available. Tissue from surgical procedures was fixed immediately, either in buffered formalin for light microscopy or in 3.5% phosphate-buffered glutaraldehyde (pH 7.2) for transmission electron microscopy. The latter was stored after 2 h in 1% glutaraldehyde in the same buffer.
Light microscopy
Five-micron serial paraffin sections were stained by the following techniques, all according toRomeis (1989): hematoxylin and eosin (HE), Masson's trichrome stain, Azan stain, the periodic acid Schiff (PAS) procedure for neutral carbohydrates, Alcian blue at pH 2.5 for polyanions, Nile-blue sulfate for various lipids and lipofuscin. Specific carbohydrate components were detected by the lectins Helix pomatia agglutinin (HPA), peanut agglutinin (PNA), wheat germ agglutinin (WGA), Ulex europaeus agglutinin I (UEAI), Ricinus communis agglutinin I (RCAI), and Canavalia ensiformis agglutinin (ConA); sugar specificities are listed in Table I. The biotinylated lectins (purchased from Sigma, Deisenhofen, Germany) were applied to the tissue sections, followed by peroxidase-conjugated streptavidin, and then 2,3-diaminobenzidine. Immunohistochemical staining for lysozyme, SC and IgA, actin and cytokeratins, and estrogen and androgen receptors was performed according to the avidin-biotin horseradish peroxidase complex method using the Histostain Plus Kit from Zymed (Carlton Court, San Francisco, CA). The primary antibodies were diluted and handled as follows: antilysozyme (DAKO, Hamburg, Germany) 1:1000, pretreatment microwave irradiation; antiSC (DAKO) 1:200, preincubation 0.2% trypsin at 37°C; anti-IgA (DAKO) 1:10, preincubation 0.2% trypsin at 37°C; antiMUC1 (Abcam, Cambridge, UK) 1:100, pretreatment microwave irradiation; antiactin (ICN, Eschwege, Germany), directed towards all six known vertebrate isoactins, 1:800, no preincubation; anti-CK19 (DAKO) 1:100, preincubation 0.2% trypsin at 37°C; anti-CK7 (DAKO) 1:100, preincubation 0.2% trypsin at 37°C; anti estrogen and androgen receptor (DAKO) 1:50, pretreatment microwave irradiation. Controls, in which the primary antibody was replaced by buffer, were treated identically.
Electron microscopy
Material from four persons (two females and two males) was embedded in Araldite. Prior to embedding the samples were postfixed in 2% osmium tetroxide. Thin sections were stained with uranyl acetate (saturated solution in 70% methanol) and lead citrate and analyzed in a Philips CM 10 electron microscope.
Results
General morphologic observations
In the human eyelid the tubular glands of Moll were located near the lash follicles within the margins of the lids (Figure 1a). Proximal portions of the glands were partially embedded in muscle tissue of the palpebral part of the orbicular ocular muscle. The number of glandular profiles comprised about one (rarely) to 20 per section. The secretory part of the glands of Moll consisted of a layer of glandular cells and basally located myoepithelial cells. The height of the glandular cells varied considerably in correlation with the assumed secretory status (see above). We found glandular profiles with very flat cells, others with cuboidal cells, and again others with tall prismatic cells, the latter representing the active form of the gland (Figure 1b, c). Many of these prismatic cells formed an apical protrusion. The lumen of the tubule was wide and might contain homogeneous pinched-off blebs, which were derived from the apex of the glandular cells. The ducts of the apocrine glands were lined by two layers of cuboidal cells and were connected with hair follicles. We could not find differences in structure or number between males and females. In one case we were able to obtain the upper and lower eyelid and analyzed the medial, middle, and lateral part of the lid. We did not analyze this tissue quantitatively, but we found similar numbers of the glands of Moll in all parts of the lids.
Figure 1.
