Aqueous Humor Dynamics and the Blood-Aqueous Barrier

IOP facilitates blank% water content in the cornea

78%

What are the main functions of the Aqueous humor?

1. Provides nutrients to ocular tissues

2. Maintains corneal curvature

3. Transmits light

4. Absorbs UV light

5. Transports waste products away

What is the aqueous humor secreted by?

The ciliary epithelium lining the ciliary processes

What is the secretion of the aqueous humor driven by? (Two things)

1. Active ionic transport across the ciliary epithelium

2. Hydrostatic and osmotic gradients between posterior chamber and the ciliary process vasculature and stroma

What is the general path of aqueous humor flow?

Around the lens and through the pupil into the anterior chamber

What drives aqueous movement in the anterior chamber?

Convection flow

Is secretion of aqueous humor solely done by the ciliary epithelial processes?

Fluid transport rates by ciliary epithelia are insufficient alone to account for the rate of AH formation

Where else besides the ciliary epithelia is there secretion of aqueous humor? (Mechanism)

Protein and aqueous diffuses from the ciliary body stroma, to the root of the iris, accumulates in the iris stroma and is then released into the aqueous humor of the anterior chamber

What is the convection flow of aqueous humor in the anterior chamber driven by?

Temperature differences in the anterior chamber and density of AH due to temperature changes

What are the temperature differences in the anterior chamber caused by?

AH is is warmer near the iris because its vascularized and colder near the avascular cornea

What causes aqueous humor to flow up to the avascular cool cornea?

Warmer AH is less dense and its buoyancy causes it to rise

What happens once the convection currents bring AH to the cornea?

Cooler AH sinks due to its increased density

What are the two pathways by which AH is drained?

Conventional route and the Uveoscleral/unconventional route

What is the general conventional route for AH drainage?

Through the trabecular meshwork, across the inner wall of Schlemm’s canal into its lumen, through collector channels, deep scleral/intrascleral/episcleral plexus (aqueous veins), and the episcleral vein

What is the general uveoscleral/unconventional route of AH drainage?

Across the iris root, through uveal meshwork, and anterior face of the ciliary muscle, through the connective tissue between muscle bundles, into the suprachoroidal space, and through the sclera

Which route does the majority of aqueous humor drain?

Conventional route (45-65%)

What route does the minority of aqueous humor drain?

Unconventional/uveoscleral route (35-55%)

Which route of AH drainage decreases in facility with age?

Unconventional

What is the role of the blood aqueous barrier?

Enables aqueous humor to have a composition different from the protein-laden filtrate of plasma that enters the ciliary body stroma

What are the two major components of the BAB?

Non leaky tight junctions, non-fenestrated blood vessels of the iris

Where are the non leaky tight junctions that form the blood-aqueous barrier found?

1. Nonpigmented epithelium of the ciliary body

2. Posterior iris epithelium

3. Iris vasculature

4. Inner wall of Schlemm’s canal

What is the source of aqueous humor proteins?

Fenestrated capillaries of the ciliary body

Why is it possible for there to be proteins in the aqueous humor?

Proteins can exit into the aqueous humor because of the lack of containing epithelium

Where is protein concentration in the aqueous humor higher?

Peripherally near the trabecular meshwork than centrally

What is the pathway of AH protein infiltration into the aqueous humor?

Infiltrates ciliary stroma, through the iris root and out at the filtration angle

How does the protein concentration of of the AH compare to the protein concentration of the blood plasma?

Protein concentration of AH is far less than in the blood plasma

What are the similarities between protein types in AH and blood plasma?

1. Albumin

2. Fibrinolytic and pro-coagulation proteins

3. Growth factors and cytokines

4. Complement proteins

What is the most abundant aqueous humor protein and what does it do?

Albumin (~50%) which maintains oncotic presure

What is an AH protein unique to the eye and what does it do?

Myocilin; helps maintain extracellular homeostasis (helps maintain ECM proteins)

What pathology is Myocilin associated with?

Glaucoma

What is a major pathological issue associated with AH proteins?

Flare

What is Flare due to?

Breakdown of the blood aqueous barrier

What does Flare cause in the anterior chamber?

Loss of transparency of AH due to Tyndall effect which can be viewed by the slit lamp

What is Flare a sign of?

Uveitis

What is Uveitis?

Inflammation of the uvea due to ocular tissue damage, pathogens, or toxins

What does Uveitis cause?

An accummulation of proteins and cells in the aqueous humor

What are the major anatomical types of uveitis and what tissues do they involve?

1. Anterior Uveitis: ciliary body/iris

2. Intermediate: Vitreous/peripheral retina

3. Posterior Uveitis: Choroid, vitreous, retina

4. Pan Uveitis: Includes all the tissues

Is Uveitis found isolated or found with other illnesses?

Can be found isolated or found with other illneses

What are the 2 etiological categories of Uveitis?

Non-infectious and Infectious

What are the causes of non-infectious uveitis?

1. Idiopathic (includes many cases)

2. Associated with immunological diseases

3. Injury

What are the infectious causes of Uveitis?

