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. 2005 Jan;206(1):37–45. doi: 10.1111/j.0021-8782.2005.00363.x

An immunohistochemical study of the extracellular matrix of the tarsal plate in the upper eyelid in human beings

Stefan Milz 1, Joerg Neufang 1, Ichiro Higashiyama 2, Reinhard Putz 1, Michael Benjamin 2
PMCID: PMC1571450  PMID: 15679869

Abstract

The superior tarsus is a plate of tissue that stiffens the upper eyelid, gives it support and determines its form. The purpose of the present study was to relate the composition of its extracellular matrix to its function and to report regional differences that may influence the activity of its Meibomian glands. Fourteen methanol-fixed specimens were cryosectioned for immunohistochemistry and labelled with a panel of monoclonal antibodies against a wide range of collagens, glycosaminoglycans and proteoglycans. Labelling was detected with avidin–biotin–peroxidase. A further six specimens were formalin-fixed for routine histology. The tarsal plate immunolabelled strongly for types I, III and VI collagen and for aggrecan, versican, tenascin, cartilage oligomeric matrix protein (COMP) together with a variety of glycosaminoglycans (notably chondroitin 6 sulphate). A region of strong labelling for aggrecan, dermatan sulphate and chondroitin 6 sulphate immediately surrounded the Meibomian glands. The site of labelling corresponded to a layer of acellular and amorphous matrix seen histologically that we have termed the ‘territorial matrix’. The results suggested that the tarsal plate is a specialized connective tissue that is neither purely fibrous nor cartilaginous, yet has an aggrecan content that probably contributes to its stiffness. Its unique character highlights the challenge in choosing an ideal mechanical substitute. As patients with rheumatoid arthritis often have problems relating to tear film deficiency, the ability of aggrecan or COMP to act as autoantigens may be significant. An immune reaction directed against these molecules could alter tarsal gland function by interfering with the interaction between the glands and their territorial matrix.

Keywords: aggrecan, autoimmune response, extracellular matrix, glycosaminoglycans, proteoglycans, Meibomian glands

Introduction

The superior tarsus is a plate of tissue that stiffens the upper eyelid, gives it support and determines its form (Williams et al. 1995). Its curved shape enables it to maintain close contact with the globe during fast blinking movements. Embedded within the plate are the Meibomian (tarsal) glands. These produce an oily secretion that spreads as a surfactant over the globe and contributes to an aqueous barrier that remains functional after blinking (McCulley & Shine, 2004). The secretion reduces evaporation by adding a hydrophobic layer to the surface of the tear film (Williams et al. 1995; Lozato et al. 2001). It thus follows that any alteration in tarsal gland secretion will change the composition of the film and this could lead to a variety of symptoms including dry eye, keratonconjunctivitis sicca and even corneal ulcerations (Shimazaki et al. 1998; Jain et al. 2001). In exocrine glands elsewhere in the body, the connective tissue stroma around the glandular epithelium can modulate the activity of the secretory cells and changes in stromal composition can even be associated with disease (Bissell, 1998; Hagios et al. 1998; Goicovich et al. 2003). It is thus of interest to establish the character of the extracellular matrix (ECM) of the tarsal plate and in particular the ECM that immediately surrounds the Meibomian glands. We have subsequently referred to this ECM as the ‘territorial matrix’.

The composition of the ECM also determines the physical properties of the tarsal plate. These properties are an important surgical consideration in reconstructing the upper eyelids of patients with tarsal deficiencies (Jordan et al. 1990; Jordan & Anderson, 1997; Yaqub & Leatherbarrow, 1997; Mullner & Langmann, 1999; Kamiya & Kitajima, 2003). The substitute tissue needs to have a similar consistency to the tarsal plate itself and be grafted together with a mucosa that can functionally replace the conjunctiva and its underlying lamina propria. A mechanically stable, superior tarsus is also essential for the insertion of levator palpebrae superioris (Landolt, 1985). Among the graft tissues that have been most frequently used are various forms of cartilage – notably from the ear and nasal septum (Jordan et al. 1990; Kamiya & Kitajima, 2003). Mucoperiosteum from the hard palate and aortic wall tissue have also been used (Jordan & Anderson, 1997) and a material called ‘chondroplast’ that is prepared from irradiated bovine cartilage (Mullner & Langmann, 1999). According to Ito et al. (2001), ear cartilage is too stiff, but fascia lata is not stiff enough. Yet the latter is a dense fibrous connective tissue – and this is also how the tarsal plate is commonly classified in modern anatomy texts (Williams et al. 1995). It is of interest, however, that there are several statements in the older histological literature that the plate is ‘cartilage-like’, ‘fibrocartilaginous’ or that the eyelid contains ‘lid cartilage’ (Böhm & von Davidoff, 1895; Szymonowicz, 1924; Wallraff, 1960). Such descriptions seem to be largely based on the mechanical properties of the tissue.

