Ocular Glands produce most of the Tear Fluid and its components

Professional Secretory Cells produce most of the components of the ocular surface fluid termed tears.

The Secretory Cells are typically associated into larger accumulations with blood vessel and nerves termed glands.

But secretory cells can also occur interspersed as single cells among´conventional´ epithelial cells such as the goblet cells of the conjunctiva. 

The aqueous lacrimal glands provide most of tears

The main Lacrimal Gland

The main lacrimal gland produces most of the required aqueous tear secretion. It is located “upstream” of the conjunctiva in the upper temporal orbita and has two lobes, the orbital lobe towards the orbita and the palpebral lobe that is close to the conjunctiva in its orbital zone. The two lacrimal gland lobes are separated by the tendon of the levator palpebrae muscle that lifts the upper eye lid to open the eye.

The lacrimal gland delivers the aqueous tears onto the conjunctival surface by several individual excretory ducts that open to the conjunctiva in the temporal fornix fold of the conjunctiva.

Accessory lacrimal glands

There are few small accessory lacrimal glands located in the orbital and tarsal parts of the conjunctiva. The glands of Krause are located in the orbital loose connective tissue. The glands of Wolfring, which are rather few, are located still inside the upper edge of the tarsal plate, closely adjacent to the end of the Meibomian glands. They  produce a minor volume of aqueous tears that is, as assumed from the relative tissue mass of the glands, to be around one third of the total volume. They are located close to the conjunctiva and deliver their products through short excretory ducts onto the conjunctival surface and into the conjunctival sac. A certain amount of water may enter the tear fluid through the conjunctival epithelium.

Secretory products of the aqueous tear glands

The aqueous glands produce the same type of aqueous tear fluid. The aqueous tears provide moisture and the supply with a plethora of nutritive and regulatory factors that is both necessary for the health and regulation of the ocular surface.

The sources of the proteins in the tears are:

• in part a product of own secretion by the lacrimal gland cells,

• partly they are actively transported through the epithelium and

• in part they get from the blood plasma by passive leakage through the gland, into the tears. Glycoproteins such as mucins are also produced by lacrimal glands.

Goblet cells produce secretory mucins

Interspersed among the ordinary conjunctival cells are the goblet cells. The are one of the two epithelial cell populations of the conjunctiva and derive from the same stem cell as the ´ordinary´ epithelial cells, but, in contrast to the latter, goblet cells differentiate into professional secretory cells

Goblet cells produce secretory mucins. In the conjunctiva this is identified as the Mucin Muc5AC. Mucins are very large, highly hydrated carbohydrate (polysaccharide) molecules that can bind large amounts of water and thus hold the aqueous secretions from lacrimal glands on the ocular surface as a water-mucin gel that basically constitutes most of the tear fluid.  

However, since the ocular epithelial surface was reported to be non-wettable in principle, by Holly and Lemp dating back to the 1970s in the early days of ocular surface research, the ocular surface has to make use of another class of mucin molecules. These are the cell bound mucins of the glycocalyx that can bind water to the epithelial surface (please see Ocular Surface - Conjunctiva).

Mucins make the ocular epithelial surface wettable

Mucins make the ocular epithelial surface wettable, i.e. able to bind the water of the aqueous tears to the cell surface. Consequently, in the early experiments, the lost wettability of a ´cleaned´ corneal surface could be restored by replacing mucins.

Secretory Mucins are packed in goblet cells into mucin granules.  The granules are already detectable with ordinary stains in high magnification light microscopy but are better seen upon use of specific mucus stains such as Periodic-Acid Schiff (PAS).

The structure of intracellular mucin granules is better recognizable in Transmission Electron Microscopy (TEM) where they contain lamellar or undulated sub-structures representing the very large aggregated mucin molecules that unfold upon release at the surface.

Meibomian glands inside the eye lids produce lipids that form an oil at body temperature

The Meibomian glands inside the tarsal plates of both the upper and lower eye lids produce lipids that are liquid at body temperature and thus form an oil. The Meibomian oil covers the water-mucin main phase of the tear film as a surface layer - like a lid on a pot of warm water.

Thereby the Meibomian lipids have, among probably many others,  at least two important functions as the surface layer of the pre-corneal tear film:

• Meibomian oil constitutes the most superficial smooth tear film layer that represents the air-tear-interface. This is the main refractory unit of the eye and is responsible for about three quarters of the refractive power of the eye and thus for visual acuity. Therefore it is not surprising that a loss of visual acuity is an early and often reported finding in tear deficiency.

