Ocular Immunity

Question 1

Why is ocular immunity such an important topic?

Answer 1

Eye is exposed to external environment but if it were to have an immune repose tissue damage may occur which can lead to loss of sight
Corneal Endo and retinal cells also cannot regenerate

Question 2

What are the anatomic and physical barriers of the eye?

Answer 2

Eyelids and eyelashes

Question 3

What are the defense mechanisms of the tears?

Answer 3

Mucins
Antimicrobial proteins/peptides
Complements
Immunoglobulins

Question 4

What are the defense mechanisms of the ocular surface epithelium?

Answer 4

Tight junctions
PRRs

Question 5

What are the Eye-associated Lymphoid Tissues?

Answer 5

LGALT (Lacrimal gland)
CALT (Conjunctiva)
LDALT (Lacrimal drainage)

Question 6

What is the sources of antimicrobial peptides in the eye?

Answer 6

Lacrimal glands and epithelium
Serum exudates
Infiltrating cells (PMNs)

Question 7

What is the function of antimicrobial peptides in the eye?

Answer 7

Interfere with microbial adherence (lactoferrin)

Disrupt microbial membrane (lysozymes, cathelicidin,
PLA2, defensins, complement factors)

Interfere with microbial growth (lipocalin A, lactoferrin)

Neutralize and aggregate toxins and microorganisms (sIgA and defensins)

Question 8

Describe the process and success rate of corneal transplants.

Answer 8

Most corneal transplants are not tissue typed and are between unrelated individuals

90% successful
No systemic immunosuppressive therapy
Only topical immunosuppressive

Question 9

What is the definition of immune privilege? What are some examples in the eye and outside of the eye?

Answer 9

Ability of tissues to tolerate the introduction of foreign antigens without eliciting an inflammatory immune response
Ex: corneal allograft acceptance
AC, cornea, vitreous cavity, subretinal space
brain, testes

Question 10

What 3 components allow for ocular immune privilege?

Answer 10

Physical and anatomical barriers
Local immune regulation
Eye-derived systemic immune deviation (ACAID= Anterior chamber associated immune deviation)

Question 11

Describe the blood ocular barrier that plays a role in ocular immune privilege.

Answer 11

Iris & retinal vessels: non-fenestrated vascular endothelium, tight junctions

Ciliary body & Iris epithelium and RPE: epi cells linked by
tight junctions

Question 12

How does the absences of vascular supply aid in ocular immune privilege?

Answer 12

Avascularity→limits the movement of granulocytes,
lymphocytes, monocytes and plasma proteins and antigens from blood to tissues
• Cornea
• Lens

Question 13

Where in the eye do we have lymphatics and where are they absent?

Answer 13

Absent: normal cornea, lens, iris, ciliary body,
retina, choroid, sclera and all the intraocular compartments

Present: eyelids, lacrimal glands, conjunctiva,
limbus, and episclera

Question 14

Describe the mechanism of lymphatic vessels in the limbus extending to the cornea.

Answer 14

Under inflammatory conditions, the limbal lymphatics can give rise to new lymphatics, which can extend into the cornea.

Infection, corneal transplant rejection, and dry eye disease are common conditions in which lymphangiogenesis occurs.

Question 15

What contributes to the immunosupressive environment of the eye?

Answer 15

Presence of soluble immuno-modulatory factors in
aqueous humor

Presence of immuno-modulatory ligands on the surface of ocular parenchymal cells.

Presence of few and immature APCs in the cornea

Induction of both CD4+ T regs and CD8+ Tregs

Corneal endothelial and retinal cells do not express
MHC1a, so are not recognized by cytotoxic lymphocytes.

Aqueous humor has low levels of IgG, but other isotypes are absent.

Question 16

What immunosupressive factors exist in the aqueous humor?

Answer 16

Aqueous humor inhibits proliferation, cytotoxic activity, and production of pro-inflammatory cytokines in T cells.

• Suppresses production of the proinflammatory IFN-Ɣ,

• Induces production of the regulatory cytokine TGF β.

