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Immunology of age-related macular degeneration

Key Points

  • Age-related macular degeneration (AMD) is the leading cause of blindness in elderly individuals in the developed world. It features a progressive deterioration of the central retina. Numerous, sometimes contradictory, pro-inflammatory signals and pathways have been implicated in disease initiation and progression.

  • In the healthy retina, ocular immune-based surveillance has an essential role in maintaining visual homeostasis.

  • As the retina ages and deteriorates, diverse pro-inflammatory agonists induce improper local immune activation. Diverse immune pathways including complement, the inflammasome, Toll-like receptor activation, adaptive immunity and others are implicated in driving retinal damage in AMD.

  • Extraocular immune cell recruitment mediates pathological angiogenesis in neovascular AMD, which is a prevalent condition that is defined by the growth of unwanted, abnormal blood vessels in the normally avascular macular area.

  • Numerous completed and ongoing immune-based clinical trials for AMD have been unanimously unsuccessful. This may be the result of our collective lack of understanding and appreciation of the 'friend–foe' relationship between retinal degeneration and immunity.

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness in aged individuals. Recent advances have highlighted the essential role of immune processes in the development, progression and treatment of AMD. In this Review we discuss recent discoveries related to the immunological aspects of AMD pathogenesis. We outline the diverse immune cell types, inflammatory activators and pathways that are involved. Finally, we discuss the future of inflammation-directed therapeutics to treat AMD in the growing aged population.

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Figure 1: Retinal anatomy in health and disease.
Figure 2: An integrated model of AMD pathogenesis.

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Acknowledgements

J.A. is supported by US National Institutes of Health (NIH) grants (R01EY018836, R01EY020672 and R01EY022238), the Doris Duke Charitable Foundation, USA, the Ellison Medical Foundation, USA, the Burroughs Wellcome Fund, USA, the Reeves Foundation, USA, a Dr. E. Vernon Smith and Eloise C. Smith Endowment and a Research to Prevent Blindness Unrestricted Grant, USA. J.P.A. is supported by NIH grants (AI041592, AR007279, AR0483335, GM099111 and HL112303), the Edward N. and Della L. Thome Memorial Foundation, USA, and Alexion Pharmaceuticals, USA. B.D.G. is suported by the National Center for Advancing Translational Sciences, USA, grants UL1TR000117 and UL1TR000117. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Correspondence to Jayakrishna Ambati.

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Competing interests

J.A. is named as an inventor on patent applications filed by his employer (University of Kentucky, USA) on technologies related to AMD diagnosis and therapy, and he is a co-founder of iVeena, Inc., USA. which is involved in the commercial development of AMD therapies. J.P.A. is involved in Compliment Corporation, USA (Scientific Advisory Board, 2010–present); Kypha, Inc., USA (Scientific Advisory Board, 2012); Genentech Inc., USA (Consultant, 2007–present); Idera Pharmaceuticals, USA (Consultant, 2007–present); KEREOS Incorporated, USA (Consultant, 2009–present); Alnylam Pharmaceuticals, Inc., USA (Consultant, 2010–present); Celldex Therapeutics, USA, formerly Avant Immunotherapeutics, Inc. (Consultant, 2008–present); and Alexion Pharmaceuticals, Inc., USA (Consultant, 2011–present).

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PowerPoint slides

Glossary

Retina

A highly organized and specialized neural network where light is converted into electrical impulses. Diseases of the retina such as age-related macular degeneration are leading causes of blindness in the developed world.

Macula

A specialized region of the retina densely populated with cone photoreceptors, which is responsible for fine visual acuity. Degeneration of the macular photoreceptors following either atrophy of the retinal pigmented epithelium (geographic atrophy) or fluid leakage from choroidal neovessels (neovascular age-related macular degeneration (AMD)) is the cause of vision loss in AMD.

Complement factor H

(CFH). A negative regulator of alternative complement pathway activation. Single nucleotide polymorphisms in CFH that reduce its inhibitory potential are responsible for a substantial proportion of the genetic risk for the development of age-related macular degeneration.

