week 1 immunology of the eye

Question 1

two types of immune system?

Answer 1

innate, adaptive

Question 2

things involved in innate immune response

Answer 2

immediate= Anti-microbial proteins, Complement, Mast cells, Macrophages, Inflammation,

Recruitment/activation of phagocytes
Inflammation

Question 3

things involved in adaptive immune response

Answer 3

CD4, CD8, Bcells

Question 4

innate IS of eye

Answer 4

• Blink reflex
• Physical and chemical properties of eye surface
• Limit exposure/size

Question 5

what properties does the blink reflex possess to help Innate IS

Answer 5

TEARS – PHYSICAL

• Flushing out
• Mucous layer = anti-adhesive

Question 6

what properties do the chemical properties of the eye possess to help Innate IS

Answer 6

TEARS – CHEMICAL

Lysozyme: v. gram –ve bacteria, fungi (destroy bacteria cell wall)
Lactoferrin and transferrin: v. gram +ve bacteria
Tear lipids: antibacterial to cell membranes/scavenger of bacterial products
Angiogenin: antimicrobial effect within tear film
Secretory IgA: prevents attachment
Complement
IL-6, IL-8, MIP: antimicrobial molecules that recruit leucocytes

Question 7

what properties do the immune cells in the eye possess to help Innate IS

Answer 7

TEARS – CELLULAR

Neutrophils:
-Attracted by chemotaxis
-Scavengers – release free radicals, enzymes
Macrophages:
-Phagocytosis of damaged cells
-Help to trigger adaptive immune system
Conjunctival mast cells:
-Vasoactive mediators

Question 8

what three things does the adaptive IS require?

Answer 8

1-Antigen presenting cells (APC = dendritic cells, B cells, macrophages)
2-Lymphatic drainage to lymph node
3-Variety of effector cells (incl. CD4+ T cells, CD8+ T cells, B cells)

Question 9

what type of cell are langerhans cells in the eye? function and how does it achieve this?

Answer 9

macrophages

Principle APC for external eye
Rich in Class II MHC molecules

Question 10

where are langerhans cells in the eye found?

Answer 10

Abundant at corneo-scleral limbus, less in peripheral cornea, absent from central 1/3rd of cornea

Question 11

what is the only part of the eye with lymphatic drainage?

Answer 11

conjunctiva

Question 12

what allows regulated migration of lymphoid cells in conjunctiva?

Answer 12

Specialised endothelial venules

Question 13

what do dendritic cells act as in conjunctiva?

Answer 13

APC’s

Question 14

the conjunctiva is a MALT, what is this? what is found there?

Answer 14

Mucosa associated lymphoid tissue (MALT)
Macrophages, Langerhans cells and mast cells frequent the MALT, neutrophils/eosinophils only there if recruited

please note commensal bacteria are found on conjunctiva

Question 15

what is described a being made from a tough collagen coat?

Answer 15

Cornea and Sclera

Question 16

describe the IS in the Cornea and Sclera

Answer 16

Avascularity
No lymphatics/lymphoid tissue
Relative lack of APCs
Langerhans cells only in peripheral cornea
Downregulated immune environment

Question 17

what does the lacrimal drainage system contain?

Answer 17

Diffuse lymphoid tissue and follicles (40-50%) in mucosa (MALT)

Question 18

what does the lacrimal gland contain?

Answer 18

More plasma cells (IgA) and CD8+ T cells compared to conjunctiva
T cells in small groups around intralobar ducts
Resting lymphoid cells very rarely observed

Question 19

describe the IS in the Vitreous, choroid & retina

Answer 19

Blood-ocular barrier
Relative lack of APCs
Downregulated immune environment

therefore lots of potential for damage to occur=”petri dish with protective covering”

Question 20

what is immune privilege

Answer 20

They are able to tolerate the introduction of antigens without eliciting an inflammatory immune response

Question 21

what sites have immune privilege?

Answer 21

Brain/CNS (controversial)
Testes
Placenta/foetus(EG: baby is foreign material but IS does not attack it)
EYES

Question 22

what sites in the eye are immune-privileged?

Answer 22

Cornea
Anterior chamber
Lens
Vitreous cavity
Subretinal space

Question 23

what are the ocular immune privilege mechanisms?

Answer 23

• Unique anatomical features of a blood-tissue barrier and a lack of direct lymphatic drainage
• Ocular microenvironment is rich in immunosuppressive molecules and inhibitory cell surface molecules that influence the reactivity of immune cells
• Anterior chamber-associated immune deviation (ACAID)

Question 24

what is Anterior chamber-associated immune deviation (ACAID)?

Answer 24

• The placement of foreign antigen into the ocular microenvironment can induce a systemic form of tolerance to the foreign antigen = ACAID
• ‘Peripheral tolerance’ to ocular antigens
• Active mechanisms that downregulate the immune response within the eye

Question 25

what are the immunological hallmarks of ACAID?

Answer 25

• Generation of primed CD4+ T and B cells that produce non-complement-fixing antibodies
• Inhibition of delayed-type hypersensitivity (CD4+ Th1) and B cells that secrete complement-fixing antibodies (inhibition of a cell-mediated immune response)

Question 26

what is the function of ACAID?

Answer 26

ACAID protects the eye and visual axis from the collateral damage of an immune response to infection by suppressing a future potentially damaging response to infection.

Question 27

how is ocular immune privilege established?