Question 17

What is TGF-B produced by and found in within the eye?

Answer 17

Macrophages, monocytes, T and B cells

Normal Aqueous humor, tears

Question 18

What does TGF-B inhibit within the eye?

Answer 18

T lymphocyte and thymocyte proliferation

IL-2 receptor expression

B cell proliferation and immunoglobulin production

Development of CTLs (but not activity of CTLs)

Generation and activity of lymphokine activated killer (LAK) and NK cells, etc.

Activation of lymphocytes and macrophages

Question 19

What is the function of Vasoactive intestinal peptide (VIP) in ocular immunity?

Answer 19

suppresses lymphocyte proliferation; found in AH, choroid, anterior and posterior uvea

Question 20

What is the function of alpha-melanocyte stimulating hormone in ocular immunity?

Answer 20

suppresses interferon Ɣ, anti-inflammatory TGF ß

Question 21

What is the function of calcitonin gene related protein in ocular immunity?

Answer 21

inhibits DTH (delayed-type hypersensitivity, type IV)

Question 22

What is the function of cortisol in ocular immunity?

Answer 22

General immunosupressive substance in AH

Question 23

What is the function of NK cell inhibitory factor in ocular immunity?

Answer 23

Inhibits NK cell activity

Question 24

What is the function of complement regulatory proteins in ocular immunity?

Answer 24

Inhibits complement proteins

Question 25

What are 3 membrane bound proteins and their function in ocular immunity?

Answer 25

FAS-ligands
• Fas-L binds to immune cells with Fas-L receptors →induces apoptosis
• Expressed in the eye by the corneal epithelium,
endothelium, iris, ciliary body and throughout the retina.

Program cell death protein (PD-L1 or PD-L2)
• Inhibit T cell proliferation
• Inhibit cytokine secretion
• T cell apoptosis

Complement regulatory proteins
• Inhibit complement proteins

Question 26

What is ACAID? What is it induced by?

Answer 26

Anterior chamber associates immune deviation
Systemic form of tolerance that occurs when a foreign antigen is placed into an ocular micro environment

Induced by:
• Soluble protein antigens • Viral antigens
• Allo-transplantation antigens • Tumor antigens

Question 27

What cellular responses are involved with ACAID?

Answer 27

Th1 and Th2 (impaired DTH) and Th17 cells are suppressed, cytotoxic T cells combat antigens

Question 28

What antibody responses are involved with ACAID?

Answer 28

Impaired production of complement fixing antibodies, increased production of non-complement fixing antibodies

Question 29

What cytokine profile is associated with ACAID?

Answer 29

IFN-Ɣ suppressed, IL-10 produced, TGFβ stimulates APC that favors the development of regulatory T cells

Question 30

What are the requirements for ACAID?

Answer 30

Non-inflamed eye
Intact spleen
Intact thymus
Intact sympathetic nervous system

Question 31

What is the clinical significance of ACAID?

Answer 31

Delayed type hypersensitivity would be the most effective defense however the eye cannot do this

Eye uses cytotoxic T cells and non complement fixing antibodies to combat pathogens

Reduces risk of inflammation and promotes allograft acceptance

Question 32

What are the benefits of ACAID?

Answer 32

Reduced risk for immune-mediated inflammation in the eye

Corneal allograft acceptance

Prevents ocular autoimmunity

Ex. Prevents stromal keratitis in HSV1 (herpes simplex type 1) infections because delayed type hypersensitivity is inhibited.
– Stromal keratitis is seen in only 20% of HSV1 infections

Question 33

What can be the adverse effects of ACAID?

Answer 33

Herpes simplex virus (virus may spread via neurons)
Ocular tumors (stop spread systemically but often not ocular tumors themselves)
Eye is vulnerable to autoimmune uveitis
Benefits outweigh the risks

Question 34

When does rejection occur for a corneal transplant?

Answer 34

Immune elements gain access to the graft via blood vessels

Failure to eliminate immune effector elements at the host-graft interface ie defective expression of FasL or PD1 or complement regulatory proteins

Abolishment of ACAID