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Deeper INSIGHT into ...

The CONJUNCTIVA

 

 

 

 

 

Overview of the conjunctiva

The CONJUNCTIVAL SAC is shown in a schematic diagram (left) and in a respective histological light micrograph (right) where the relatively loose structure of the conjunctiva at the back side of the eye lid can be compared to that of the opposing cornea of the eye ball on the other side. In between is KESSING´s Space - a narrow tear-filled separation of the back side of the upper eye lid from the eye ball that reduces friction between these two areas during eye movements and the blink.

The overwhelming part of the anterior eye ball around the cornea is covered by the conjunctiva. This is the main support tissue of the cornea in terms of wetting, nutrition, defense and many other functions.

The conjunctiva extends from the corneal limbus over the eye ball and, by forming the (upper and lower) fold of the fornix, onto the posterior surface of the eye lids. The conjunctiva thus ´conjuncts´ the eye lids with the eye ball. Consequently, the conjunctiva forms the ´CONJUNCTIVAL SAC´, that is opened to the environment only at the palpebral fissure, where the light has to get in, through the central cornea, for the visual function. The conjunctival sac is filled with the tears that are supplied from the lacrimal gland via several excretory ducts, opening into the temporal upper fornix of the conjunctiva.

In fact, the CONJUNCTIVA is of utmost importance for the support of the whole moist ocular surface - the aqueous glands derive from the conjunctiva and remain connected with it and the mucin producing goblet cells are an integral part of it. In addition, the conjunctiva has many different function in order to maintain its support of the whole ocular surface ... whereas the cornea basically only has the function ´not to worry and remain clear´. This is certainly important for vision ... but not very impressive by observation with the ´naked eye´  ;-)

Even though the conjunctiva is of utmost importance for the ocular surface it does not have a very impressive structure - at least in clinics and without further imaging devices. So, by now it becomes clear the conjunctiva has a lot of important ´inner values´ and it is clearly an organ for the real connoisseur.

 

The Conjunctiva is a structurally unremarkable organ at first glance ... but the backbone and ´maintenance genius´  of the ocular surface

A normal human CONJUNCTIVA from the nasal part with the adjacent cornea and the corneal limbus around it. The conjunctiva is basically transparent because it is a thin organ, only composed of a narrow epithelium and a mostly equally thin connective tissue lamina propria with support structures like blood vessels, nerve fibers and defense cells. Therefore the normal conjunctiva is typically only identified by its vessels that reach from the periphery towards the corneal limbus, where they stop since the cornea is avascular.

The conjunctiva appears macroscopically just as a faint moist membrane with a few, normally equally faint and narrow, vessels. This faint mucosal membrane is almost translucent and covers the underlying whitish sclera of the eye ball.

The conjunctiva is in fact so unimpressive that it has not even made it into conventional wisdom - because when we think of the conjunctiva, we typically think of the ´white in the eye´ which is actually already the sclera of the eye ball underneath.

Like with so many organs in the body, we only take notice of the conjunctiva when it becomes ill - here: more visible and reddish-inflamed by vascular injection or painful or often both    

´who knows that he or she has a liver ... as long as it does not hurt´ .     

 

 

The Conjunctiva has different zones along the ocular surface

The conjunctiva has different topographical zones along its extension from the corneal limbus along the fold of the fornix to the lid margin.

The most common classification is into the bulbar conjunctiva on the eye ball overlying the sclera and into the palpebral conjunctiva that covers the eye lids from behind.

More specifically the bulbar, fornical, orbital, tarsal and marginal conjunctiva are differentiated.

It can be debated whether the limbal zone is already a zone of the conjunctiva or still belongs to the cornea. The name of this zone as the ´Limbus corneae´ i.e. the corneal limbus would suggest, that it must be allocated to the cornea. The marginal conjunctiva is basically equivalent to what is now known as the Lid Wiper region, that starts at the crest of the posterior lid border and extends into tarsal direction.

There are certain morphological differences between the different zones with respect to the amount of the loose connective tissue underneath the epithelium, to the thickness of the epithelium, to the amount of lymphoid tissue withing and underneath the epithelium and to the goblet cells and probably several other parameters.

 

Structure of the Conjunctiva

 The CONJUNCTIVA in the tarso-orbital zone. The tarsal conjunctiva typically has a stratified two-layered cuboidal epithelium whereas that of the fornix is multilayered (see image below). In the orbital zone there is a transition. The epithelium seen here has 2-3 cell layers. Typical for this region is the large number of free bone marrow derived protective cells. They are the diffuse part of the ´ Eye-Associated Lymphoid Tissue ´ (EALT)  that extends all along the ocular surface from the lacrimal gland, along the conjunctiva and in the lacrimal drainage system.   

