Monday, March 14, 2011

Ocular Immune System (Privilege)

The ocular immune system is the immunological defense system which protects the eye from infection, regulating healing processes following injuries. Although the interior of the eye lacks lymph vessels, it is highly vascularized, and many immune cells reside in the uvea, including mostly macrophages, dendritic cells, and mast cells. These cells fight off intraocular infections, and intraocular inflammation can manifest as uveitis (including iritis) or retinitis.

Ocular immune responses of the cornea

The cornea of the eye is immunologically a very special tissue. Its constant exposure to the exterior world means that it is vulnerable to a wide range of microorganisms while its moist mucosal surface makes the cornea particularly susceptible to attack. At the same time, its lack of vasculature and relative immune separation from the rest of the body makes immune defense difficult. Lastly, the cornea is a multifunctional tissue. It provides a large part of the eye’s refractive power, meaning it has to maintain remarkable transparency, but must also serve as a barrier to keep pathogens from reaching the rest of the eye, similar to function of the dermis and epidermis in keeping underlying tissues protected. Immune reactions within the cornea come from surrounding vascularized tissues as well as innate immune responsive cells that reside within the cornea.

nnate immune responses defend against pathogens and toxin in a non-discriminatory manner. They provide an inherent barrier against corneal infection while also serving as a primary mode of defense that is present from birth. For instance, the orbit and the eyelid can guard against both traumatic events and exterior debris that may contain microorganisms. Other components of the ocular innate immune system include tears, epithelial cells, keratocytes, corneal nerves, the complement system, and interferons.

Acquired immune responses are much more pathogen-specific than their innate immune counterparts. These pathways are cell-mediated and are understood to be controlled in part by Langerhans cells in the cornea. These Langerhans cells are antigen-presenting cells, which pick up pieces of invading pathogens and use them to elicit an immune response. Cell-mediated immune responses are usually slower acting and more efficient, but can cause damage to surrounding tissue, resulting in damage to the vision.

Ocular Immune Privilege

The eye attempts to limit local immune and inflammatory responses to preserve vision. This phenomenon, known as ocular immune privilege, is mediated by a combination of local and systemic mechanisms. While immune privilege is believed to protect the eye from day-to-day inflammatory insults, it is not absolute and its mechanisms are still incompletely understood.

The eye has a special relationship with the immune system, known as immune privilege. The term was coined in the 1940s by Sir Peter Medawar, who noticed that foreign tissue grafts placed in the anterior chamber (AC) of the eye were not rejected. While the concept of immune privilege is simple, research into its nature has revealed its highly complex character, which is still incompletely understood. Multiple mechanisms combine to maintain immune privilege:

(a) Physical barriers (efficient blood-retina barrier and lack of efferent lymphatics) prevent free entry and exit of cells, and even larger molecules, into and out of the eye. The integrity of the blood-retinal barrier is routinely measured in the clinic by the fluorescein test and provides a widely accepted measure of ocular health. Nevertheless, the concept of sequestration of the eye from the immune system has recently been debated, mostly on the basis of the phenomenon known as anterior chamber-associated immune deviation (ACAID).

(b) The inhibitory ocular microenvironment, composed of cell-bound and soluble immunosuppressive factors within the eye, inhibits the activity of immune-competent cells. The soluble factors include transforming growth factor-beta (TGF-ß) (which can also be membrane-bound), neuropeptides such as alpha-melanocyte-stimulating hormone (a-MSH), vasoactive intestinal peptide, and others. Ocular resident cells directly inhibit immune cells (at least in culture) by secreting soluble factors and by contact-dependent mechanisms. Retinal glial Müller cells were the first to be identified, but their inhibitory surface molecules were not characterized. The pigmented epithelia of the retina (RPE) and the iris/ciliary body (IPE) not only inhibit T cells, but also induce them to become T regulatory (Treg) cells. Surface-bound molecules involved in these processes include CD86 [which engages cytotoxic T lymphocyte antigen 4 (CTLA-4) on T cells], FasL, thrombospondin, and galectins.

(c) Finally, the eye actively regulates systemic immune responses. The classic example is ACAID, a unique and highly orchestrated immune response to antigens injected into the AC. It involves migration from the eye to the spleen of F4/80+ antigen-presenting cells that interact with invariant natural killer T cells and B cells and culminates in elicitation of systemic regulatory immunity through induction of CD4+ afferent and CD8+ efferent Treg cells. Proteins and even cells or cellular fragments were shown to pass from the AC directly into the blood through a highly porous structure known as the trabecular meshwork. While some regard this as negating the concept of ocular antigen sequestration, elicitation of ACAID requires puncturing of the eye with a needle and perturbation of ocular integrity. It is therefore likely that ACAID is more representative of a response to trauma rather than of a mechanism of tolerance to tissue-specific antigens contained in the healthy eye. A less controversial example is post-recovery tolerance, in which spleen cells from mice that have recovered from experimental autoimmune uveitis (EAU) contain regulatory activity, whose generation is dependent on the presence of eye. This type of tolerance was shown to involve the melanocortin pathway and cannot be induced in melanocortin-5 receptor knockout mouse, but whether it is a-MSH from the eye that is involved has not been determined.

A highly successful application of the ocular immune privilege is corneal transplantation. Corneal allografts are up to 90% successful without tissue matching and without systemic immunosuppressive therapy. On the downside, however, ocular immune privilege may leave the eye vulnerable to autoimmunity by impeding peripheral tolerance to eye-specific antigens sequestered behind the blood-retinal barrier.