1. Viral infection (HSV/VZV/CMV)

2. MIcrobial (Syphilis/Lyme/Mycobacteria)

What is TNF-alpha?

An inflammatory cytokine produced by macrophages

TNF-alpha is often elevated in patients with blank.

Uveitis

TNF-alpha receptors are found in blank.

Uveal pigmented cells

What is TNF-alpha normally critical for?

Initiating immunity to pathogens

What happens when TNF-alpha levels become too high?

Instigates levels of inflammation, cell death, and tissue degeneration

How do the upregulated inflammatory pathways contribute to uveitis?

1. Recruitment of immunological cells to anterior chamber

2. Overwhelm ocular immune privilege mechanisms

3. Breakdown in the blood aqueous barrier (tight junctions) leads to enhancement of inflammation

What main thing occurs during the breakdown in the blood aqueous barrier due to Uveitis which leads to enhancement of inflammation?

Disruption of ocular epithelial tight junctions

How are ocular epithelial tight junctions disrupted (three ways)?

Reduction of TJ protein/mRNA expression, Modification of TJ proteins, Enzymatic cleavage of TJ proteins

What does disruption of ocular epithelial tight junctions/breakdown of the BAB allow?

Allows access of more immune cells to propagate inflammation pathways

What are the two main uveitis treatments?

Anti-TNF drugs and Corticosteroids

What are anti-TNF drugs?

Antibodies designed to prevent TNF from binding to receptors on ocular cells

What do anti-TNF drugs do?

Prevents signaling of TNF-alpha pathway

What do corticosteroids do to treat uveitis?

Reduces ability of cells to produce pro-inflammatory molecules and proteins

What is ocular immune privilege/immune privilege in general?

The ability to tolerate foreign antigens without instigating an inflammatory immune response

What is another important quality of immune privileged tissues?

They don’t instigate rejection when implanted in ectopic sites

What are the two reasons why inflammation pathways in the eye need to be reduced?

1. Disrupts vision

2. Some ocular tissues cannot regenerate and need to be protected from inflammatory pathways

What specific tissues in the eye cannot regenerate and therefore need to be protected from inflammatory pathways?

Corneal endothelium and retinal neurons

Examples of immune privileged sites in the eye (Part 1)?

Cornea, anterior chamber, vitreous cavity

Examples of immune privileged sites in the eye (Part 2)?

Subretinal space, lens, RPE, retina

What are the three overarching characteristics of the nature of ocular immune privilege?

1. Immunological ignorance

2. Peripheral tolerance of eye-derived antigens

3. Intraocular immunosuppressive microenvironment

What are the ways immunological ignorance is achieved in the eye?

1. Blood Aqueous barrier

2. Absence of lymphatic drainage pathways

3. Lack of MHC class II antigens and reduced MHC class I in dendritic cells

Lymphatics only drain what ocular structures?

Conjunctiva, sclera, choriocapillaris

How does the absence of lymphatic drainage pathways promote immunological ignorance (and therefore immune privilege)

Shields ocular antigens from the immune system

What is the state of corneal dendritic cells?

They are in varying states of maturity

When is a corneal dendritic cell deemed to be “immature”?

Incapable of interacting/activating T-cells

When is a corneal dendritic cell deemed to be "mature”?

Capable of interacting with and activating T-cells

What is maturity of resident corneal dendritic cells based on ultimately?

Presence of major histocompatibility complex class II proteins (MHC class II)

Central corneal dendritic cells are mostly (immature/mature)?

Immature

How can injury/infection affect the maturity of corneal dendritic cells?

Can cause them to change from immaturity to maturity

Corneal dendritic cell presentation of an antigen mechanism:

1. Antigen proteins are endocytosed by dendritic cells

2. Combined with MHC class II molecules inside cells

3. Then moved to the cell surface (antigen presentation)

How is peripheral tolerance of eye-derived antigens achieved?

Via ACAID

What does ACAID stand for?

Anterior-Chamber-Associated Immune Deviation

What is the mechanism of ACAID?

1. Anterior chamber antigen presenting cells (APCs) detect antigen

2. Migrate through the trabecular meshwork, through blood to the spleen/thymus

3. APCs eventually inhibits systemic immune response in the spleen

What does ACAID essentially do?

Creates a high threshold to make sure there is really something wrong in the eye before ramping up inflammation (Promotes transparency and protects sensitive cells from potential damage)

Does the ACAID mechanism only occur in the anterior chamber?

Similar process occurs in vitreous and subretainl space

Why does immune privilege involve an intraocular immunosuppressive microenvironment in addition to the other mechanisms?

Despite other immunosuppressive measures, innate/adaptive immune cells can still gain access to the eye

What are present to build an intraocular immunosuppressive microenvironment?

Immunosuppressive factors

What do immunosuppressive factors do?

Function to inhibit various immunological functions

What are the two main types of immunosuppressive factors in the eye?

Soluble factors and cell-associated factors (look at the specific kinds on slides)

What are the types of soluble intraocular immunosuppressive factors?

Neuropeptides, cytokines, growth factors

What are cell associated factors?

Cell-surface molecules that either bind and inhibit antigens or activate anti-inflammatory pathways