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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
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