The purpose of the present study is to promote a better understanding of the physical characteristics of the superior tarsal plate and its local association with the Meibomian glands. We have done this by analysing the immunohistochemical composition of the plate ECM. In order to define the tissue more accurately than hitherto, we have employed a panel of monoclonal antibodies directed against ECM components typical of dense fibrous connective tissue and/or cartilage.

Materials and methods

Immunohistochemistry

The tarsal plate of 14 individuals (both sexes; mean age 78 years, range 55–87 years) was removed from right or left upper eyelids from bodies donated to the Department of Anatomy at the University of Munich. The plate was dissected out from an incision made at the edge of the eyelid. Only eyelids without any macroscopically detectable pathology were chosen. Tissue samples were fixed for at least 3 days in 90% methanol at 4 °C. The tissue was then infiltrated with 5% sucrose in phosphate-buffered saline (PBS) for 12 h and cryosectioned at 12 µm on an HM 500 OMV Microm cryostat. Sections were immunolabelled with a panel of monoclonal antibodies directed against collagens (types I, II, III and VI), glycosaminoglycans (chondroitin 4 and 6 sulphates, dermatan and keratan sulphates), proteoglycans (aggrecan, link protein, tenascin and versican) and other molecules (cartilage oligomeric matrix protein – COMP). Full details of the antibodies are given in Table 1, together with pretreatment procedures. The activity of endogenous peroxidase was blocked with 0.3% hydrogen peroxide in methanol, any non-specific binding of the secondary antibody was reduced by incubating the sections with appropriate horse serum block and all sections were counterstained with Mayer's haematoxylin. Antibody binding was detected with a Vectastain ABC ‘Elite’ avidin–biotin–peroxidase kit (Vector Laboratories, Burlingame, CA, USA) and control sections were obtained by omitting the primary antibody. All control sections were unlabelled (see Fig. 2o).

Table 1.

List of monoclonal antibodies used, together with their dilutions, pretreatments and sources

Antigen Antibody Pretreatment Source Reference
Collagen I Col 1 Hyal. (1.5 U mL−1) Sigma Mayne (1988)
(1: 2000) Ch. ABC (0.25 U mL−1)
Collagen II CIICI Hyal. (1.5 U mL−1) DSHB Holmdahl et al. (1986)
(1 : 6) Ch. ABC (0.25 U mL−1)
Collagen III FH-7 A Hyal. (1.5 U mL−1) Sigma Olsen & Ninomiya (1993)
(1 : 4000) Ch. ABC (0.25 U mL−1)
Collagen VI 5C6 Hyal. (1.5 U mL−1) DSHB Hessle & Engvall (1984)
(1 : 10) Ch. ABC (0.25 U mL−1)
Dermatan-sulphate 2B6 Ch. ABC B. Caterson Caterson et al. (1985)
(1 : 1500) (0.25 U mL−1)
Chondroitin-4-sulphate 2B6 Ch. ACII B. Caterson Caterson et al. (1985)
(1 : 1500) (0.25 U mL−1)
Chondroitin-6-sulphate 3B3 Ch. ABC B. Caterson Caterson et al. (1985)
(1 : 150) (0.25 U mL−1)
Chondroitin-6-sulphate (native) 3B3 PBS B. Caterson Caterson et al. (1990)
(1 : 150)
Chondroitin-6-sulphate (oversulphated) 7D4 PBS B. Caterson Caterson et al. (1985)
(1 : 350)
Keratan-sulphate 5D4 PBS B. Caterson Caterson et al. (1983)
(1 : 1500)
Aggrecan 12/21/1C6 Reduction & alkylation B. Caterson Calabro et al. (1992)
(1 : 5) Ch. ACII (0.25 U mL−1)
Link protein 9/30/8A4 Reduction & alkylation B. Caterson Calabro et al. (1992)
(1 : 5) Ch. ACII (0.25 U mL−1)
Versican 12C5 Ch. ACII (0.25 U mL−1) DSHB Asher et al. (1991), (1995)
(1 : 5)
Tenascin T2H5 Ch. ACII (0.25 U mL−1) Serotec Verstraeten et al. (1992)
(1 : 100)
Cartilage oligometric matrix protein Comp PBS Serotec none
(1 : 20)
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All the antibodies are mouse monoclonals, except for COMP, which is a rat monoclonal. DSHB, developmental studies hybridoma bank; Ch ACII, chondroitinase ACII (Sigma); Ch ABC, chondroitinase ABC (Sigma); Hyal, hyaluronidase (Sigma); reduction and alkylation are according to the scheme described in Milz et al. (2002).