The CONJUNCTIVA in the tarso-orbital zone. The tarsal conjunctiva typically has a stratified two-layered cuboidal epithelium whereas that of the fornix is multilayered (see image below). In the orbital zone there is a transition. The epithelium seen here has 2-3 cell layers. Typical for this region is the large number of free bone marrow derived protective cells. They are the diffuse part of the ´Eye-Associated Lymphoid Tissue´ (EALT)  that extends all along the ocular surface from the lacrimal gland, along the conjunctiva and in the lacrimal drainage system.   

The schematic structure of the bulbar CONJUNCTIVA near the corneal margin (limbus). At the bottom of the Tear Film is the epithelium of the conjunctiva that seals its underlying connective tissue layer (Lamina propria). The loose connective tissue in the Lamina propria is composed of loosely arranged collagen fibers and contains many cells as well as blood vessels (red) and nerve fibers. It is sitting on the densely arrange collagen of the underlying Sclera - the solid wall of the Eye Ball.

As a typical mucosa, the conjunctiva consists of two layers. One is the epithelium composed of densely accumulated epithelial cells and the other is the lamina propria composed of a loose connective tissue. Both layers a separated by the basement membrane that is a meshwork of extra-cellular macro-molecules that are ´glued´ together and provide the attachment structure for the epithelium.

Loose Connective Tissue of the Lamina Propria

Lamina ´propria´ from the latin word proprius says that this connective tissue is ´next´ to the epithelium in the sense that it belongs in a way to the epithelium. In line with this, the lamina propria has a loose structure that is different from other deeper layers of connective tissue that may occur underneath. The conjunctiva lies on the dense connective tissue of the Sclera of the wall of the eye ball and on the dense connective tissue of the tarsal plate at the back side of the eye lids. In the latter position, it forms the tarsal conjunctiva - in the former position it is the bulbar conjunctiva..

One biological sense of a loose lamina propria is, that it can act as a layer that allows a certain passive movement of the epithelium relative to the underlay without causing too much friction - this is necessary during eye movements and blinking and is also of relevance in contact lens wear (please see the images above and below).

 The loose connective tissue of the Lamina propria underneath the conjunctival epithelium allows a passive movement of the epithelium relative to the connective tissue and to the underlying sclera. This is necessary during eye movements and blinking as shown here, particularly during contact lens wear..

The loose connective tissue of the Lamina propria underneath the conjunctival epithelium allows a passive movement of the epithelium relative to the connective tissue and to the underlying sclera. This is necessary during eye movements and blinking as shown here, particularly during contact lens wear..

CELLS in the Lamina propria

Another advantage of the loose collagen meshwork is that it provides space for the a multitude of interspersed ´free´ cells that are mainly bone marrow derived cells with defense functions. They migrate through the tissue or are resident here for different amounts of time.

Some ´fixed´/ resident cells (fibroblasts) are the house-keeeping cells that produce the collagen matrix to accommodate the free cells and a rich network of support structures such as blood- and lymph-vessels and nerves. ... in contrast to the apparently ´more interesting´ fibrocytes of the cornea (keratocytes - see there) their mates in the conjunctiva have not received a specific name.

 

The Conjunctival Epithelium consists of TWO Cell Populations

The CONJUNCTIVA of the FORNIX has a multi-layered epithelium, which certainly contains goblet cells for production of the water-binding mucins. The cells in the surface layer are cuboidal or, as seen here, often columnar.  (Mucins in the Goblet cells and on the surface are artificially colored on the photo)

The Epithelium of the conjunctiva is mainly stratified cuboidal with typically two cell layers. In the fornix the number of cells layers increases and the superficial cell layer can become columnar.

Conjunctival epithelial cells consist of TWO CELL POPULATIONS:

  • (1) the ´ordinary´epithelial cells that build the tight cell layer and of
  • (2) the goblet cells that are interspersed secretory cells for production of secretory mucins that are released into the tear film and form its basal phase.

Both conjunctival cell populations derive from the same stem cells that give rise to two populations in a certains sequence of cell divisions.

The marginal CONJUNCTIVA in the LID WIPER region is multi-layered with up to 10 epithelial cell layers and cuboidal to columnar at the surface - goblet cell of the built-in lubrication system of the LID WIPER are interspersed at the surface and, as a novel finding, also within goblet cell crypts in the depth of the epithelium.

A multitude of GOBLET CELLS are interspersed throughout the human conjunctival epithelium as single intra-epithelial secretory cells. In certain laboratory animal species, like rat and mouse, goblet cells can also occur aggregated in clusters that may be regarded as small ´glands´.  In the human conjunctiva, goblet cells have a certain topographical distribution with highest concentration of goblet cells in the lower nasal conjunctiva as observed by KESSING in the 1970s.

