EDITORIAL

A RENEWED APPRECIATION FOR OCULAR IMMUNE PRIVILEGE

UNA NUEVA APRECIACIÓN DEL PRIVILEGIO OCULAR INMUNE

JERRY Y. NIEDERKORN, Ph.D¹

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world and has been the topic of intense investigation in recent years. The pathogenesis of AMD is complex and involves a spectrum of genetic and environmental factors. Recently, three independent research teams have simultaneously identified a single nucleotide polymorphism in the genome that results in a three- to seven-fold increase in the risk of developing AMD (1-3). The polymorphism occurs in the gene that encodes complement factor H, a key regulator of the complement cascade and inflammation. The role of complement activation and inflammation in the pathogenesis of AMD was proposed over three years ago by Anderson et al (4) and fits neatly with the aforementioned reports indicating a strong association between polymorphism in the factor H gene and AMD. One of the hallmarks of AMD is the formation of drusen, which are insoluble deposits of proteinaceous molecules and cell debris that accumulate at the interface between Bruch's membrane and the retinal pigment epithelium (RPE). Drusen contain a variety of inflammation-related proteins, including c-reactive protein, complement components (including the C5b-9 complex), and even immunoglobulin. The presence of c-reactive protein in drusen is particularly interesting, as it is an acute phase proinflammatory molecule that can directly activate the complement cascade. However, the deposition of the C5b-9 complement complex is inhibited by complement factor H. Thus, malfunction of complement factor H, due to a single nucleotide substitution, could affect the buffering effect of factor H on the complement cascade and culminate in chronic inflammation and AMD.

The complement system is a crucial component of both innate and adaptive immune responses. In addition to perforating the cell membranes of pathogens and producing osmotic lysis, complement activation products are potent chemoattractants and activators of inflammatory cells, especially neutrophils. Activation of the complement cascade is an important mechanism for controlling bacterial infections, but if unchecked, the complement system can inflict significant damage to normal host cells. Many mammalian tissues, including those in the eye, are protected from complement-mediated injury by complement regulatory proteins (CRP), which are expressed in the cell membranes and are also present in body fluids, such as the aqueous humor and vitreous of the eye. It has been proposed that low levels of complement activation are part of the normal homeostatic process for controlling minor bacterial infections and that CRP function to protect innocent bystander cells from complement-mediated injury under these conditions. In support of this hypothesis, Sohn and coworkers have shown that administration of an antibody that blocks one of the CRP - called cell surface regulator of complement (Crry) - results in severe anterior uveitis in rats (5). However, the uveitis that occurs in anti-Crry treated animals can be reversed by depleting systemic stores of complement with cobra venom factor. One might argue that disrupting the function of CRP through the administration of an antibody to a CRP (i.e., Crry), is analogous to the perturbation of complement regulation that occurs when the function of a key CRP, complement factor H, is altered by a single amino acid substitution. The strong association between factor H polymorphism and AMD suggests that tight regulation of the immune system in the eye is crucial for maintaining normal vision. This has important implications in the context of ocular immune privilege and its impact on the integrity of the visual axis.

The immune privilege of the eye is a widely recognized, but often misunderstood concept. Stated in its simplest terms, immune privilege is the condition in which immune processes are either excluded or significantly blunted in specific anatomic sites in the body. The anterior chamber of the eye is a time-honored example of an immune privileged site. The immune privilege of the anterior chamber of the eye was recognized almost 125 years ago when the Dutch scientist van Dooremaal noted the prolonged survival of human tumor cells and fetal cartilage grafts transplanted into the anterior chamber of the rabbit eye. Since then, numerous investigators have confirmed ocular immune privilege through the long term survival of histoincompatible tissue grafts placed into the anterior chamber of laboratory animals.

This year marks the 100^th anniversary of the first successful human corneal transplant, which was performed before the human major histocompatibility complex was recognized and before corticosteroids were available to the ophthalmologist. In spite of these handicaps, corneal transplants have been enormously successful and are beneficiaries of ocular immune privilege.

The immune privilege of the eye is a compilation of anatomical, physiological, and immunological adaptations that collectively exclude, down regulate, neutralize, or eliminate immune effector elements that might damage ocular tissues, which have limited regenerative capacities. Although immune privilege was discovered through laboratory manipulations, its importance lies in its impact in protecting the eye from immune-mediated inflammation. Unlike other organs, which can tolerate inflammation and retain normal function, inflammation in the eye can have devastating consequences. In the final analysis, the eye has only one known function – to promote the unfettered transmission of light images to the retina and the delivery of neurological signals to the brain. The recent discovery that polymorphism of complement factor H is associated with AMD is further testament to the importance of immune privilege in the preservation of vision.

¹ University of Texas Southwestern Medical Center.
E-mail: Jerry.Niederkorn@UTSouthwestern.edu

REFERENCES

1. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385-389.

2. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421-424.

3. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419-421.

4. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002; 134: 411-431.

5. Sohn JH, Kaplan HJ, Suk HJ, Bora PS, Bora NS. Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Invest Ophthalmol Vis Sci 2000; 41: 3492-3502.