Light micrographs of the human gland of Moll. (a) Low-power magnification of a human eyelid with glands of Moll (arrowheads) located at an eyelash (L); note the orbicularis oculi muscle (O) and the Meibomian gland (M) embedded in the tarsus. Azan stain. Scale bar: 400 
m. (b) Active apocrine gland with tall apical cell protrusions (arrowheads) and glandular blebs in the lumen. The active glandular tubule borders an inactive gland with flat glandular cells (arrows). HE stain. Scale bar: 40 m. (c) Higher magnification of an active gland of Moll demonstrating the pinching-off mechanism; arrowheads, nucleus of myoepithelial cell. HE stain. Scale bar: 10 m.
Under the electron microscope, active apocrine glandular cells exhibited tall apical protrusions with loosely distributed microvilli at the apical membrane. Cells that appeared to pinch off the apical protrusion according to the apocrine secretion mode had no microvilli at their apical membrane. The apical protrusion could be 12 m high and contained, if well developed, few organelles and granules (Figure 2a, b, e). Shortly before being pinched off usually no organelles were to be found in the protrusion. The lateral membrane formed numerous narrow interdigitating folds (Figure 2c). The cellular apices were interconnected by tight and intermediate junctions as well as by desmosomes. In the cytoplasm of glandular cells the most striking structures were irregularly shaped granules with components of different electron density. These membrane-bound granular structures were mainly supranuclear and consisted of highly electron-dense material, medium-dense fine-particulate matter, and lucent lipidic material (Figure 2f). These granules are interpreted to represent lipofuscin granules, i.e., lysosomal residual bodies. In addition, secretory granules that were electron dense and variable were visible in the cytoplasm (Figure 2e). Abundant mitochondria were detected throughout the cytoplasm (Figure 2d). Furthermore the cytoplasm contained well-developed rough and smooth endoplasmatic reticulum and the Golgi apparatus was of medium dimensions. Myoepithelial cells occasionally contained heteromorphic lipofuscin granules.
Figure 2.
Electron micrographs of the human gland of Moll. (a) Tall active glandular cells. Scale bar: 10 m. (b) Several irregularly shaped granules in the supranuclear cytoplasm (arrowheads). Scale bar: 10 m. (c) Relatively inactive cuboidal glandular cells; note the repeated foldings of the lateral membrane (arrowheads). Scale bar: 100 nm. (d) Glandular cells with abundant mitochondria (arrowheads). Scale bar: 10 m. (e) Secretory granules (arrows) and irregularly shaped granules (arrowheads) in the cytoplasm. Scale bar: 1 m. (f) Higher magnification of irregularly shaped granules (residual bodies) composed of highly electron-dense, medium-dense, and lucent lipidic components. Scale bar: 1 m.
IgA
The IgA staining was variable. Some glandular cells exhibited abundant IgA-positive granular structures in the cytoplasm (Figure 3a), whereas the cytoplasm of other cells remained unstained. Other cells showed only an apical staining of the cell and several glandular tubules contained IgA-positive material in the lumen of the gland. Positive staining of cells in the connective tissue around the glandular tubules was not observed.
Figure 3.
Defensive proteins of the human gland of Moll. (a) IgA-positive granular structures in apocrine glandular cells. (b) Antilysozyme immunoreactivity in granules (arrows) of the glandular cells. (c) Low magnification of immunostaining with antiSC demonstrating the positive reaction of the material in the lumen and the apical part of the cells. (d) AntiMUC1 is located predominantly in the upper part of the cell and in the protrusions. (e) AntiMUC1 shows a variable staining pattern in the cytoplasm with more intensive stained cells (arrows) next to weakly stained cells. Scale bars: 20 m.
SC
The SC of IgA was expressed with medium to strong intensity in the cytoplasm and with strong intensity in the apical region of the cell (Figure 3c). Also the secretory product in the lumen was strongly stained.
Lysozyme
The lysozyme staining pattern was variable. Often this protein was expressed in distinct granules in the cytoplasm (Figure 3b). In some glandular cells a narrow apical zone of the cell was stained, and the material in the lumen of several glands reacted positively.