Fig. 2.

Fig. 2

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Immunohistochemical labelling patterns of the tarsal plate (TP). (a) Uniform labelling for type I collagen in the ECM in both the tarsal plate and the underlying lamina propria (L). Scale bar, 100 µm. (b) No labelling for collagen II was detected in the tarsal plate. The region illustrated here is between Meibomian glands – corresponding approximately to the position of the label ‘TP’ in Fig. 1(a). Scale bar, 50 µm. (c) Type III collagen labelling was less strong than type I, but labelling was again uniformly distributed both in the ECM of the tarsal plate (illustrated here) and in the lamina propria beneath the conjunctival epithelium (not illustrated). Scale bar, 50 µm. (d,e) Chondroitin 4 sulphate labelling clearly distinguished between the tarsal plate and the surrounding connective tissue, both near the attached end of the plate (d) and near the free margin of the eyelid (e). Scale bars, 300 µm. (f) Keratan sulphate was present throughout the ECM of the tarsal plate and the surrounding lamina propria (L). Scale bar, 100 µm. (g) Strong labelling for dermatan sulphate was present not only in the plate, but also in the lamina propria. Scale bar, 100 µm. (h) Chondroitin 6 sulphate labelling was found both in the ECM of the plate and in the peripheral parts of the Meibomian glands (MG). Scale bar, 50 µm. (i) Weak labelling for the native epitope of chondroitin 6 sulphate was present in the ECM of the tarsal plate. However, the territorial matrix of the glands was unlabelled (*). Note that labelling was strongest in the peripheral part of the glands themselves (arrows). Scale bar, 50 µm. (j) Labelling for the oversulphated epitope (7D4) was strongest in the region of the glands (arrows). Scale bar, 200 µm. (k) Labelling for aggrecan was present throughout the ECM of the plate and the lamina propria. Scale bar, 200 µm. (l) Streaky labelling for versican both in the central part of the plate (TP) near the Meibomian glands (MG) and in the lamina propria (L). Note that the peripheral part of the plate was unlabelled (arrows). Scale bar, 100 µm. (m) Tenascin labelling in the tarsal plate and the lamina propria (L). Note that labelling was strong in the peripheral part of the tarsal plate (arrows) in the region where versican labelling is weak (compare with l). Labelling was more patchy around the Meibomian glands (MG). Scale bar, 100 µm. (n) Uniform labelling for cartilage oligomeric protein (COMP) in the ECM of the tarsal plate and the lamina propria (L). Only the epithelial cells of the conjunctiva and the Meibomian glands remain unlabelled. Scale bar, 100 µm. (o) Control section (PBS alone) showing a lack of labelling in both the glands and the tarsal plate itself. Note that the nuclei have been stained with haematoxylin. Scale bar, 50 µm.

Histology

In order to provide an adequate structural context for the immunohistochemical data, the middle third of one upper eyelid (right or left) was removed from each of six cadavers donated to Cardiff University for Anatomical investigation (both sexes; mean age 84 years, range 75–93 years). The cadavers had been perfused with a fixative containing formaldehyde and alcohol (for details see Rufai et al. 1995). None of the eyelids showed any macroscopic evidence of pathology. All tissue was post-fixed for 1 week in 10% neutral buffered formal saline, dehydrated with graded alcohols, cleared in xylene and embedded in paraffin wax. After histological processing, serial sagittal sections of each eyelid were cut at 8 µm. Two sections were mounted on each of 50 slides at two sample points that were at least 2 mm apart in the central region of the block and stained with Masson's trichrome, alcian blue (pH 2.5), Weigert's elastic stain or toluidine blue.

Results

The upper tarsus is a curved plate of tissue that contains numerous Meibomian glands (Fig. 1a–c). Superiorly, it ends relatively abruptly in a region in which accessory lacrimal glands are present (Fig. 1a,c), but near the free margin of the eyelid it becomes less distinct and expands to surround the Meibomian gland ducts, eyelashes and glands of Moll (Fig. 1a,d). Histologically, it can be classified as a dense fibrous connective tissue that contains numerous collagen fibres, together with sparsely distributed fibroblasts and a number of small blood vessels (Fig. 1e). However, immediately around some of the Meibomian glands, there is a layer of amorphous and acellular, territorial matrix (Fig. 1f). Although elastic fibres were present throughout the tarsal plate, they were especially conspicuous around the main ducts of the Meibomian glands and around some of the glands themselves (Fig. 1g). Only slight metachromasia was detected in the superior tarsal plate with toluidine blue (near the Meibomian glands – not illustrated), and the plate stained strongly and uniformly with alcian blue.

