Nadja Knop

The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland.

The tarsal glands of Meibom (glandulae tarsales) are large sebaceous glands located in the eyelids and, unlike those of the skin, are unassociated with hairs. According to Duke-Elder and Wyler,1 they were first mentioned by Galenus in 200 AD and later, in 1666, they were described in more detail by the German physician and anatomist Heinrich Meibom, after whom they are named. Lipids produced by the meibomian glands are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension.2 Hence, meibomian lipids are essential for the maintenance of ocular surface health and integrity. Although they share certain principal characteristics with ordinary sebaceous glands, they have several distinct differences in anatomy, location, secretory regulation, composition of their secretory product, and function. Functional disorders of the meibomian glands, referred to today as meibomian gland dysfunction (MGD),3 are increasingly recognized as a discrete disease entity.4–8 In patients with dry eye disease, alterations in the lipid phase that point to MGD are reportedly more frequent than isolated alterations in the aqueous phase. In a study by Heiligenhaus et al.,9 a lipid deficiency occurred in 76.7% of dry eye patients compared with only 11.1% of those with isolated alterations of the aqueous phase. This result is in line with the observations by Shimazaki et al.10 of a prevalence of MGD in the absolute majority of eyes with ocular discomfort defined as dry eye symptoms. These observations noted that 64.6% of all such eyes and 74.5% of those excluding a deficiency of aqueous tear secretion were found to have obstructive MGD, or a loss of glandular tissue, or both.10 Horwath-Winter et al.11 reported MGD in 78% of dry eye patients or, if only non-Sjogren patients are considered, in 87% compared with 13% with isolated aqueous tear deficiency. It may thus be accepted that MGD is important, conceivably underestimated, and possibly the most frequent cause of dry eye disease due to increased evaporation of the aqueous tears.5,9–12 After some excellent reviews of MGD4,7,8,13,14 in the past, many new findings have been reported in recent years, and other questions remain to be identified and resolved. A sound understanding of meibomian gland structure and function and its role in the functional anatomy of the ocular surface15 is needed, to understand the contribution of the meibomian glands to dysfunction and disease. Herein, we seek to provide a comprehensive review of physiological and pathophysiological aspects of the meibomian glands.

Nonobvious obstructive meibomian gland dysfunction.

This review presents the rationale and supporting data for a recent paradigm shift in our understanding of meibomian gland dysfunction (MGD). The historical understanding of MGD has been that of an infectious hypersecretory disorder with obvious signs of inflammation, hypersecretion, and purulent excreta. The current understanding of MGD now includes the polar concept of a less obvious or nonobvious type of hyposecretory obstructive MGD, where inflammation and other signs of pathology may be absent unless special examination techniques are employed. A new term, nonobvious obstructive MGD (NOMGD), is used to describe what may be the most common form of obstructive MGD. Obstructive MGD is an area of growing importance because obstructive MGD is now recognized to be the most common cause of evaporative dry eye, and because NOMGD seems to be the precursor to obvious obstructive MGD, it is also an important area to understand. The prevalence of NOMGD seems to be very high but currently significantly underdiagnosed. This review presents the relevant anatomy and physiology, concepts of obstructive MGD, the usual absence of inflammation in obstructive MGD, nomenclature and classification of obstructive and NOMGD, clinical diagnosis of NOMGD emphasizing the necessity for diagnostic expression, the use of a new instrument for diagnostic expression providing a standardized method of assessing meibomian gland functionality, the complementary roles of the aqueous and lipid layers, and the specific treatment of NOMGD, emphasizing that the success of treatment of all forms of obstructive MGD is dependent on the relief of the obstruction.

Anatomy and Immunology of the Ocular Surface

The ocular surface, in a strict sense, consists of the cornea and its major support tissue, the conjunctiva. In a wider anatomical, embryological, and also functional sense, the ocular mucosal adnexa (i.e. the lacrimal gland and the lacrimal drainage system) also belong to the ocular surface. This definition includes the source and the eventual drainage of the tears that are of utmost importance to ocular surface integrity. The ocular surface is directly exposed to the external environment, and therefore is endangered by a multitude of antigens and pathogenic microorganisms. As a mucosa, it is protected by the mucosal immune system that uses innate and adaptive effector mechanisms present in the tissue and tear film. Immune protection has two partly opposing tasks: the destruction of invading pathogens is counterbalanced by the limitation of inflammatory events that could be deleterious to the subtle structure of the eye. The immune system of the ocular surface forms an eye-associated lymphoid tissue (EALT) that is recognized as a new component of the mucosal immune system. The latter consists of the mucosa-associated lymphoid tissues in different organs of the body. Mucosa- and hence eye-associated lymphoid tissues have certain characteristics that discriminate them from the central immune system. The mechanisms applied are immunological ignorance, tolerance, or an immunosuppressive local microenvironment, all of which prefer non-reactivity and anti-inflammatory immunological responses. The interaction of these mechanisms results in immune privilege of the ocular surface. During eye closure, the ocular surface appears to have different requirements that make an innate pro-inflammatory environment more attractive for immune defense. The structural and functional components that contribute to this special immune regulation will be the focus of this chapter.

