Good news-bad news: the Yin and Yang of immune privilege in the eye

Abstract

The eye and the brain are prototypical tissues manifesting immune privilege (IP) in which immune responses to foreign antigens, particularly alloantigens are suppressed, and even completely inhibited. Explanations for this phenomenon are numerous and mostly reflect our evolving understanding of the molecular and cellular processes underpinning immunological responses generally. IP is now viewed as a property of many tissues and the level of expression of IP varies not only with the tissue but with the nature of the foreign antigen and changes in the limited conditions under which privilege can operate as a mechanism of immunological tolerance. As a result, IP functions normally as a homeostatic mechanism preserving normal function in tissues, particularly those with highly specialized function and limited capacity for renewal such as the eye and brain. However, IP is relatively easily bypassed in the face of a sufficiently strong immunological response, and the privileged tissues may be at greater risk of collateral damage because its natural defenses are more easily breached than in a fully immunocompetent tissue which rapidly rejects foreign antigen and restores integrity. This two-edged sword cuts its swathe through the eye: under most circumstances, IP mechanisms such as blood-ocular barriers, intraocular immune modulators, induction of T regulatory cells, lack of lymphatics, and other properties maintain tissue integrity; however, when these are breached, various degrees of tissue damage occur from severe tissue destruction in retinal viral infections and other forms of uveoretinal inflammation, to less severe inflammatory responses in conditions such as macular degeneration. Conversely, ocular IP and tumor-related IP can combine to permit extensive tumor growth and increased risk of metastasis thus threatening the survival of the host.

Keywords: eye; immune privilege; para-inflammation.

FIGURE 1

Anatomy/physiology of the eye to include ocular immune cells. (A) The eye is composed of three layers: an outer layer (cornea/sclera), an inner layer (retina), and a middle layer (uvea, a continuous structure comprising iris, ciliary body, and choroid). The anterior chamber lies between the iris and the cornea, the posterior chamber between the lens and the iris, and the vitreous cavity (containing the vitreous gel, a type II/XI collagenous avascular extracellular matrix) describes the main chamber of the eye behind the lens. The human eye maintains a pressure between 10 and 20 mm Hg, which is generated by the unidirectional flow of fluid (aqueous humor secreted by the ciliary body) from the posterior chamber into the anterior chamber, and leaving the eye via the trabecular meshwork, to drain into the episcleral veins. The “fundus oculi” is the view of the retina/choroid seen through the ophthalmoscope; the central fovea/macula is a cone photoreceptor-rich area, 500 microns in diameter, subserving central visual acuity. The remaining retina provides peripheral vision (visual field) and all visual information is transmitted through retinal neuronal cells, via the optic nerve, which synapse in the lateral geniculate body intracranially. The uvea contains a network of resident innate immune cells (DCs and macrophages) and is highly vascular (seen in section and en face views in the figure). The retina contains few conventional resident myeloid cells, but has a population of microglial cells (see text). Normal ocular tissues are devoid of lymphocytes. The cornea contains a population of passenger leukocytes mostly in its peripheral rim as well as some lymphatics in this region connecting with lymphatics in the conjunctiva. (B) Eye health is dependent on having a normal intraocular pressure, which is maintained between 12 and 20 mm Hg by the flow of aqueous fluid from the posterior chamber of the eye (the space between the posterior surface of the iris and the anterior surface of the lens) and the anterior chamber (the space between the posterior surface of the cornea and the anterior surface of the iris). The vitreous cavity is the intraocular compartment behind the lens and in front of the retina. Aqueous fluid is secreted by the epithelial cells of the ciliary body into the posterior chamber and flows through the pupil of the iris into the anterior chamber to drain through the trabecular meshwork at the angle of the eye between the iris and the cornea, into the subconjunctival space, to be finally removed by interstitial fluid flow into the episcleral veins and the subconjunctival lymphatics.

FIGURE 2

Blood–retinal barrier (BRB). The BRB is created by tight junctions at two sites: between endothelial cells of the retinal vessels that supply the inner retina (ganglion cells and bipolar cells) and the retinal pigment epithelium (RPE cell; which filters blood from the fenestrated, leaky choroidal vessels). The RPE regulates two-way transport of fluid, nutrients, and waste between the outer retina (photoreceptors) and the fast flowing, high volume choroidal bloodstream. The choroid stroma contains resident innate immune cells to maintain homeostasis in the outer retina (see Forrester et al., 2010) as well as fibroblasts and melanocytes. Breakdown of the BRB can thus occur either at the retina vessels or at the RPE layer.

FIGURE 3

Circulation of immune cells to and from the eye. Myeloid cells (macrophages and DCs) traffic from the bone marrow to the eye via the blood and populate some ocular tissues, predominantly the uvea (iris, ciliary body, and choroid); a few cells enter the peripheral retina and cornea. When ocular tissues are perturbed, bone marrow-derived cells, carrying antigen from the eye, can be found in the eye-draining lymph node (DLN; see text). However whether there is transport of steady-state antigen to the DLN is not known. Both cell-associated and soluble antigen injected into the eye, or applied to the abraded cornea, can be detected in the spleen after several hours. Resting T and B cells circulate normally through the uveal blood vessels of eye but do not cross the blood–ocular barriers; it is presumed they communicate with eye-derived antigen presenting cells in the secondary lymphoid tissues (spleen and lymph node) and respond appropriately to promote tolerance or immunity as in other tissues (see text).

FIGURE 4

Age-related macular degeneration (AMD) occurs in two forms: dry, atrophic damage to the retinal photoreceptor and RPE cells with chronic progressive loss of visual acuity; and wet AMD in which new vessels originating from the choroidal layer, penetrate the basement membrane of the RPE cells and leak fluid or blood into the subretinal space with rapid loss of vision. (A) Diagram of dry AMD showing drusen under the RPE layer, and extensive atrophic damage to RPE cells. (B) Diagram of wet AMD showing in-growth of new blood vessels into the subretinal space, causing extensive destruction of RPE and photoreceptor layers.