Erich 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.

The role of eye-associated lymphoid tissue in corneal immune protection

Because the cornea is optimized for refraction, it relies on supporting tissues for moistening and nutrition and in particular for immune protection. Its main support tissue is the conjunctiva, in addition to the lacrimal gland, the latter which provides soluble mediators via the tear film. The cornea and conjunctiva constitute a moist mucosal surface and there is increasing evidence that apart from innate defence mechanisms, also lymphoid cells contribute to the normal homeostasis of the corneal surface. A Medline‐based literature search was performed in order to review the existing literature on the existence, composition and functions of mucosa‐associated lymphoid tissue (MALT) at the ocular surface for corneal protection. The existence of lymphoid cells at the ocular surface and appendage has been known for many years, but for a long time they were believed erroneously to be inflammatory cells. More recent research has shown that in addition to the known presence of lymphoid cells in the lacrimal gland, they also form MALT in the conjunctiva as conjunctiva‐associated lymphoid tissue (CALT) and in the lacrimal drainage system as lacrimal drainage‐associated lymphoid tissue (LDALT). Together this constitutes an eye‐associated lymphoid tissue (EALT), which is a new component of the mucosal immune system of the body. When the topographical distribution of CALT is projected onto the ocular surface, it overlies the cornea during eye closure and is hence in a suitable position to assist the corneal immune protection during blinking and overnight. It can detect corneal antigens and prime respective effector cells, or distribute protective factors as secretory IgA.

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.

TFOS DEWS II pathophysiology report

The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

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.

The TFOS International Workshop on Contact Lens Discomfort: Report of the contact lens interactions with the ocular surface and adnexa subcommittee

Efron, N., Jones, L., Bron, A. J., Knop, E., Arita, R., Barabino, S., … Markoulli, M. (2013). The TFOS International Workshop on Contact Lens Discomfort: Report of the Contact Lens Interactions With the Ocular Surface and Adnexa Subcommittee. Investigative Opthalmology & Visual Science, 54(11), TFOS98. https://doi.org/10.1167/iovs.13-13187

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.

Pathways of corneal and ocular surface inflammation: A perspective from the Cullen symposium

The goal of this symposium was to coalesce information presented by 22 investigators in the field of corneal and ocular surface inflammation into common pathways of inflammation. The perspective elucidated in this article defines the components of the normal ocular surface immune architecture and describes the consensus reached on the mechanisms/pathways involved in 1) acute inflammation; 2) late-stage (chronic) response; and 3) allergic disease. Seven diagrams didactically illustrate mechanisms. This paper is the introductory article in a supplement containing 18 articles by the symposium participants.

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.