• Meibomian oil retards the aqueous evaporation that occurs at the opened palpebral fissure where the ocular surface and the tear fluid, that are roughly at body temperature, are exposed to the environmental ambient air. This leads to a rapid evaporation of water. Evaporation of the tear water causes the downstream effects known from dry eye disease such as loss of tear volume and resultant hyper-osmolarity of the remaining tear fluid, increased friction, tear film instability with short break-up time etc.

There may be other minor sources of lipids at the ocular surface and lipids may also have other functions, such as. e.g. to aid in spreading of the tear fluid into a pre-ocular film. Even though lipids were known to be relevant for ocular surface integrity, their eminent importance for tear film integrity and development of dry eye disease when they are deficient, has only in recent years been fully recognized during the TFOS MGD Workshop Report (2011). Evidence was revealed that points to Meibomian gland dysfunction (MGD) as the main underlying cause of dry eye disease in about four fifths of dry eye patients.

Anatomy of the Meibomian Glands

The Meibomian glands have a characteristic morphology as compared to other sebaceous glands. 

The ductal system

Meibomian Glands are not associated with a hair follicle - in contrast to  the hair-associated sebaceous glands of the skin

• have a very elongated gland body - in contrast to the skin glands with short and stout morphology

• have a differentiated ductal system composed of:

  • an orifice that opens on the posterior lid margin just anterior to the Line of MARX

  • a short excretory duct

  • a long central duct

  • several smaller shorter lateral ductules that lead to

  • spherical secretory acini

    • which they connect to the central duct for the transport of the secretum

the arrangement of the spherical secretory acini, hanging with their ductules along the long central duct, has been compared to a chain of onions   

The Meibomian Glands are holocrine sebaceous glands

The holocrine secretion mode of the Meibomian Glands glands is easily understandable when they are investigated in light microscopy. ´Holo´-´crine´ means that the whole cells (Greek ´holos´) are consitute/ disintegrate/ produce (Greek ´crinein´). Holocrine therefore describes that the whole cells disintegrate and eventually for the lipid secretum of the gland.

If this is true, it should be detectable in light microscopy if this technique is of any value for understanding the structure and potential function of tissues and organs. ... AND ... indeed, it can be seen in respective light microscopical images of sufficient resolution, that

• the secretory cells (termed Meibocytes) in the spherical secretory acini become larger in size,

• whereas the nucleus is shrinking

• at the same time the cytoplasm

  • becomes increasingly pale and empty in ordinary histology where the lipids are diluted

  • because the meibocytes are increasingly filled with lipid droplets

  • ... so even though the meibocytes increasingly loose their information-store in the nucleus they still have a productive metabolic machinery running that is biased to produce large amounts of lipids

When the nucleus is shrinking while the cell body becomes larger, this is always a negative sign for the vitality of the cell or, at least, it indicates a negative prognosis for the further survival of the respective cell. Still, since the cells are actively producing lipids this process is termed a ´maturation´

... as can be expected from the consideration that the ultimate sign of maturation likely is death, the meibocytes also eventually loose their nucleus, the cell membrane ruptures and the whole cell thus ´disintegrates´ or dissolves. By dissolving, the whole cell transforms into the lipid secretory product termed ´Meibum´

... from this we can further conclude, that the Meibomian oil will basically consist of all the remnants of the meibocytes - which is apparently true. So, Meibum is in fact a mixture of many constituents with the variety of different lipids representing the vast majority of components. 

The process of meibocyte maturation proceeds in the acini from the basal region and finishes in the center, where the connecting ductule starts and the meibum enters the ductular system.

Since each meibocytes is lost during the secretory process but the acinus does not end its existence after one ´round´of lipipd production and instead continuously produces lipids, we must further assume that there should be a replacement of the meibocytes that are lost in action. This is indeed true, because in the basal cell layer in the periphery of the acinus on the basement membrane, there are stem cells that continuously divide and constitute new cells that start the maturation process.

The time of a meibocyte, from the start of maturation at the basement membrane until it disintegrates in the center of the acinus, takes roughly around one and a half week which may be slightly different in different species. 

The meibomian glands will be covered together with their important dysfunction in a separate section – for more details please go there