Fig. 1.

Fig. 1

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Routine histology of the tarsal plate (TP). (a) The plate contains Meibomian glands (MG) and accessory lacrimal glands (AG). Its concave side lies close to the conjunctival epithelium (E) and is separated from it by a thin lamina propria (LP). Between the plate and the skin of the eyelid lies the orbicularis oculi muscle (M) and the tendon fibres (T) of levator palpebrae superioris. Scale bar, 1 mm. (b) Embedded within the connective tissue of the tarsal plate are numerous Meibomian glands (MG), and bundles of large myelinated nerve fibres (N) are visible in the connective tissue adjacent to the plate. Scale bar, 100 µm. (c) At the upper edge of the tarsal plate, the Meibomian glands are replaced by accessory lacrimal glands (AG). Here, the end of the plate is well defined. Scale bar, 200 µm. (d) Near the free margin of the eyelid, the tarsal plate becomes less distinct and flares out between the Meibomian gland ducts (D) and the eyelashes (L). Glands of Moll (GM) are present in this region and the muscle of Riolan (R – the ciliary part of the orbicularis oculi) can also be seen. Scale bar, 100 µm. (e) A high-magnification view of the dense fibrous connective tissue of the tarsal plate showing numerous bundles of collagen fibres (CF) and sparsely distributed fibroblasts (F). Note the small blood vessel (BV) present in the tissue. Scale bar, 20 µm. (f) The conspicuous layer of amorphous and acellular matrix (AC) surrounding a Meibomian gland (MG). Scale bar, 30 µm. (g) Strong staining for elastic fibres (EF) around the main ducts (D) of the Meibomian gland and some of the glands (MG) themselves. Scale bar, 50 µm. All sections are stained with Masson's trichrome stain except (g), which is stained with Weigert's elastic stain.

The immunohistochemical labelling patterns are summarized in Table 2 and representative sections are illustrated in Fig. 2. The superior tarsal plate labelled strongly for types I, III and VI collagens throughout, but type II collagen was absent in all specimens (Fig. 2a–c). Chondroitin 4 and keratan sulphates were detected in all tarsal plates (Fig. 2d–f) and labelling for the former clearly distinguished between the plate and neighbouring connective tissues. Dermatan and chondroitin 6 sulphate were also present in all plates and were particularly conspicuous immediately around the Meibomian glands (Fig. 2g,h). Furthermore, chondroitin 6 sulphate was detected in the peripheral cells of the glands themselves (Fig. 2h). The native epitope recognized by antibody 3B3– and the oversulphated epitope detected by 7D4 were strongly localized both within the Meibomian glands and in their territorial matrix (Fig. 2i,j). However, the epitopes could also be detected elsewhere in the tarsal plate.

Table 2.

Summary of immunohistochemical labelling profiles

Collagens Glycosaminoglycans Proteoglycans and glycoproteins Other molecules
I II III VI KS DS, C4S C4S C6S Agg Link Vers Ten COMP
Territorial matrix around Meibomian glands 14 0 14 14 10 14 12 14* 14 2 13 11 10
Remainder of tarsal plate matrix 14 0 14 14 14 14 14 14* 14 0 11 14 10
Lamina propria 14 0 14 14 10 12 6 14 14 0 4 13 4
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The figures indicate the number of positive labellings out of a total of 14 eyelids examined. KS, keratan sulphate; DS, dermatan sulphate; C4S, chondroitin 4 sulphate; C6S, chondroitin 6 sulphate; Agg, aggrecan; Link, link protein; Vers, versican; Ten, tenascin.

*

In 11 eyelids, the territorial matrix of the Meibomian glands labelled for the native C6S epitope (3B3–) and in nine it labelled for the oversulphated epitope 7D4.

Aggrecan was present in all superior tarsal plates and strong labelling was found in the territorial matrix around the Meibomian glands (Fig. 2k). Weak labelling for link protein was detected in two specimens (not illustrated). Versican was found in 13 specimens and was again conspicuous around the glands (Fig. 2l). Tenascin was present in all the connective tissues around the tarsal plate, but was unevenly distributed within the plate itself – some regions labelled intensely, but periglandular areas were often weakly stained (Fig. 2m). COMP also displayed an uneven labelling pattern within the tarsal plate (Fig. 2n).