 

Conjunctival Goblet cells produce secretory mucins that bind the water at the ocular surface

Goblet cells produce secretory mucins that are packed inside the cell into spherical secretory granules. The mucins are released from the goblet cells onto the cell surface through a narrow opening.

Released mucins near a goblet cell typically have a cloudy appearance in light microscopy (see image above) which suggests that their concentration is immediately diluted after release by water binding and transformed into a mucin-water gel that constitutes the main phase of the tear film.

Goblet cells can contain small or large volumes of mucins, depending on their functional state and they are innervated similar to the aqueous lacrimal glands. 

More information on Goblet Cells can be found in the section on the ´Glands of the Ocular Surface´.

 

THE CONJUNCTIVAL EPITHELIUM IS a TIGHT Barrier AGAINST PASSIVE ENTRANCE OF SUBSTANCES BUT HAS ALSO Transport- and SECRETORY FUNCTIONS

The main function of the conjunctival epithelium is to provide a TIGHT BARRIER to seal the interior of the ocular surface against the uncontrolled entrance of foreigns particles including more or less non-pathtogenic substances like dust or pollen and pathogenic antigens such as microbes. 

Therefore the conjunctival cells have a terminal bar of connecting intercellular junctions like desmosomes and the zonula adherens (adherens junction) but also sealing junctions in form of tight junctions that limit the para-cellular transport. Desmosomes, linked to the intracellular intermediate filaments can transmit tensile forces and hold the epithelial cells together. 

Apart from sealing the conjunctival epithelium has TRANSPORT and  SECRETORY FUNCTIONS. This applies for example to the

  • TRANSPORT

    • of polymeric IgA antibodies
      • they are produced by plasma cells in the lamina propria, and
      • transported through the epithelium with the help of a cell based transporter molecule name poly-Ig-Receptor (pIgR) 
      • since IgA is the main protein of the tear film, at least during night time, and the main protective molecule
      • its function is very important and
      • the epithelial transporter is strongly expressed in the epithelium (see image above)

 

    • water is transported through aquaporin channels and ion pumps in the cell membrane of the conjunctival epithelial cells and contributes to a conceivably minor but unknown amount of the aqueous tear fluid. The water transport is regulated, at least in part, by P2Y2 dependent mechanisms

  • SECRETION

    • of proteins such as the lubricative protein Lubricin - see image above.
      • this is a glycoprotein, product of the proteoglycan 4 (PRG4) gene. It is originally known from the lubrication of joints but is also produced by cells of the conjunctiva and cornea (see photomicrographs)
      • Lubricin presence at the Ocular Surface significantly reduces friction between the cornea and conjunctiva and lubricin deficiency may play a role in promoting corneal damage in Dry Eye Disease
      • Members of the Ocular Surface Center Berlin (OSCB) were the first to demonstrate the production and location of lubricin in human conjunctival and corneal cells in immunohistochemistry together with colleagues in Boston, MA, and Calgary, CAN,  who verified the production by RT-PCR and verified the lucricative effect in an ocular surface model.of

 

  • The Conjunctiva secretes TWO types of Mucins
    • the glycoprotein Mucin Muc5AC. This is a secretory mucin produced by a subpopulation of conjunctival epithelial cell (goblet cells) that derive from the same stem cell as the ´ordinary´ epithelial cells.
    • the membrane bound Mucins that form the Glycocalyx - a fuzzy coat of sugar molecules that can bind the aqueous phase of the tear fluid 

 

The mucosa-associated lymphoid tissue of the conjunctiva is a part of the Eye-Associated Lymphoid Tissue (EALT)

Lymphoid cells together with their accessory cells such as macrophages, dendritic cells, granulocytes and mast cells,  are resident at the normal ocular surface.

They are prominent in the normal conjunctiva mainly in the lamina propria but also as intra-epithelial cells. Physiologically the lymphoid cells are non-inflammatory and continuously involved in the protective maintenance of mucosal immune regulation with a a focus in tolerance in order to avoid inflammatory tissue destruction. These cells do not need to immigrate in order to interact in local immunological processes. This is an important difference from the previous perception that lymphoid cells immigrate as “inflammatory cells” into a primarily lymphocyte-free normal ocular surface as a secondary or tertiary event in inflammatory disease processes.

The lymphoid cells occur in some lymphoid follicles in certain locations. Most of the cells form a diffuse lymphoid tissue. This population consists of the diffusely interspersed lymphoid effector cells and of accessory cells such as macrophages, and is present in all ocular surface tissues. The diffuse cells may be inconspicuous to the unaccustomed eye or, on the other hand, if their presence was noted, they were previously considered as pathological.

The amount of such lymphoid cells varies in different locations, e.g. at the bulbar conjunctiva lymphoid cells are relatively scarce whereas they are more frequent in the orbital conjunctiva and in the fornix.