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  • Review Article
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Ocular immune privilege: therapeutic opportunities from an experiment of nature

Key Points

  • Through immune privilege, the eye protects itself against sight-destroying immune responses and inflammation, using newly appreciated immunoregulatory strategies.

  • Immunological ignorance of eye-derived antigens is achieved by: reduced expression and altered peptide presentation of MHC class I and II molecules by ocular cells; elimination of lymphatic vessels and the link to regional lymphoid organs; blood–ocular barriers that shield the eye from blood-borne effector cells and molecules of the innate and adaptive immune systems.

  • Peripheral tolerance of eye-derived antigens is achieved by: selective migration of eye-derived antigen-presenting cells (APCs) through the blood to the spleen; the formation of multicellular clusters, containing natural killer T cells, B cells and eye-derived APCs, in the marginal zones of the spleen. At these sites, inductive microenvironments emerge wherein naive antigen-specific T cells are recruited, activated and induced to differentiate into regulators that suppress both T helper 1 (TH1)- and TH2-cell effector mechanisms.

  • A local immunosuppressive and anti-inflammatory microenvironment is mediated by: the secretion of soluble immunomodulatory cytokines, growth factors and neuropeptides into intraocular fluids, such as the aqueous humor; the expression of immunomodulatory molecules by ocular parenchymal cells; innate and adaptive immune effector cells and molecules that enter the eye are inhibited, modified or neutralized.

  • Immune privilege suggests new treatment strategies with the potential to suppress autoimmune diseases, to promote acceptance of solid organ allografts, and to inhibit immunopathogenic inflammation.

Abstract

Most higher animals require sight for survival, yet even minor distortions of the visual axis can cause blindness. For this reason, intraocular inflammation is incompatible with good vision. Nature has found a way to provide the eye with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Nature's way — known as 'immune privilege' — arises from anatomical, cellular and molecular specializations of the eye and the immune system. Knowledge of these unique characteristics indicates new ways to prevent and treat autoimmune and immunopathogenic diseases of the eye, as well as other organs and tissues, and to promote acceptance of cornea and other types of solid-tissue allograft.

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Figure 1: Anatomy of the visual axis of the eye.
Figure 2: Blood and lymph drainage from the eye.
Figure 3: The camero–splenic axis and the cellular origins of anterior-chamber-associated immune deviation.
Figure 4: Reprogramming effector T cells into regulators in the anterior chamber.

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Acknowledgements

I am grateful to my long-standing colleagues, whose countless discussions about ocular immune privilege have helped to illuminate the meaning of this experiment of nature: H. J. Kaplan, J. Y. Niederkorn, J. Stein-Streilein, B. R. Ksander, A. W. Taylor and M. Reza Dana. And thanks to P. Mallen for the original concepts for the artwork. Some of the research work described in this review has been supported by grants from the National Eye Institute.

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DATABASES

LocusLink

CD4

CD8

CD86

CD95

CD95L

CGRP

CIITA

CTLA4

CXCL2

IFN-γ

IL-6

IL-10

MIF

α-MSH

TGF-β

TGF-β2

TNF

VIP

Glossary

HETEROTOPIC GRAFT

A graft that is placed in a non-physiological site (for example, skin allografts being transplanted into the subcapsular sinus of kidney).

PIGMENT EPITHELIUM

Pigmented epithelial cells derived from the neuroectoderm that line the posterior surface of the iris (iris pigment epithelium) form a second epithelial layer beneath the aqueous-humor-secreting epithelial cells of the ciliary body (ciliary-body pigment epithelium), and form the posterior wall of the neurosensory retina (retinal pigment epithelium).

NEUROSENSORY RETINA

The portion of the retina that is an extension of the brain and that receives light images and transforms them into electrical information that is sent to the visual cortex of the brain.

INTRAOCULAR IMMUNOSUPPRESSIVE MICROENVIRONMENT

Fluids in restricted tissue compartments of the eye that contain cells and molecules that suppress innate and adaptive immune effectors.

ORTHOTOPIC GRAFT

A graft that is placed in its physiological site (for example, skin being transplanted to a cutaneous surface).

IMMUNOPROTEOSOMES

Cytosolic molecular complexes that degrade endogenous proteins into small peptides that are destined to be loaded onto MHC class I and II molecules for cell-surface expression.

TRANSPORTERS OF ANTIGEN PROCESSING

(TAPs). Cytoplasmic chaperones that carry peptides from the proteosomes into the endoplasmic reticulum to be loaded onto newly synthesized MHC class I molecules.

CLASS II TRANSACTIVATOR

(CIITA). A transcription co-factor to the MHC class II promoter that is activated in cells treated with interferon-γ. After CIITA activation, MHC class II α and β chain genes, as well as invariant chain genes, are de-repressed.

INVARIANT CHAIN

(Ii). A protein encoded by a gene that is activated, along with MHC class II genes, by the class II transactivator. The Ii shields the peptide-binding groove of newly formed MHC class II molecules until they traffic to endosomes.

CONJUNCTIVA

The portion of the ocular surface that is adjacent to the cornea that is covered with mucous membrane epithelium.

CANAL OF SCHLEMM

A circular vein that is linked to the venous draining to the heart and that receives aqueous humor through the trabecular meshwork.

HIGH-RISK EYES

Eyes with inflamed or neovascularized corneas that lack immune privilege and promote rejection of orthotopic corneal allografts.

NON-COMPLEMENT-FIXING ANTIBODIES AND COMPLEMENT-FIXING ANTIBODIES

Isotopes of immunoglobulins that either bind through their Fc portions to antibodies (fixing) or do not (non-fixing). Complement-fixing antibodies initiate complement activation by the classical pathway. Complement-non-fixing antibodies eliminate antigens and pathogens by mechanisms that are unrelated to complement activation.

ACAID

(Anterior-chamber-associated immune deviation). A form of eye-derived tolerance in which T helper 1 (TH1)- and TH2-mediated immunity is suppressed, but non-inflammatory adaptive immune effectors are present.

TRABECULAR MESHWORK

A ring of sponge-like tissue that surrounds the cornea immediately beneath the corneal limbus and that acts as the conduit through which aqueous humor drains directly from the anterior chamber into the canal of Schlemm and then to the venous circulation.

CILIARY BODY

A specialized ocular structure behind the lens that secretes aqueous humor.

AQUEOUS HUMOR

(AqH). The clear immunosuppressive and anti-inflammatory fluid that fills the anterior chamber of the eye.

NEUROPEPTIDES

Molecules that are secreted at nerve termini that not only function as neurotransmitters but also bind receptors on non-neural cells, influencing their functional programme.

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Streilein, J. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 3, 879–889 (2003). https://doi.org/10.1038/nri1224

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