Neovascular AMD

(also known as exudative or 'wet' age-related macular degeneration). Characterized by degeneration of the macula following fluid leakage from choroidal neovessels that have invaded the retina. The use of vascular endothelial growth factor A-targeted therapies has revolutionized the management of this disease, which accounts for the majority of blindness that results from AMD.

Photoreceptors

Specialized neurons that are responsible for the conversion of light into biochemical signals.

Blood–retinal barrier

A tightly controlled transport barrier that is maintained by tight junctions in the retinal capillary endothelium (comprising the inner blood–retinal barrier), and by the Bruch membrane and the retinal pigmented epithelium monolayer (comprising the outer blood–retinal barrier). Integrity of the blood–retinal barrier is important for control of fluid leakage, solute transport and immune quiescence, all of which support the functional homeostasis of the retina.

Retinal pigmented epithelium

(RPE). A monolayer of epithelial cells that has multiple essential roles in visual function, including recycling components of the visual cycle, secreting trophic factors and maintaining the outer blood–retinal barrier. The RPE is widely considered to be the focal point of age-related macular degeneration pathogenesis, in which breakdown of the RPE leads to secondary photoreceptor degeneration.

Drusen

Discrete extracellular deposits that commonly precede the development of age-related macular degeneration, and that are comprised of numerous cellular and inflammatory factors.

Geographic atrophy

(also known as end-stage 'dry' age-related macular degeneration (AMD) or atrophic AMD). A disease affecting the macula in which the retinal pigmented epithelium can no longer support photoreceptor function owing to spontaneous degeneration of large confluent regions. Although geographic atrophy occurs less frequently than neovascular AMD (approximately 50% as common), there are no currently approved therapies.

Immune privilege

The property of a tissue being tolerant to antigen. Retinal immune privilege is maintained by blood–retinal barrier integrity and the absence of functional lymphatic circulation.

Fundus photography

A common method for visualizing the retinal pigmented epithelium, retina and retinal circulation photographically. Funduscopy is used by ophthalmologists to diagnose retinal disorders such as age-related macular degeneration.

Para-inflammation

A state in which tissue homeostasis is maintained by low-grade inflammatory-based clearance of noxious stimuli. In the retina, para-inflammation may persist and ultimately contribute to age-related macular degeneration through increased immune cell infiltration and activation at sites of tissue damage.

Genome-wide association studies

(GWASs). The process by which genetic variations and disease phenotypes are statistically correlated. Linkage studies carried out with markers located across the entire genome that were traditionally carried out with approximately 300 markers of simple sequence-length repeats but that have been more recently carried out with approximately 1–5 million single nucleotide polymorphisms.

Alternative pathway of complement activation

An evolutionarily ancient innate immune process by which microorganisms are destroyed through opsonization and activation of the membrane attack complex. According to the 'complement hypothesis', misactivation of, and/or the inability to appropriately inhibit, the alternative pathway results in retinal tissue damage and drives age-related macular degeneration pathology.

Carboxyethylpyrrole-adducted proteins

Proteins that are modified through the oxidation of the fatty acid docosahexaenoic acid. These adducts are abundant in the retina. They can have direct pro-inflammatory effects through pattern recognition, and autoantibodies that recognize them are abundant in the circulation of patients with age-related macular degeneration.

M1 macrophages

A pro-inflammatory or 'classically activated' subset of macrophages, which are characterized by phagocytic activity and expression of particular inflammatory cytokines (such as tumour necrosis factor) and inflammatory mediators (such as inducible nitric oxide synthase).

M2 macrophages

A pro-angiogenic or 'alternatively activated' subset of macrophages, which are characterized by the expression of particular angiogenic cytokines (such as vascular endothelial growth factor A) and anti-inflammatory mediators (such as arginase).

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Ambati, J., Atkinson, J. & Gelfand, B. Immunology of age-related macular degeneration. Nat Rev Immunol 13, 438–451 (2013). https://doi.org/10.1038/nri3459

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