Purpose
To describe the immune alterations associated with age-related macular degeneration (AMD); and, based on these findings, to offer an approach to possibly prevent the expression of late disease.
Design
Perspective.
Methods
Review of the existing literature dealing with epidemiology, models, and immunologic findings in patients.
Results
Significant genetic associations have been identified and reported, but environmentally induced (including epigenetic) changes are also an important consideration. Immune alterations include a strong interleukin 17 family signature as well as marked expression of these molecules in the eye. Oxidative stress as well as other homeostatic altering mechanisms occur throughout life. With this immune dysregulation there is a rationale for considering immunotherapy. Indeed, immunotherapy has been shown to affect the late stages of AMD.
Conclusion
Immune dysregulation appears to be an underlying alteration in AMD, as in other diseases thought to be degenerative and attributable to aging. Para-inflammation and immunosenescence may importantly contribute to the development of disease. The role of complement factor H still needs to be better defined, but in light of its association with ocular inflammatory conditions such as sarcoidosis, it does not appear to be unique to AMD but rather may be a marker for retinal pigment epithelium function. With the strong interleukin 17 family signature and the need to treat early on in the disease process, oral tolerance may be considered to prevent disease progression.
Age-related macular degeneration (AMD) continues to be the most common cause of irreversible central vision loss in developed countries, affecting 25–35 million people worldwide. It has been estimated that 1.75 million patients have late AMD in the United States, defined as geographic atrophy or neovascular AMD in at least 1 eye, and an additional 7.3 million have at least 1 large drusen. Population-based estimates indicate that late AMD will affect over 3 million people in the United States by 2020. A putative role for the immune system in the pathogenesis of AMD has been suggested since the 1980s and more recently. Clearly, a better understanding of the mechanisms leading to this disorder is of great public health import. This review will discuss the myriad observations that can support a unified hypothesis for immune mediation of AMD and a possible therapeutic strategy.
What Does the Epidemiology of Age-Related Macular Degeneration Tell Us?
Recent data from more than a decade of follow-up of participants in the Age-Related Eye Disease Study demonstrated an increased risk of developing AMD associated with medium-sized drusen, but not small drusen <65 μm in diameter (early AMD). In addition, the presence of medium drusen, but not small drusen, increased the risk of progression to large drusen and pigmentary changes (intermediate AMD), putting individuals at risk for progression to late AMD. This suggests that small drusen may be necessary but not sufficient for the development of late AMD. However, once medium-sized drusen (between 65 and 125 μm) develop, the risk of progression to large drusen, pigmentary changes, and eventually late AMD increases. Persons with bilateral medium-sized drusen have a 40%–50% 5-year risk of developing large drusen and a 20% 5-year risk of developing late AMD, compared with a less than 5% risk for those with no drusen or small drusen. Thus these data support the notion that the disease process begins much earlier than the when it becomes clinically problematic in the seventh and eighth decade of life.
Genetics vs the Environment
Genetic and genomic approaches, such as family linkage analysis and genome-wide association studies, have revealed important genetic contributions to AMD pathogenesis. A significantly higher concordance rate of AMD in monozygotic twins than in dizygotic twins and in families further corroborates a genetic predisposition to AMD. Recent genetic meta-analysis has confirmed 19 loci (principally complement factor H [CFH], serine protease HTRA1/age-related maculopathy susceptibility protein 2) that account for up to 50% of the heritability of AMD susceptibility. Nevertheless, it remains unclear how exactly these genetic risk factors contribute to the pathogenesis of disease. Further, they may reflect a predisposition to a loosening of the normal downregulatory immune environment of the eye, since other inflammatory disorders have a similar association (see below).
Nongenetic risk factors such as smoking, dietary intake, and body mass index have been associated with development of AMD. Interestingly, Gottfredsdottir and associates report that the concordance of AMD between couples, who are genetically unrelated but share long-term environmental exposure, is as high as 70.2%, which is significantly higher than the 0.25% chance that 2 aged white individuals both have late AMD. Therefore, in addition to genetic susceptibility, environmental modulators may also play a crucial role in AMD etiology. Furthermore, there are compelling animal data to support such environmental modulation on the backdrop of genetic susceptibility. Administering high omega-3 fatty acid diets to chemokine-deficient mice that show retinal lesions akin to the pathology of AMD reverses such lesions and suppresses inflammation, perhaps through a reduction in arachadonic acid metabolism. It is interesting to speculate that noninheritable nongenetic environmental influences beyond deoxyribonucleic acid could be key to the control of AMD pathogenesis, and this so-called epigenetic regulation may be an important area for further investigation, in particular through the interrogation of DNA methylation and histone modification patterns in AMD patients.
