OCULAR IMMUNOLOGY

Dr Aditi Singh

THE OCULAR IMMUNE RESPONSE

THE REGULATORY COMPONENTS OF THE ANTERIOR SEGMENT

The eye is more sensitive than most tissues to the consequences of injury and repair.

THE OCULAR IMMUNE RESPONSE INVOLVES –

Local: conjunctiva cornea and sclera anterior chamber,anterior uvea and vitreous retina/retinal pigment

epithelium/choriocapillaries choroid

Regional:

lacrimal gland,

lymph nodes,

neuroanatomic integration

Systemic: ACAID(anterior chamber associated immune

deviationspleen,thymus,MALT(mucosal associated lymphoid tissue)

TEAR FILM AND LACRIMAL APPARATUS

The tear film and lacrimal gland play an important role in ocular immune response.

The normal components of tear film are lipids

,polysaccharides and proteins.

Lipid layer : secreted by memobian gland. functions to retard evaporation.

Mucin layer : secreated by the intraepithelial goblet

cells . facilitates the wetting of the ocular surface.

Aqueous layer made up of water, mucinous proteoglycans, growth factors

Important antibacterial components lysozyme, lactoferrin, β lysine, SIgA (Serum Immunoglobulin A). 

LACTOFERRIN

Prevents complement activation

decreases inflammation

Preventing the formation of

C3a C5a

Inhihibits the formation of C3 convertase

LYSOSOSYME

Lyse cell wall of

Gram positive bacteria

SIgA

bacteriolysis

β lysine : ruptures bacterial cell membranesSIgA: modulates the normal flora of the

ocular adnexa Tear IgG: increases during acute inflammation

LACRIMAL GLAND:

IgA and IgDadaptive immune response

Th(T helper cells)

With age-IgA decreases

IMMUNOPATHOLOGY

Autoantibodies in the lacrimal gland play an important role in mediating lacrimal gland inflammation

SJOGREN’S SYNDROME

lacrimal and the salivary glands

infiltrated with Th(helper T cells) Tc(cytotoxic T cells) B cells

INFLAMED LACRIMAL GLANDS

IFN γ •Inflammatory mediator

ICAM1MHC II

•Cell surface proteins

T cell •Increases inflammation

CONJUNCTIVA:

The conjunctiva is a complex element of mucosal immune defence system and actively participates in the ocular immune response against the foreign agents.

It is composed of two layers : a)an epithelial layer b)connective tissue layer called substantia

propria.

IMMUNOCOMPETENT CELLS IN CONJUNCTIVA

fibroblasts

Plasma cells

Epithelialcells

Endothelialcells

Mast cells

MALT(MUCOSAL ASSOCIATED LYMPHOID TISSUE)

MALT

Ocular surface &

adnexa

respiratory tract

Gut & Genitourinary

tract

Ocular MALT

Lacrimal gland, tear

film

Conjunctiva

(CALT)cornea

MALT share certain specific immunological features:

Rich investment of APCs(Antigen Presenting Cells)

Specialized structures for localized antigen processing(eg: Peyer’s patches and tonsils)

Unique effecter cells (eg: intraepithelial T lymphocytes and abundant mast cells)

Predominant leukocyte in the conjunctiva is T CELLS (90%)

76%CD 8

14%CD 4

T Cells

Lymphocyte distribution:

Ts(suppressor Tcells) outnumber Th (helper T)cells.

Most of them are in the epithelium.

In the fornix ,lymphocytes are more concentrated in the substantia propria.

The high endothelial venules(HEV) characteristic of MALT have been demonstrated in the conjunctiva.

One of the most important immunoregulatory cells of the ocular surface are the APCs(antigen presenting cells).

LCs(langerhans cells) are the principal APCs of the ocular surface.Their densest distribution is along the medial epibulbar region and inferior forniceal region.

The substantia propria is richly infiltrated with mast cells.

o Mast cells traditionally have been associated with certain allergic diseases .

Have been found in the conjunctival epithelium of patients with vernal keratoconjunctivitis or giant papillary conjunctivitis.

ANTERIOR CHAMBER ANTERIOR UVEA AND VITREOUS:

The anterior chamber is a fluid filled cavity.

Circulating aqueous humor provides a unique medium for intercellular communication among cytokines,immune cells and resident tissue cells of the iris ,ciliary body and corneal endothelium.

A partial blood ocular barrier is present .

Fenestrated capillaries in the cilliary body allow a size dependent concentration gradient of plasma macromolecules to permeate the interstitial tissue.

The tight junctions between the pigmented and the non pigmented epithelium provide a more exclusive barrier,preventing interstitial macromolecules from permeating directly through the ciliary body into the aqueous humour.

IMMUNOREGULATORY SYSTEMS:

The anterior uvea has an immunoregulatory system that has been described as immune privilege.

Immune privilege is mediated by influences on both the afferent and the effector phase of the immune response arc.

Anterior Chamber Associated Immune Deviation(ACAID).