The lid wiper and muco-cutaneous junction anatomy of the human eyelid margins: an in vivo confocal and histological study

The inner border of the eyelid margin is critically important for ocular surface integrity because it guarantees the thin spread of the tear film. Its exact morphology in the human is still insufficiently known. The histology in serial sections of upper and lower lid margins in whole‐mount specimens from 10 human body donors was compared to in vivo confocal microscopy of eight eyes with a Heidelberg retina‐tomograph (HRT II) and attached Rostock cornea module. Behind the posterior margin of the Meibomian orifices, the cornified epidermis stopped abruptly and was replaced by a continuous layer of para‐keratinized (pk) cells followed by discontinuous pk cells. The pk cells covered the muco‐cutaneous junction (MCJ), the surface of which corresponded to the line of Marx (0.2–0.3 mm wide). Then a stratified epithelium with a conjunctival structure of cuboidal cells, some pk cells, and goblet cells formed an epithelial elevation of typically about 100 μm initial thickness (lid wiper). This continued for 0.3–1.5 mm and formed a slope. The MCJ and lid wiper extended all along the lid margin from nasal to temporal positions in the upper and lower lids. Details of the epithelium and connective tissue were also detectable using the Rostock cornea module. The human inner lid border has distinct zones. Due to its location and morphology, the epithelial lip of the lid wiper appears a suitable structure to spread the tear film and is distinct from the MCJ/line of Marx. Better knowledge of the lid margin appears important for understanding dry eye disease and its morphology can be analysed clinically by in vivo confocal microscopy.

Transcription, Translation, and Function of Lubricin, a Boundary Lubricant, at the Ocular Surface

IMPORTANCE Lubricin may be an important barrier to the development of corneal and conjunctival epitheliopathies that may occur in dry eye disease and contact lens wear. OBJECTIVE To test the hypotheses that lubricin (ie, proteoglycan 4 [PRG4 ]), a boundary lubricant, is produced by ocular surface epithelia and acts to protect the cornea and conjunctiva against significant shear forces generated during an eyelid blink and that lubricin deficiency increases shear stress on the ocular surface and promotes corneal damage. DESIGN, SETTING, AND PARTICIPANTS Human, porcine, and mouse tissues and cells were processed for molecular biological, immunohistochemical, and tribological studies, and wild-type and PRG4 knockout mice were evaluated for corneal damage. RESULTS Our findings demonstrate that lubricin is transcribed and translated by corneal and conjunctival epithelial cells. Lubricin messenger RNA is also present in lacrimal and meibomian glands, as well as in a number of other tissues. Absence of lubricin in PRG4 knockout mice is associated with a significant increase in corneal fluorescein staining. Our studies also show that lubricin functions as an effective friction-lowering boundary lubricant at the human cornea-eyelid interface. This effect is specific and cannot be duplicated by the use of hyaluronate or bovine serum albumin solutions. CONCLUSIONS AND RELEVANCE Our results show that lubricin is transcribed, translated, and expressed by ocular surface epithelia. Moreover, our findings demonstrate that lubricin presence significantly reduces friction between the cornea and conjunctiva and that lubricin deficiency may play a role in promoting corneal damage.

[Meibomian glands : part III. Dysfunction - argument for a discrete disease entity and as an important cause of dry eye].

Meibomian gland dysfunction (MGD), mainly synonymous with posterior blepharitis but typically without prominent inflammatory alterations of the lid margin, is a discrete disease entity and a frequent cause of wetting deficiencies of the ocular surface leading to dry eye disease that deserves increased recognition by clinicians. The history, classification, pathology, influencing factors, diagnostics and therapy are explained and discussed. MGD is mainly based on an obstructive mechanism caused by hyperkeratinization of the excretory duct and/or increased viscosity of the secretion (meibum) with subsequent deficiency of the tear film lipid layer. MGD is influenced by the hormonal status and by chemical and mechanical noxes as well as genetic defects and it occurs more frequently in women and generally increases with age. It results in stasis of meibum inside the glands, dilatation of the ductal system and eventually in atrophy and loss of glandular tissue (gland dropout). Careful investigation of the eyelids and lid margins with eversion, if necessary, should therefore be performed in every case of a wetting defect, notably before fitting contact lenses. Particularly important is the inspection of the meibomian orifices and diagnostic expression by mild mechanical compression of the lid.

Local production of secretory IgA in the eye-associated lymphoid tissue (EALT) of the normal human ocular surface.