An Aging Retina vs an Aging Immune System
Age is the most significant risk factor for AMD. Despite an increased understanding of metabolic and physiologic changes that occur with age, we still do not know the exact changes that cause disease or indeed drive disease progression. Throughout life, tissue-resident immune cells and supporting stromal cells (eg, retinal pigment epithelium [RPE] and glia) in retina and choroid are capable of controlling as well as mounting immune responses, which results in preservation of cellular function by adequately dealing with danger signals and maintaining health. In the aging eye, and especially at the level of the RPE, there is an accumulation of oxidative products such as reactive oxygen species, further increasing oxidative stress, as well as the accumulation of lipofuscin and A2E, which presumably alter the metabolism and health of the RPE. This increasing stress could activate the cell to further contribute to tissue damage. The increasing “stress” needs to be counterbalanced by mechanisms that attempt to return the cell to a homeostatic state. One such mechanism is para-inflammation, first proposed by Medzhitov and well described in the eye. Medzhitov has described it as “… a tissue adaptive response to noxious stress or malfunction and has characteristics that are intermediate between basal and inflammatory states.” Here the immune system’s reparative mechanisms are theorized to be a basic protective mechanism through life. This concept has been furthered in the eye by Schwartz and associates, who have further speculated about the role of protective autoimmunity of T cells, yet another putative reparative mechanism.
The association of CFH with AMD is well founded in many studies. While CFH variants have been consistently reported to be associated with AMD in humans, they have also been reported as being associated with 2 ocular inflammatory disorders involving the retinal pigment epithelium, multifocal choroiditis and posterior ocular sarcoidosis. Animal models have been used as a platform for mechanistic studies. They can be informative as to the individual components of the immune response to the eye. Following the demonstration of complement deposition that occurs in AMD, attention at the mouse level has focused on whether manipulation of the immune system delivers phenotypes similar to AMD. Animal studies in AMD were initially confounded by the presence of an independent retinal degeneration mutation (Rd8) in many of the AMD models used and by the lack of a macula and the binuclear nature of the rodent RPE, unlike that of humans. However, there remains strong evidence to support the concept that dysregulation of the immune response causes AMD-like phenotypes. Other genetic associations with AMD also point toward a key role for immunity. Serine protease HTRA1/age-related maculopathy susceptibility protein 2 genes are critical for the production of transforming growth factor, which plays an important role in the control of inflammation and interacts with matricellular proteins such as thrombospondin.
All this needs to be put in the context of an aging systemic immune system. Increasing age results in what has been described as immunosenescense, with reduced lymphocyte numbers as well as an enrichment of myeloid cells in peripheral blood and lymphoid tissue, and an increased number of memory T cells (both CD4+ and CD8+), especially Th17 cells. In addition, there are changes in the innate immune system, such as reduced phagocytosis and an increased production of proinflammatory cytokines, including interleukin 6 and interleukin 8, in aged macrophages, with the potential that this will reduce their ability to clear extracellular debris and apoptotic cells in vivo and as well induce a shift in macrophage subtypes from the “M2” to the “M1” subtype. It has been suggested that immunosenescence may in part be driven by a persistent cytomegalovirus (CMV) infection, which, although not causing overt clinical disease, is continually activating the immune system. Indeed, some older individuals have an inordinately large number of circulating CD4 cells that are directed against CMV. The immune dynamics of a degenerating retina, as shown in animal models, includes an alteration in RPE function and both activation and infiltration of innate immune cells, resulting in a para-inflammatory environment whereby homeostasis is lost and pathology is exacerbated.
Alterations in Innate and Adaptive Immune Responses With Aging
With the failure of para-inflammation in aging, it is plausible that following RPE release of small drusen and new antigen presentation, retinal or subretinal immune surveillance could be activated. This could lead to consequent activation of T cell–mediated adaptive immune responses in the periphery, including B cell activation and antibody production, and could eventually lead to progression down the path of developing medium drusen, large drusen, and, eventually, late AMD.
In support of a role for such adaptive immune responses in the development of AMD are recent reports in humans that suggest complement C5a promotes Th17 cell–mediated inflammation, providing a potential link between innate and adaptive immunity in the pathogenesis of AMD. In addition, although innate immune responses are often observed at nonocular infectious sites, identification of elevated cytokines circulating in the blood as well as the retina in AMD patients suggests that AMD may be systemically driven through memory T cell responses. T cell involvement seems to be quite prominent, with evidence of circulating interleukin 22 and interleukin 17 in the sera of AMD patients early, by the sixth decade, before any indication of visual disturbance. We also have seen that with enhanced C5a expression on T cells, greater amounts of interleukin 17 are produced. Overexpression of the interleukin 17 receptor C in the retina is seen. Also noted is an anamnestic response in some AMD patients’ T cells to fragments of the retinal S-antigen, similar to that seen in uveitis patients (unpublished data). Similarly, the observations of autoantibodies (including antiretinal antibodies) in AMD patients is potentially important and their presence offers evidence that assessment of the adaptive immune response may provide biomarkers for subgroups of patients at risk of AMD progression, or targets for novel therapies.
