Immune mechanisms in inflammatory and degenerative eye disease

Highlights

• Inflammatory responses in the eye are modulated by its immune-regulatory environment.

• Distinct immunopathological processes drive uveitis and age-related degenerative diseases.

• Uveitis and age-related degenerative eye disease may share autoimmune underpinnings.

• Uveitis mechanisms may shed light on inflammatory processes in degenerative eye disease.

• Age-related macular degeneration may illuminate general mechanisms of para-inflammation.

It has recently been recognized that pathology of age-associated degenerative eye diseases such as adult macular degeneration (AMD), glaucoma and diabetic retinopathy, have strong immunological underpinnings. Attempts have been made to extrapolate to age-related degenerative disease insights from inflammatory processes associated with non-infectious uveitis, but these have not yet been sufficiently informative. Here we review recent findings on the immune processes underlying uveitis and those that have been shown to contribute to AMD, discussing in this context parallels and differences between overt inflammation and para-inflammation in the eye. We propose that mechanisms associated with ocular immune privilege, in combination with paucity of age-related antigen(s) within the target tissue, dampen what could otherwise be overt inflammation and result in the para-inflammation that characterizes age-associated neurodegenerative disease.

Introduction

The eye is a prototypic immune privileged tissue that resists immunogenic inflammation through multiple mechanisms 1, 2. Inflammatory and immune-mediated diseases in the eye must therefore be viewed against the backdrop of ocular immune privilege. Nevertheless, the eye is subject to inflammatory and para-inflammatory processes. Noninfectious uveitis describes a group of potentially blinding inflammatory ocular conditions of obscure etiology; disease progression in uveitis is thought to be driven at least in part by autoimmune mechanisms. Current concepts in ocular inflammation and the mechanisms that drive it stem largely from studying uveitis in animal models. More recently, it has been recognized that processes that had once been believed to be purely degenerative, such as AMD, diabetic retinopathy, and glaucoma, also involve inflammatory and immune elements [3]. Moreover, studies in patients and in animal models have implicated autoimmune processes in degenerative diseases of the eye 4, 5, suggesting some anti-inflammatory therapies that are effective for uveitis may be useful for the treatment of AMD.

However, the inflammation observed in uveitis is different from that associated with degenerative conditions in the eye. While uveitis has a major adaptive immune component, AMD and similar degenerative conditions primarily involve innate immune elements 6, 7, 8. While uveitis is associated with overt inflammation, AMD is slow and insidious (para-inflammation), and acute inflammation is characteristically absent. Here, we critically examine the processes of inflammation and para-inflammation in the eye, comparing and contrasting the associated cellular and molecular mechanisms 9, 10. Synthesis of the available evidence suggests that (i) autoimmune processes are involved as drivers (if not etiologic triggers) of both the overt inflammatory disease known as uveitis, and the para-inflammatory disease typified by AMD; (ii) unlike retinal antigens, the target AMD antigens in the retina are scarce, which limits the adaptive immune response but not innate immune processes; and (iii) the inhibitory ocular microenvironment as part of ocular immune privilege is able to dampen innate immune responses, but is less effective in limiting the function of effector T cells. This in turn enables effector T cells that encounter abundant target antigen in the eye to break down ocular immune privilege and precipitate the development of overt inflammation typical of uveitis.