Mucin & Glycocalyx Dysfunction

Older diagrams often show the tear film as three neat layers:

lipid→aqueous→mucin

with mucin forming a thin layer directly against the cornea. This model is useful for basic teaching, but it does not accurately represent what we now understand about the tear film.

The modern picture is more complex. The main body of the tear film is often described as a mucoaqueous phase, in which water, proteins, electrolytes and secreted mucins coexist. At the ocular surface itself, membrane-associated mucins extend from the epithelial cells and form an important part of the glycocalyx — a carbohydrate-rich interface between the epithelial cells and the tears.

So when we talk about a mucin/glycocalyx problem, we are not simply talking about one missing layer. We are talking about disruption of an important system that helps connect the tear film with the ocular surface.

The Ocular Surface, Mucins & Glycocalyx: how it normally works

Several different mucins are found at the ocular surface, and they do not all perform exactly the same role.

One particularly important secreted mucin is MUC5AC, which is produced by goblet cells in the conjunctiva. It becomes part of the mucoaqueous tears and contributes to hydration, lubrication and protection of the ocular surface. Secreted mucins can also help trap debris and microorganisms so that they can be removed from the eye.

Other mucins — particularly MUC1, MUC4 and MUC16 — are associated with the membranes of epithelial cells. These membrane-associated mucins contribute to the glycocalyx covering the exposed epithelial surface. Together with other molecules, this glycocalyx creates a highly specialized interface between the living cells of the ocular surface and the tear film above them. It contributes to surface hydration, lubrication and barrier function and helps the tear film interact normally with the epithelial surface.

A mucin/glycocalyx problem can involve several different changes:

• •there may be fewer healthy conjunctival goblet cells
• •the amount or properties of secreted mucins such as MUC5AC may change
• •expression or structure of membrane-associated mucins can be altered
• •the glycocalyx itself can become disrupted
• •the epithelial surface underneath it can become damaged, further changing the interface between the tears and the eye

These abnormalities are related, but they are not identical. This is why mucin deficiency, goblet-cell loss and glycocalyx dysfunction should not be treated as interchangeable terms. They describe different parts of the same broader ocular-surface system.

A healthy ocular surface needs to remain compatible with the tear film covering it. This is sometimes described in terms of wettability.

Think about placing a drop of water on two different surfaces. On one surface, the water spreads easily. On another, it beads up and pulls away. The ocular surface is obviously much more complex than either of these examples, but the basic idea is useful: the physical and biochemical properties of the surface influence how fluid behaves on it.

Mucins and the glycocalyx help create an ocular surface over which the tear film can spread and remain appropriately distributed. If that interface becomes abnormal, the tear film may become less stable even when other components of the tears are present.

This is an important idea: tear-film instability does not always mean that the problem began with evaporation or insufficient tear production. Sometimes the interaction between the tears and the surface itself is part of the problem.

The glycocalyx is not simply a coating that makes the eye “wet.” It is part of the ocular surface barrier. Membrane-associated mucins and their carbohydrate structures interact with other molecules, including galectin-3, to help create a protective barrier over the epithelial cells.

When this system is disrupted, several things can happen. The surface may become less easily wetted by tears. Barrier function can become impaired. Friction between the eyelid and ocular surface may increase. And the tear film can become more prone to localized instability and breakup.

This means that a tear film can contain fluid and still fail to behave normally because the surface underneath it is no longer providing the right interface.

Goblet cells are specialized cells located in the conjunctiva. One of their major roles is producing and secreting MUC5AC, the principal gel-forming mucin of the human ocular surface. MUC5AC contributes to the mucoaqueous tears and has important roles in lubrication, hydration and protection.

Studies have repeatedly found reduced tear concentrations of MUC5AC in people with dry eye, and reduced goblet-cell density can also occur in dry-eye disease.

But again, the relationship should not be reduced to:

“fewer goblet cells = less mucin = dry eye.”

The ocular surface is a dynamic system. Mucin production and secretion are regulated processes, different mucins perform different functions, and changes in one component can occur alongside changes in epithelial cells, inflammation, tear volume and other parts of the system. Both the quantity and the normal regulation of mucins matter.

Normally, blinking redistributes the tear film across a surface that is capable of interacting with it. If the tear–surface interface is disrupted, that freshly spread tear film may become unstable more quickly. Localized areas can begin to break up before the next blink. This exposes the underlying ocular surface to greater stress.

And once tear-film instability and surface stress develop, they can begin to affect other parts of the system. For example, ocular-surface stress and inflammation can further affect epithelial cells, goblet cells and mucin expression. This can create a feedback loop:

surface disruption→poorer tear-film stability→greater surface stress→further surface disruption

This is one of the reasons dry eye can become self-perpetuating.

Not always — and this is where the categories can overlap.

The glycocalyx is physically associated with the epithelial cells of the ocular surface. If those cells become damaged, the glycocalyx and membrane-associated mucins can also be affected. At the same time, disruption of the glycocalyx can reduce barrier function and make the ocular surface more vulnerable. So the relationship can work in both directions.

This is why dry-eye mechanisms do not always fit into perfectly isolated boxes. TFOS DEWS III separates mucin/glycocalyx deficiency as a tear-film driver and ocular-surface cellular damage/disruption as another potential driver. That distinction is useful for understanding the system, even though these abnormalities can interact in real life.

Ocular-Surface Damage & Disruption

Just like lipid and aqueous deficiencies, mucin/glycocalyx dysfunction does not have to occur alone. A person may simultaneously have abnormalities involving tear volume, tear-film lipids, blinking, inflammation or the epithelial surface itself.

And one abnormality can influence another. For example, an unstable tear film can increase ocular-surface stress. Surface stress and inflammation can affect goblet cells and epithelial function. Changes in mucins and the glycocalyx can then make the tear film still less stable.

So once again, the useful question is not always “Which single type of dry eye do I have?” It may be more useful to ask: “Which parts of my tear-film and ocular-surface system are not functioning normally?”

There are many different reasons why the mucin/glycocalyx system can become disrupted. Some involve diseases or inflammation of the ocular surface, some affect goblet cells or epithelial cells, and others may be related to medications, environmental exposure, nutritional problems or other conditions.

Those are questions about why the problem developed. Here, the important thing is to understand what the problem actually is: an abnormal interaction between the tear film and the ocular surface involving mucins, the glycocalyx or both.