PURPOSE Secretory IgA (SIgA) is a critical local defense mechanism of mucosal immunity. Although the conjunctiva, as part of the ocular surface, has a mucosa-associated lymphoid tissue, the production of SIgA by local plasma cells and its transport is unequivocally accepted to occur only in the upstream lacrimal gland (LG). The molecular components were therefore investigated by immunohistochemistry (IHC) and their local production verified by RT-PCR. METHODS Tissues from 18 conjunctivas and 9 LGs of human donor eyes with normal ocular surfaces were analyzed by histology and IHC. Different zones of 12 further conjunctivas and LG tissues were analyzed by RT-PCR for the presence of the respective mRNA. RESULTS Plasma cells were present in the diffuse lymphoid tissue of all investigated specimens and showed an intense immunoreactivity for IgA. This immunoreactivity was absent when the antiserum was preadsorbed with the protein. The luminal epithelium, with the exception of goblet and basal cells, was strongly positive for the epithelial transporter molecule secretory component (SC) in the conjunctiva and interconnecting excretory duct similar to the LG. PCR products for IgA, the monomeric IgA-joining molecule (J-chain) and SC were regularly found in all conjunctival zones and in the LG in gel electrophoresis and were sequenced. CONCLUSIONS The local production of SIgA is for the first time verified by RT-PCR in the human conjunctiva and in the LG. This finding points to an active role of the conjunctiva in secretory immune protection of the ocular surface and supports the presence and importance of EALT at the normal ocular surface.

[Meibomian glands. Part II: physiology, characteristics, distribution and function of meibomian oil].

The oily secretion (meibum) of the Meibomian glands forms the superficial layer of the pre-ocular tear film and reduces evaporation of the aqueous phase. Meibum is a complex mixture of various lipids and minor protein components as well as other components of the secretory meibocytes, which form a clear liquid at body temperature. The exact composition and functions of meibum are still partly unknown, in particular the interaction of the water insoluble non-polar lipids with the polar, partly water soluble, lipids and potentially with proteins, which altogether interact to maintain the connection with the underlying aqueous tear phase. Meibum is transported within the gland by the force of secretory pressure from continuous secretion and by muscular action of the orbicularis muscle and Riolans muscles during blinking. After delivery of meibum onto the posterior lid margin the oil moves from the posterior lid margin reservoir onto the tear meniscus and is pulled as a thin layer onto the pre-ocular tear film every time the lid opens. During lid closure it is compressed and a small part is continuously renewed. Meibum also has a barrier function against the spillage of tears over the inner border of the lid and against the entry of skin lipids (sebum) from the free lid margin.

The lid wiper contains goblet cells and goblet cell crypts for ocular surface lubrication during the blink.

Purpose: The conjunctival side of the upper and lower inner eyelid borders, termed the lid wiper, has a thickened epithelial lip for apposition to the globe, assumed to distribute the preocular tear film. The human lid wiper structure and its goblet cells are investigated. Methods: Conjunctival whole mounts, including lid margins from 17 eyes of human body donors, were investigated by routine histology and semithin plastic sections, using histology, histochemistry, and immunohistochemistry. Results: In routine histology, the conjunctival lid wiper epithelium regularly showed goblet cells, single and in clusters, at the luminal surface and also deep within the epithelium without apparent surface contact. Semithin sections revealed that the deep goblet cells were often connected to cryptal epithelial infoldings that opened to the surface, hence making their mucins available at the surface. The goblet cells produced mucins of neutral (periodic acid-Schiff) and acidic (Alcian blue) type and stained positive for the gel-forming mucin MUC5AC. Surprisingly, MUC5AC-negative goblet cells were also observed in the lid wiper. Conclusions: Contrary to conventional assumptions, the lid wiper is part of the conjunctiva. It contains previously undescribed goblet cell crypts deep in the epithelium, suitable as an internal lubrication system for reduction of friction between the lid margin and the globe. This provides the first evidence of the morphological basis for the hydrodynamic type of lubrication and a more conclusive understanding of lid-margin lubrication and tear film distribution. It is another strong indication that the lid wiper is that area in apposition with the globe for distributing the thin preocular tear film during the blink.

Growth Hormone Influence on the Morphology and Size of the Mouse Meibomian Gland

Purpose. We hypothesize that growth hormone (GH) plays a significant role in the regulation of the meibomian gland. To test our hypothesis, we examined the influence of GH on mouse meibomian gland structure. Methods. We studied four groups of mice, including (1) bovine (b) GH transgenic mice with excess GH; (2) GH receptor (R) antagonist (A) transgenic mice with decreased GH; (3) GHR knockout (−/−) mice with no GH activity; and (4) wild type (WT) control mice. After mouse sacrifice, eyelids were processed for morphological and image analyses. Results. Our results show striking structural changes in the GH-deficient animals. Many of the GHR−/− and GHA meibomian glands featured hyperkeratinized and thickened ducts, acini inserting into duct walls, and poorly differentiated acini. In contrast, the morphology of WT and bGH meibomian glands appeared similar. The sizes of meibomian glands of bGH mice were significantly larger and those of GHA and GHR−/− mice were significantly smaller than glands of WT mice. Conclusions. Our findings support our hypothesis that the GH/IGF-1 axis plays a significant role in the control of the meibomian gland. In addition, our data show that GH modulates the morphology and size of this tissue.