Ocular Immunity Flashcards
Why is ocular immunity such an important topic?
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
What are the anatomic and physical barriers of the eye?
Eyelids and eyelashes
What are the defense mechanisms of the tears?
Mucins
Antimicrobial proteins/peptides
Complements
Immunoglobulins
What are the defense mechanisms of the ocular surface epithelium?
Tight junctions
PRRs
What are the Eye-associated Lymphoid Tissues?
LGALT (Lacrimal gland)
CALT (Conjunctiva)
LDALT (Lacrimal drainage)
What is the sources of antimicrobial peptides in the eye?
Lacrimal glands and epithelium
Serum exudates
Infiltrating cells (PMNs)
What is the function of antimicrobial peptides in the eye?
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)
Describe the process and success rate of corneal transplants.
Most corneal transplants are not tissue typed and are between unrelated individuals
90% successful
No systemic immunosuppressive therapy
Only topical immunosuppressive
What is the definition of immune privilege? What are some examples in the eye and outside of the eye?
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
What 3 components allow for ocular immune privilege?
Physical and anatomical barriers
Local immune regulation
Eye-derived systemic immune deviation (ACAID= Anterior chamber associated immune deviation)
Describe the blood ocular barrier that plays a role in ocular immune privilege.
Iris & retinal vessels: non-fenestrated vascular endothelium, tight junctions
Ciliary body & Iris epithelium and RPE: epi cells linked by
tight junctions
How does the absences of vascular supply aid in ocular immune privilege?
Avascularity→limits the movement of granulocytes,
lymphocytes, monocytes and plasma proteins and antigens from blood to tissues
• Cornea
• Lens
Where in the eye do we have lymphatics and where are they absent?
Absent: normal cornea, lens, iris, ciliary body,
retina, choroid, sclera and all the intraocular compartments
Present: eyelids, lacrimal glands, conjunctiva,
limbus, and episclera
Describe the mechanism of lymphatic vessels in the limbus extending to the cornea.
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.
What contributes to the immunosupressive environment of the eye?
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.
What immunosupressive factors exist in the aqueous humor?
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.
What is TGF-B produced by and found in within the eye?
Macrophages, monocytes, T and B cells
Normal Aqueous humor, tears
What does TGF-B inhibit within the eye?
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
What is the function of Vasoactive intestinal peptide (VIP) in ocular immunity?
suppresses lymphocyte proliferation; found in AH, choroid, anterior and posterior uvea
What is the function of alpha-melanocyte stimulating hormone in ocular immunity?
suppresses interferon Ɣ, anti-inflammatory TGF ß
What is the function of calcitonin gene related protein in ocular immunity?
inhibits DTH (delayed-type hypersensitivity, type IV)
What is the function of cortisol in ocular immunity?
General immunosupressive substance in AH
What is the function of NK cell inhibitory factor in ocular immunity?
Inhibits NK cell activity
What is the function of complement regulatory proteins in ocular immunity?
Inhibits complement proteins
What are 3 membrane bound proteins and their function in ocular immunity?
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
What is ACAID? What is it induced by?
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
What cellular responses are involved with ACAID?
Th1 and Th2 (impaired DTH) and Th17 cells are suppressed, cytotoxic T cells combat antigens
What antibody responses are involved with ACAID?
Impaired production of complement fixing antibodies, increased production of non-complement fixing antibodies
What cytokine profile is associated with ACAID?
IFN-Ɣ suppressed, IL-10 produced, TGFβ stimulates APC that favors the development of regulatory T cells
What are the requirements for ACAID?
Non-inflamed eye
Intact spleen
Intact thymus
Intact sympathetic nervous system
What is the clinical significance of ACAID?
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
What are the benefits of ACAID?
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
What can be the adverse effects of ACAID?
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
When does rejection occur for a corneal transplant?
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