Mucin 1 (MUC1)
This membrane-associated mucin was stained in active glandular cells with weak to medium intensity in the cytoplasm and with strong intensity at the apical membrane of the cells (Figure 3d). MUC1-positive material (pinched-off apical protrusions and irregularly shaped floccular structures) was often found also in the glandular lumen. Sporadically, the staining pattern of the cytoplasm was variable with stronger stained cells located next to cells with weaker staining intensity (Figure 3e). Sometimes the Golgi apparatus was marked. Also in inactive glandular cells the antibody bound strongly to the apical part of the cell.
Androgen receptor
In our material, only in few epithelial cells was a positive nuclear reaction for the androgen receptor found. This is in remarkable contrast to the axillary apocrine glands, in which the vast majority of nuclei are androgen-receptor positive (own observations).
Estrogen receptor
The glands of Moll exhibited no nuclear reaction with the antibody to the estrogen receptor.
Nile-blue
In active glandular cells supranuclear granules were stained (Figure 4a). But also in inactive glands some positive granules could be found.
Figure 4.
Lipid and carbohydrate histochemistry of the human gland of Moll. (a) Nile-blue-positive staining in active glandular cells marking lysosomes (arrows). (b) ConA strongly marked the apical part of the cells and positive granules in the cytoplasm. (c), (d) HPA (c) and RCAI (d) show a similar staining pattern: strong staining of the supranuclear region (Golgi apparatus, arrows) and of the apical membrane of the glandular cells. (e) Also WGA bound strongly to the tall protrusions of the cells. Scale bars: 20 m.
PAS reaction
Generally, the glandular cells stained weakly or negatively with PAS. A strong reaction, however, was seen in single supranuclear granules and in the homogeneous material inside the lumen, and also in the protrusions of active glandular cells. In inactive glandular cells the apical part of the cells was intensively stained.
Alcian blue (pH 2.5)
Alcian blue stained the apical part of inactive glandular cells strongly. Several protrusions of active glandular cells and the material in the lumen also stained strongly, whereas in the rest of the cytoplasm no or very weak staining was observed.
ConA
The cytoplasm gave a weak to medium stain. Not infrequently, ConA-positive granules were detected in the cytoplasm. The apical part of the glandular cells and the intraluminal material stained strongly (Figure 4b).
HPA
The entire glandular cell was stained with HPA in medium intensity. The apical part of the cell and the material in the lumen gave a stronger stain. Consistently, in the supranuclear region HPA-positive granules were found; also the Golgi apparatus reacted positively (Figure 4c).
RCAI
A negative to weak reaction was observed in the cytoplasm. The apical part of the cell and the secretory material in the lumen as well as distinct supranuclear granules stained strongly (Figure 4d).
WGA
This lectin bound with strong intensity to the apical part of active (Figure 4e) and inactive glandular cells and to the secretory product of the lumen. In some cells a positve reaction could be observed in supranuclear granules in the cytoplasm.
PNA
The PNA staining was variable with often negative or weak but occasionally also medium staining intensity of the cytoplasm. All cells showed a strong apical PNA reaction and a positive reaction of the material in the lumen.
UEAI
A rather intensive UEAI-positive staining could be detected in the apical part of some glandular cells and in the luminal material. Otherwise, the cytoplasm stained with weak to medium intensity. Inactive glandular cells often showed no UEAI binding.
Actin
Both the active and inactive glandular cells showed a medium or strong staining with the antiactin antibody. In inactive glandular cells the reaction is homogeneous throughout the cytoplasm. In medium-active cells the staining was stronger in the apical part of the cell than in the basal part. In highly active glandular cells the basis of the apical protrusions was marked (Figure 5a). Here a peripheral ring or plate of actin could be detected in several cells; the protrusion itself remained unstained. The myoepithelial cells stained strongly.Table II
Figure 5.
Immunohistory of the cytoskeleton of the human gland of Moll. (a) Antiactin immunoreactivity marking intensively a zone at the base of the apical protrusion (arrowheads). (b) CK19 is present in the entire glandular cells with a strong apical staining. (c), (d) CK7 is expressed either weakly and irregularly in relatively inactive glandular cells (c) or strongly in active cells (d) with no staining in the pinching-off protrusions. Scale bars: 20 m.