Alterations in Innate and Adaptive Immune Responses With Aging
With the failure of para-inflammation in aging, it is plausible that following RPE release of small drusen and new antigen presentation, retinal or subretinal immune surveillance could be activated. This could lead to consequent activation of T cell–mediated adaptive immune responses in the periphery, including B cell activation and antibody production, and could eventually lead to progression down the path of developing medium drusen, large drusen, and, eventually, late AMD.
In support of a role for such adaptive immune responses in the development of AMD are recent reports in humans that suggest complement C5a promotes Th17 cell–mediated inflammation, providing a potential link between innate and adaptive immunity in the pathogenesis of AMD. In addition, although innate immune responses are often observed at nonocular infectious sites, identification of elevated cytokines circulating in the blood as well as the retina in AMD patients suggests that AMD may be systemically driven through memory T cell responses. T cell involvement seems to be quite prominent, with evidence of circulating interleukin 22 and interleukin 17 in the sera of AMD patients early, by the sixth decade, before any indication of visual disturbance. We also have seen that with enhanced C5a expression on T cells, greater amounts of interleukin 17 are produced. Overexpression of the interleukin 17 receptor C in the retina is seen. Also noted is an anamnestic response in some AMD patients’ T cells to fragments of the retinal S-antigen, similar to that seen in uveitis patients (unpublished data). Similarly, the observations of autoantibodies (including antiretinal antibodies) in AMD patients is potentially important and their presence offers evidence that assessment of the adaptive immune response may provide biomarkers for subgroups of patients at risk of AMD progression, or targets for novel therapies.
Immunotherapy: What Could Be Considered?
Corticosteroids have been used to treat AMD, without an observed clinically important effect. Theoretically, they would have the dual benefit of controlling the immune response and regulating tight junctions to shore up the blood-ocular barrier, and prevent extravasation of fluid into the retina. The lack of effect of corticosteroids is perhaps not surprising given the strong interleukin 17 signature in AMD, a characteristic of immunosenescence. In addition, this link with interleukin 17 is critical as memory CD4+ T cells expressing interleukin 17 have been shown to be steroid resistant in other inflammatory diseases, including in patients with posterior uveitis, where in vitro corticosteroid sensitivity is highly correlated with clinical responses to treatment. Almost every aspect of the complement cascade is being tested as a possible therapy for late AMD, including C3 inhibitors, an aptamer-based C5 inhibitor, a C5 antibody, an anti–factor D antibody, a complement factor B inhibitor, a peptidomimetic C5a receptor inhibitor, and others. Though anti–factor D antibody results suggest some activity, trials still await full evaluation. Although some may prove effective, these interventions do not take account of the possible role of adaptive immunity or associated systemic immune dysregulation. In addition, it is unclear whether these mechanisms are operative in all patients and at what stage of disease.
In a small, randomized, unmasked proof-of-principle study in which AMD patients with choroidal neovascularization needing repeated injections of anti–vascular endothelial growth factor (VEGF) therapy were randomly assigned to 4 groups: standard of care alone, intravenous daclizumab (directed against CD25, the alpha subunit of the interleukin 2 receptor), intravenous infliximab, or oral rapamycin (a macrocyclic lactone produced by Streptomyces hyproscopicus , also known as sirolimus). All 4 groups had monthly clinical and optical coherence tomography evaluations for evidence of intraretinal or subretinal fluid. Patients with fluid received intravitreal anti-VEGF injections monthly. Comparing the number of anti-VEGF injections, there was a decrease in the number of injections required in patients given daclizumab or rapamycin, whereas no apparent decrease was noted for either the infliximab or the standard-of-care group. This proof-of-principle study thus suggested (but did not prove) that immunosuppressive therapy could alter the course of even late-stage disease. Although there have been many clinical trials of treatments for late AMD, no one to date has tested a therapeutic intervention, other than supplements, to slow or prevent progression of AMD and the expression of the disease. An ideal preventive therapy would start before ocular symptoms begin, be nontoxic, have specificity to retinal tissue, and be targeted to the right patients at the right time. One such approach would be to reduce systemic inflammation. It will not be practical to alter immune responses in patients with biologics for several decades, as the cost and possible toxic effects prohibit such an approach. If an immunologic approach is to be tested, other methods must be sought.
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