Following injection of the antigen into the anterior chamber

the afferent phase begins

specialized macrophages in the iris recognise and

take up antigens

These macrophages leave by the trabecular meshwork and the Schlemms canal

enter the venous circulation.

preferentially migrate to the spleen. 

the antigen signal is processed

alter CD 4 helper T lymphocyte response

CD 8 regulatory cells

Downregulation of CD 4 T lymphocyte DH(delayed hypersensitivity) responses

selective suppression of selectively diminished

antigen specific DH production of complement -fixing isotype of antibodies

Especially important to the clinician is the capacity of a tissue site to sustain the second effector phase of the immune response arc,because the primary immune response arc in autoimmune diseases might have occurred outside the eye.

In this regard the ,the secondary effector phase of the anterior segment is also immunomodulatory ,and has been termed as effector blockade.

Mechanism for effector blockade are multifactorial but include production of the following:

immunomodulatory cytokine, produced by the ocular tissues

immunomodulatory neuropeptides ,produced by the ocular nerves

functionally unique APCs complement inhibitors in aqueous humor

CORNEA:

Corneal Epithelium: Many types of cell surface receptors and

proteins are present on the ocular surface epithelium.

Constitutively express MHC-1 ,but can upregulate MHC class II and may function as APC

Secreate :IL-1,IL-6,IL-8,TNF-α,INF-ϒ,TGF- α,C5a and LTB4.

Prostaglandins are also released

Corneal Stroma:

Fibroblasts down regulate lymphocyte function

Secreate several cytokines as IL-1, and TNF- α

Corneal Endothelium: Constitutively expresses ICAM-1 ,VCAM and

receptors for low- density lipoproteins.

Stimulated to express MHC class II and ICAM-1 by various cytokines including IL-1β,TNF-α and INF-ϒ

Afferent pathway of immune recognition in normal and inflamed eyes

Lymphatics: The normal cornea lacks lymphatic drainage

Afferent pathways from the anterior chamber follow the aqueous outflow to the venous system and the spleen

Vascularized corneal lymphatic beds ,however do possess lymphatic channels that drain corneal foreign body antigen or APC through conjunctival lymphatics to the regional lymph nodes.

Efferent pathways in normal and inflamed eyes

Corneal vascularisation:• The vascular limbus is an important efferent and

afferent regulatory structure of the normal cornea and plays a critical role in peripheral corneal disease and angiogenesis.

Corneal neovascularisation alters the microenvironment of the ocular surface and cornea by providing a conduit for the arrival and egress of antigen specific and nonspecific cellular elements

RETINA ,RPE CHORIOCPILLARIES AND CHOROID:

The retinal circulation demonstrates a blood –ocular barrier at the level of tight junctions between adjacent endothelial cells.

The vessels of the choriocapillaries are highly permeable to macromoleculea and allow transudation of most plasma macromolecules into the extravascular space of choroid and choriocapillaries.

The tight junction between the RPE cells provide the true physiological barrier between the choroid and the retina.

Well developed lymphatics are absent,although the retina and choroid have abundant potential APCs.

RPE can be induced to produce class II MHC molecule ,suggesting that it may also interact with T-Cells.

The density of the mast cells is moderate in the choroid ,especially around the arterioles but lymphocytes are present only in very low density.

• Eosinophils and neutrophils are absent.Local immune

response does not seem to occur. 

CLASSES OF IMMUNOLOGIC REACTIONS

TYPE I: anaphylactoid hypersensitivity

Eg: vernal catarrah

Atopic keratoconjunctivitis

TYPE II : CYTOTOXIC HYPERSENSITIVITY

It is caused by the action of the antibodies directed against antigens present on cells. The cytotoxic anaphylaxis is thus caused by antitissue antibodies.

Circulating immunoglobulins are usually combining ,in the presence of complement,with the antigens that are already present in the cell. The mechanism of this particular reaction is concerned with IgM and IgG.

This mechanism does not appear to be very important in ocular inflammation ,although it may play a role in killing virus infected cells in viral conjunctivitis.

Eg: Vogt-Koyanagi-Harada Syndrome(?) Sympathetic Ophthalmitis(?)

TYPE III: IMMUNE COMPLEX HYPERSENSITIVITY

Large quantities of soluble antigen-antibody complexes form in the blood and are not completely removed by macrophages.

These antigen-antibody complexes lodge in the capillaries between the endothelial cells and the basement membrane.

These antigen-antibody complexes activate the classical complement pathway leading to vasodilation.

The complement proteins and antigen-antibody complexes attract leukocytes to the area.

The leukocytes discharge their killing agents and promote massive inflammation. This can lead to tissue death and hemorrhage.

Disciform keratitis

Wessely immune ring caused by the “zone of optimal proportions” of antibody and antigen

TYPE IV: CELL MEDIATED /DELAYED HYPERSENSITIVITY 

Allergic contact dermatoconjunctivitis of the lid

• Sympathetic ophthalmia• Granulomatous• diseases:tuberculosis,lepro

sy and toxoplasmosis• Allograft rejection

REFERENCES:

OCULAR IMMUNOLOGY: Gilbert Smolin ,G Richard O’Connor

INTRAOCULAR INFLAMMATION AND UVEITIS:American Academy Of Ophthalmology

CORNEA:Krackmer,Mannis,Holland

DIAGNOSIS AND TREATMENT OF UVEITIS:C.Stephen Foster,George F Vittale