CK19/CK7
Glandular cells expressed these two proteins in the same manner. The staining pattern was weak to strong over the entire cytoplasm (Figure 5b, c). Often the zone between the nucleus and the base of the apical protrusion reacted more strongly than the basal part of the cell (Figure 5d). The apical protrusions, however, were never stained.
All histochemical and immunohistochemical results are summarized in Table I and Table III.
Table III - Staining results of cytoskeletal components in the gland of Moll of the human eyelid.
Full table Discussion
Secretory products
There are few published observations on the Secretory products of the glands of Moll, so that the function of these glands is still unclear. The positive reactions for SC (Fukuo et al, 1994, and this study), IgA, MUC1, and lysozyme in the glandular cells suggest an important function of the gland of Moll in immune defense. SC and IgA are components of the aquired immune system, whereas MUC1 and lysozyme are components of the innate immune defense system. Both components support the protection of the conjunctiva, cornea, and the eyelid shaft from harmful pathogens, e.g., bacteria. Whereas SC is synthesized in epithelial cells (Brown et al, 1976), IgA is produced in plasma cells and is transported by endocytosis across the glandular cells into the lumen of the gland and hence transferred to the secretion product (Tomasi and Grey, 1972). Lysozyme is a ubiquitous component of fluids and secretions in the human body, an enzyme cleaving mucopolysaccharides and mucopeptides for instance in bacterial cell walls (Mason and Taylor, 1975). The MUC1 is a transmembrane protein that was detected in the corneal and conjunctival epithelia (Inatomi et al, 1995), but also in a series of other organs, e.g., mammary gland, salivary gland, stomach, pancreas, lung, kidney, bladder, uterus, testis (Patton et al, 1995). MUC1 plays a role in preventing adhesion of pathogenic microorganisms because of its long, highly glycosylated extracellular projections that tend to impede the close approach of other cells and large particles (Patton et al, 1995). This may be relevant to the occurrence of blepharitis. As a further function it was shown that MUC1 of the milk fat globule membrane in human milk inhibits binding of S-fimbriated Escherichia coli to buccal epithelial cells by binding to the microorganisms and thus inhibiting their adherence (Peterson et al, 1998) and replication (Patton, 1999). We assume that the function of MUC1 in the eye could be similar. First it protects the glandular cell itself from microbial infections, and second it could bind pathogens in the glandular lumen, in which MUC1-positive material was regularly found. This could happen either via the apocrine mechanism by which the apical membrane with this mucin is pinched off or by a shedding process from the apical membrane (Gendler, 2001). In bovine milk it was shown that MUC1, for still unkown reasons, is unstable and dissociates readily from the membranes of secreted milk fat globules (Patton, 1999). Thereby, it may establish a defense barrier against pathogens in the glandular ducts, the eyelash shaft, and at the ocular surface. We suggest that the mucin production of the glands of Moll supplements the mucins of other epithelia at the surface of the anterior eye, such as those of the goblet cells (MUC5AC), the corneal and conjunctival epithelial cells (MUC1, MUC2, MUC4), and the lacrimal glandular cells (MUC7) (Gipson and Inatomi, 1997;Watanabe, 2002). Binding of the lectins HPA, RCAI, WGA, UEAI, and ConA corresponds to the location of MUC1 and may – at least in part – reflect individual glycocomponents of this mucin. Positive Alcian blue staining points to negatively charged glycoconjugates, which are presumably also located in MUC1. These ultrastructural observations on the secretory epithelium of the glands of Moll suggest considerable capacity of transepithelial ion and fluid transport. This assumption is based on well-developed lateral interdigitations and fair amounts of mitochondria. These features are characterized for fluid transport and can be found in the majority of cutaneous glands, too (Stoeckelhuber et al, 2000). The significance of the Nile-blue-positive lipofuscin granules in the cytoplasm of the glandular epithelial cells remains unclear. Such cytoplasmic bodies are characteristic for long-lived cell populations. They possibly indicate a high turnover of membrane material or other cellular components in the glands of Moll, which arise in correlation with the apocrine secretory mechanism.
