There is growing evidence that the immune response and the inflammatory cascade play an important role in retina disease, specifically age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion (RVO). As background to understand how inflammation contributes to retinal damage, it is important to first define the mechanisms of the immune response.
There are essentially two types of immunity: innate and antigen-specific. Innate immunity is primarily a cellular response, usually carried out by macrophages and neutrophils, triggered by stimuli that can include infection, toxic material, cellular debris from injury, or neoplastic cells.1-3 Innate immunity can also be triggered by the direct interaction of these stimuli with the parenchymal cells of tissues but is antigen-independent.
Antigen-specific immunity, on the other hand, is an acquired response in reaction to a specific antigenic molecule. 4-6 Specialized cells of the immune system process the unique antigen and produce unique antigen-specific immunologic effector cells (T and B lymphocytes) and unique antigen-specific soluble effector molecules (antibodies). The role of the T and B lymphocytes and the antibodies is to remove the specific stimulating antigenic substance, ignoring the presence of irrelevant antigenic stimuli.
Although innate or antigen-specific immunity may directly induce retinal injury or inflammation, in most cases, these pathways initiate a process that requires amplification to produce detectable clinical manifestations. This amplication process typically involves molecules generated within tissues that amplify immunity. These amplification molecules or mediators fall into several categories including: cytokines (growth factors, angiogenic factors, others); oxidants (free radicals, reactive nitrogen); plasma-derived enzyme systems (complement, kinins and fibrin); (vasoactive amines (histamine and serotonin); lipid mediators (prostaglandins, leukotrienes, other eicosanoids and platelet activating factors); and neutrophil-derived granule products. All mediators may play a role in retinal pathology but cytokines, complement, and oxidants are the mediators more likely to play significant roles in AMD, DR, and RVO.
COMPLEMENT
Complement factors have recently become the focus
of much research in AMD. Genetic alterations in various
proteins of the complement cascade are associated
with AMD. Complement factors amplify innate and
antigen-specific immunity and mediate the response
to injury.7-9 All complement factors are synthesized by
the liver and released into blood, but localized synthesis
can occur in the cornea, sclera, and retina. The
complement cascade produces different fragments
and products capable of affecting a variety of functions.
Normally, the complement system is kept at
continuous low levels in the eye via regulatory proteins.
Complement dysregulation that leads to overactive
complement activity can result in an immune
response and subsequent damage to the eye.10 Three
pathways have been identified to activate the complement
cascade: the classical pathway, the alternative
pathway, and the lectin pathway.
The classical pathway is activated mainly by antibody binding to antigen in an antigen-specific immunity response;7-9 however, endogenous stimuli, such as DNA, RNA, insoluble deposits of abnormal proteins, apoptotic cells have been shown to trigger the classical pathway.11-14 The alternative pathway is triggered by activating innate immunity activated by activating substances such as microbial substances and polysaccharides, while the lectin pathway is activated by mannose and N-acetyl glucosamine residues that that tend to be plentiful on bacterial cell surfaces.15 Oxidant injury, such as is seen in AMD, can change the surface protein expression and glycosylation, triggering overactivation of complement.14 Activation of the complement pathways creates a proinflammatory response, amplifying the immune response and drawing in more inflammatory cells to areas of damage.15,16
Table 1 illustrates the three possible mechanisms by which complement byproducts are produced and injury or inflammation is amplified.
Complement activation inhibitors can be produced by cells within tissues, including the RPE, and thus offer protection against complement-mediated injury.17,18 Many components of the complement system have been identified within Bruch's membrane and drusen, indicating a potential role for complement in AMD.19
OXIDANTS
Oxidants are continuously generated as a consequence
of normal noninflammatory cellular biochemical processes
and are highly reactive products with the potential to
damage cellular molecules and inhibit functional properties
in pathogens or host cells. During immune responses
oxidants are typically produced by neutrophils and
macrophages by various enzyme-dependent oxidase systems.
20 Oxidants can interact with several cellular targets
to cause injury. Some of the most important are: damage
to proteins (ie, enzymes, receptors) by a chemical modification;
damage to the cell membrane by lipid peroxidation
of fatty acids in the phospholipid bilayers; depletion
of ATP by a degraded mitochondrial inner membrane;
and breaks or crosslinks in DNA due to nucleotide chemical
alterations.1,21 Protective antioxidant systems have
evolved over time and include soluble intracellular antioxidants
(ie, glutathione or vitamin C), cell membranebound
lipid soluble antioxidants (ie, vitamin E), and
extracellular antioxidants.1,21 Studies suggest that oxidation-
induced lipid peroxidation in the retina and protein
damage in RPE and photoreceptors are significant stimuli
of injury.22-25 Relevant sources of oxidants in AMD are
listed in Table 2.
CYTOKINES
Cytokines are typically small proteins that are secreted
by cells and that transmit signals locally between cells.
Included in this category are proteins of the interleukin
family but also include such proteins as growth factors
and interferons. Although usually thought of as cell-type
specific (interleukins and inflammatory cells), cytokines
have such ubiquitous and broad targets that attempting
to categorize cytokines based on potential activities such
as growth factors or inflammatory cytokines is limiting.
Many areas of research have demonstrated that although
some cytokines are cell-type specific, most cytokines
have multiplicity and redundancy of source as well as
function and target. Sources of cytokines for retinal diseases
include macrophages, retinal pigment epithelial
cells and other cells of the immune system. A list of the
pertinent cytokines and cell sources are listed in Table 3.
Suggested reading for more information:
Csaky KS, Cousins SW. Immunology of age-related macular degeneration. In: Lim J, ed. Age-Related Macular Degeneration. London: Informa Healthcare; 2007:13-33.
Patel M, Chan C-C. Immunopathological aspects of age-related macular degeneration. Semin Immunopathol. 2008;30(2):97-110.
Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol. 2008;30:65-84.
Lee HBH, Pulido JS, McCannel CA, Buettner H. Role of inflammation in retinal vein occlusion. Canadian Journal of Ophthalmology. 2007;42(1):131-133.
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