Answer 27

SEPARATION: Immunological ignorance
Corneal cells have ↓ expression of MHC Class I molecules and do not express MHC Class II molecules
Normal cornea lacks blood and lymphatic vessels
INHIBITION: Development of an intraocular immunosuppressive microenvironment
Local factors within the eye inhibit components of the immune response to reinforce the protection provided by immune privilege
REGULATION: Peripheral tolerance to ocular antigens
ACAID

in short : The eye is ignorant to induction of non-self, the body is tolerant to the presence of ocular antigens, and the local environment within the eye supports these

Question 28

what is Sympathetic Ophthalmia

Answer 28

Rare, bilateral, granulomatous uveitis due to trauma (more common) or surgery (less common) to one eye

Question 29

what does Sympathetic Ophthalmia occur?

Answer 29

• Thought to be secondary to development of an autoimmune reaction to ocular antigens: exposed during the traumatic or surgical event
• Related to the physical and immunological isolation of the eye from the systemic immune system (disadvantage of immune privilege)
• Immune response occurs at elevated rates

Question 30

what is the primary mediator in Sympathetic Ophthalmia?

Answer 30

T cells
Initial wave of infiltrative cells composed of CD4+ helper T cells
Later wave of infiltrative cells are CD8+ cytotoxic Tcells

Question 31

what is the exciting eye and the sympathising eye? how to distinguish between the two?

Answer 31

The injured eye is the ‘exciting eye’ and the fellow eye is known as the ‘sympathising eye’

Clinically both eyes appear the same and it is only by history that one can identify which eye is the exciting eye

Question 32

what can happen is IS goes wrong?

Answer 32

Recurrent infections
Inadvertent injury to normal host tissues
Allergy
Hypersensitivity reactions
Autoimmune disease
Cancer
Transplant/graft rejection

Question 33

what are some AI diseases of the eye?

Answer 33

• Autoimmune uveoretinitis (inflammation of uvea & retina)
• Dalen-Fuchs nodule (epithelial cell clusters in retinal layers)
• Keratoconjunctivits sicca (‘dry eyes’)
• Lens-induced uveitis (reaction due to release of lens products)
• Retina autoantibodies (common in retinopathy associated with cancer/infection/degenerative disease)
• Sympathetic ophthalmia (bilateral granulomatous uveitis)

Question 34

definition of a hypersensitivity reaction

Answer 34

Immune response that results in bystander damage to self
‘collateral damage’

Usually exaggeration of normal immune mechanisms

Question 35

what is a type 1 HR

Answer 35

Immediate hypersensitivity

Question 36

what is a type 2 HR

Answer 36

Direct cell killing

AKA:antibody-mediated cytotoxicity

Question 37

what is a type 3 HR

Answer 37

Immune complex mediated

Question 38

what is a type 4 HR

Answer 38

Delayed type hypersensitivity

AKA: cell-mediate cytotoxicity

Question 39

pathogenesis of type 1 HR

Answer 39

mast cells express receptors for Fc region of IgE antibody on their surface →On encounter with allergen, B cells produce antigen-specific IgE antibody→allergen is cleared→Residual IgE antibodies bind to circulating mast cells via Fc receptors.
→No great consequence→After re-encounter with antigen:
-Allergen binds to IgE-coated mast cells and disrupts cell membrane
-Release of vasoactive mediators – histamine, tryptase etc
-Also increased cytokines and leukotriene transcription

Question 40

give examples of type 1 HR of eye?

Answer 40

Acute allergic

conjunctivitis (chemosis=oedema of the conjunctiva can occur)

Question 41

type 2 HR pathogenesis

Answer 41

Cells killed either by:

• Macrophages/natural killer (NK) cells
• Complement (membrane attack complex)

Question 42

give examples of type 2 HR of eye?

Answer 42

Ocular cicatricial pemphigoid

(Type of autoimmune conjunctivitis:
blistering and scarring of conjunctiva)

Question 43

give examples of type 3 HR of eye?

Answer 43

Autoimmune
corneal melting

(Outer layer of cornea melting; inner layer bulging forward possible perforation)

Question 44

type 3 HR pathogenesis

Answer 44

accumulation of immune complexes (antigen-antibody complexes) that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes

Question 45

type 4 HR pathogenesis

Answer 45

T helper cells activated by intracellular pathogens
Clonal expansion
When re-exposed, macrophages attracted
Exaggerated immune response

Question 46

give examples of type 4 HR of eye?

Answer 46

Corneal graft
rejection

(Vascularisation of host cornea reaching the donor tissue
graft rejection)

Question 47

what plays an important role in corneal transplants?

Answer 47

Immune privilege plays an important role

Question 48

what factors help maintain immune privilege?

Answer 48

Reduced and impaired expression of MHC Class I and II molecules in corneal cells – the net antigenic load is reduced

Cornea lacks blood and lymph vessels – prevents antigenic information escaping from tissues and migration of APC

Central cornea is deficient in Langerhans cells – absence of APC lengthens the time for graft recognition

Secretion of molecules with immunosuppressive properties to inhibit macrophages, NK cells, DCs, T cells, B cells

Expression of surface molecules that inhibit immune effectors

ACAID in recipients

Question 49

what are the ocular side effects of steroids?

Answer 49

Cataracts

Steroid-induced glaucoma

Question 50

summary of IS in the eye

Answer 50

Eye has limited innate and adapted responses, some of which have been ‘modified’

Concept of immune privilege helps maintain ocular clarity and good vision, but responses can be extreme and sight-threatening - [Beware of ‘sympathetic ophthalmia’]