An apocrine secretory profile
A number of features suggest that the glands of Moll possess – besides an exocrine secretory mechanism, which involves secretory granules – also an apocrine mode of secretion. Marked differences in cell height and the formation of tall apical protrusions devoid of cell organelles, secretory granules, and microvilli represent typical features of an apocrine secretory cell (Montagna et al, 1992). The mechanism of apocrine secretion was analyzed in this study with regard to the cytoskeletal components possibly involved in a pinching-off mechanism of the glandular blebs. Actin was expressed in a variable pattern. In inactive glandular cells, the basal cytoplasm was stained with medium intensity whereas the apical part of the cell stained strongly. Active glandular cells exhibit a strong actin stain in the middle of the cell between the nucleus and the tall protrusion. The staining pattern for CK19 and CK7 is similar but not identical to that of actin. Some cells express cytokeratins more strongly than others; the actin stain is more homogeneous. Tall apical protrusions that – as we assume – are not yet in the status of being pinched off are strongly marked. In glandular cells, however, in which the apical protrusions are very elongated and shortly before the assumed decapitation, the apex is totally unstained. We think that actin filaments are a decisive component in the process of decapitation of blebs and that the cytokeratins play temporarily a stabilizing role. Actin filaments are thought to form a ring or a sheet necessary for the contractile mechanism whereas a matrix of CK19 and CK7 provides a stabilizing framework. The apical enrichment of actin and to some extent cytokeratins in inactive cells seems to be the expression of filament reorganization.
Evolutionary aspects
Apocrine glands are normally known as scent glands and play an important role in olfactory communication between animals (Sliwa and Richardson, 1998) and primarily also in humans. Our observations, however, do not strongly suggest that the glands of Moll have this function. The fluid secretion of typical human apocrine scent glands is both sterile and odorless when it appears on the surface of the skin (Shelley et al, 1953). Only the aerobic diphtheroid bacteria of those bacteria found among the axillary flora are able to produce the typical (mal)odor of human sweat (Leyden et al, 1981). Although these bacteria are also present on the eyelid, it is not plausible that the secretory product is a substrate for bacteria in this sensible area of the body to produce an olfactory signal. We suspect that there are two different pathways of the apocrine gland evolution. One kind of apocrine glands is destined to have a function in reproduction and sexual behavior. These glands, as for example the apocrine axillary glands, do not develop until puberty, are active only in adults, and become atrophic in old age (Montagna et al, 1992). We know that the ceruminous glands in the ear canal contain secretory granules in their cytoplasm already in the fetal stage (Requena et al, 1998). Similar observations of the gland of Moll were made bySattler (1877). He observed the glands to be fully developed in infants. These apocrine cells obviously underwent a specific functional development. Apocrine cells in the eyelid secrete mainly substances that play a role in the defense against microorganisms and are active from birth. This was supported by our observation that the antibody reaction for androgen receptor (and estrogen receptor) is largely negative, whereas in the axillary apocrine sweat glands it is positive in the glandular cell nuclei; here, the estrogen receptor is negative, too (Choudhry et al, 1992;de Diaz Leon et al, 2000). So, these glands in the eyelid seem to function without steroid hormone stimuli.
In conclusion, we speculate that one important function of the glands of Moll is the defense against bacteria and other pathogens in the eyelid shaft and on the ocular surface.
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Acknowledgments
This study was supported by a grant from the Friedrich-Baur-Stiftung in Munich. The authors thank Dr E. Messmer (Augenklinik, Ludwig-Maximilians-Universität München), PD Dr Dr Ch. Schubert (Praxis für Hautkrankheiten, Buchholz), Prof. R. Winter (Augenklinik, Medizinische Hochschule Hannover), and M. Becker (Department of Anatomy, LMU-Munich) for providing eyelid tissue. We are particularly grateful to Sabine Herzmann, Claudia Köhler, Astrid Sulz, and Sabine Tost for excellent technical assistance. We thank Pia Unterberger for support in digitization of the images.