Discussion

The results show that the superior tarsal plate is a unique tissue that does not comfortably fit the description of a typical dense fibrous connective tissue or a typical cartilage, but is a transitional tissue with some of the features of both. Most of its characteristics are those of ordinary dense fibrous connective tissue, notably the presence of fibroblastic cells surrounded by an ECM that immunolabels strongly for types I and III collagen, and that contains versican as the typical large proteoglycan (Zimmermann, 1993). Yet despite the absence of chondrocytes and type II collagen (typical marker molecules for cartilage), the ECM of the tarsal plate contains aggrecan and chondroitins 4 and 6 sulphate. Aggrecan in particular is more typical of cartilage than ordinary connective tissue, and is a major structural macromolecule of the former (Heinegård & Oldberg, 1993). Other ECM components that we have reported in the tarsal plate are found in both cartilage and fibrous connective tissue. These include elastic fibres, type VI collagen, dermatan sulphate, keratan sulphate, tenascin and COMP.

The transitional character of the superior tarsal plate is in line with the concept that there is a continuous spectrum of tissues between dense fibrous connective tissue and hyaline cartilage and that there is no sharp dividing line between the two (Benjamin & Ralphs, 2004). The unique character of the tarsal plate tissue presumably relates to a unique set of mechanical demands that it must fulfil and this in turn explains the difficulty faced by clinicians in choosing an ideal substitute. All tissues available to surgeons have a different ECM composition from the tarsal plate itself and thus represent a compromise. An appreciation of the molecular composition of the tarsal plate provides an essential foundation for any future attempts at tissue engineering.

Aggrecan is a large, aggregating proteoglycan most typical of articular cartilage (Heinegård & Oldberg, 1993). It occupies huge supramolecular domains and its considerable capacity for attracting water largely accounts for the ability of cartilage to resist compression. It is the aggrecan content of the plate that is likely to account for the stiffness of the upper eyelid – which in turn is what lead early anatomists to refer to the presence of a ‘lid cartilage’ or ‘fibrocartilage’ (Böhm & von Davidoff, 1895; Szymonowicz, 1924; Wallraff, 1960). It is the stiffness of the tarsal plate that enables the eyelid to be moulded to the rounded shape of the globe. If the stiffness (or thickness) of the plate is inappropriate, a patient may be at risk of developing an entropion or ectropion (an inwardly rotated or an outwardly rotated eyelid, respectively; Bashour & Harvey, 2000). In such conditions, the mechanical properties of the tarsal plate do not match the tone of the overlying orbicularis oculi muscle (Bashour & Harvey, 2000). The stiffened nature of the plate also enables it to act as a ‘skeletal element’ for the insertion of levator palpebrae superiores.

It is intriguing that the distribution of aggrecan and chondroitin 6 sulphate (one of its glycosaminoglycans) within the superior tarsal plate is non-uniform. Labelling was particularly striking immediately around the Meibomian glands in a region that corresponded to an acellular zone of ECM outside the basal lamina. This hyaline-like region was commonly seen in routine paraffin sections and was richly endowed with elastic fibres. Consequently, the glands could be viewed as being encapsulated in a distinctive region of ‘territorial’ matrix that could play a role in controlling the release of the holocrine secretory product.

Finally, both COMP and aggrecan have been cited as potential autoantigens in patients with rheumatoid arthritis (RA; Krenn et al. 2000; Li et al. 2000). It may thus be significant that almost one-third of patients with RA present with ocular problems that relate to tear film deficiency, including dry eye and keratonconjunctivitis sicca (Uhlig et al. 1999; Jain et al. 2001; Ausayakhun et al. 2002; Shaw et al. 2003). This raises the possibility that there is an autoimmune response to aggrecan or COMP within the superior tarsal plate of some patients with RA. A similar association has been made between the manifestation of RA and the composition of the ECM in other tissues that can be regarded as having some cartilaginous features. This has been suggested for the alar ligaments (Boszczyk et al. 2003) and for the tendon of the superior oblique muscle and its associated trochlea (Milz et al. 2002). Any immune reaction directed against ECM components could interfere with the interaction between Meibomian glands and their surrounding ECM. This in turn may alter tarsal gland function and thus the character of the tear film.

Acknowledgments

This investigation is part of the doctoral thesis of Joerg Neufang. The results are published with permission of the Medical Faculty of the Ludwig-Maximilians-Universität München. Antibodies CIICI, 5C6, 12/21/1C6, 9/30/8A4 and 12C5 were obtained from the Developmental Studies Hybridoma Bank (DSHB) maintained by the Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA, and the Department of Biology, University of Iowa, Iowa City, IA, USA, under contract NO-HD-6–2915 from the NICHD.

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