The Immune System and AMD

Sahu A, Lambris JD. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol Rev. 2001;180:35–48. Johnson LV, et al. Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res. 2001;73(6):887–96. Anderson DH, et al. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134(3):411–31. Gehrs KM, et al. Age-related macular degeneration–emerging pathogenetic and therapeutic concepts. Ann Med. 2006;38(7):450–71. Vogt SD, et al. Distribution of complement anaphylatoxin receptors and membrane-bound regulators in normal human retina. Exp Eye Res. 2006;83(4):834–40. Mullins RF, et al. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. Faseb J. 2000;14(7):835–46. Anderson DH, et al. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res. 2004;78(2):243–56. Nozaki M, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci USA. 2006;103(7):2328–33. Richardson AJ, et al. A tag-single nucleotide polymorphisms approach to the vascular endothelial growth factor-A gene in age-related macular degeneration. Mol Vis. 2007;13:2148–52. Hageman GS, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102(20):7227–32. Edwards AO, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–4. Haines JL, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419–21. Klein RJ, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–9. Clark SJ, et al. H384 allotypic variant of factor H associated with age-related macular degeneration has different heparin-binding properties from the non-disease-associated form. J Biol Chem. 2006;281(34):24713–20. Gold B, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38(4):458–62. Yates JR, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357(6):553–61. •• van de Ven JP, et al. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat Genet. 2013;45(7):813–7. This paper identifies a missense mutation in the CFI gene that is highly associated with AMD (OR = 22.20). The specific mutation leads to decreased expression of CFI which can cause unregulated alternative complement activation. Maloney SC, et al. Choroidal neovascular membranes express toll-like receptor 3. Ophthalmic Res. 2010;44(4):237–41. Haines JL, et al. Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci. 2006;47(1):329–35. Rohrer B, et al. Eliminating complement factor D reduces photoreceptor susceptibility to light-induced damage. Invest Ophthalmol Vis Sci. 2007;48(11):5282–9. • Do DV, et al. A phase ia dose-escalation study of the anti-factor d monoclonal antibody fragment fcfd4514s in patients with geographic atrophy. Retina. 2013. This is the Phase I study for a novel anti-complement factor D antibody which is now is advanced clinical trials for the treatment of geographic atrophy. Regillo CD, Lampalizumab (Anti-factor D) In patients with geographic atrophy: The MAHALO Phase II Results in 2013 Annual Meeting of the American Academy of Ophthalmology. 2013. New Orleans, LA. Miller DM, et al. The association of prior cytomegalovirus infection with neovascular age-related macular degeneration. Am J Ophthalmol. 2004;138(3):323–8. Kalayoglu MV, et al. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2005;243(11):1080–90. Robman L, et al. Exposure to Chlamydia pneumoniae infection and age-related macular degeneration: the Blue Mountains Eye Study. Invest Ophthalmol Vis Sci. 2007;48(9):4007–11. Kumar MV, et al. Innate immunity in the retina: Toll-like receptor (TLR) signaling in human retinal pigment epithelial cells. J Neuroimmunol. 2004;153(1–2):7–15. Kleinman ME, et al. Sequence- and target-independent suppression of angiogenesis by siRNA. Nature. 2008;452(7187):591–7. Kwak N, et al. VEGF is major stimulator in model of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2000;41(10):3158–64. Edwards AO, et al. Toll-like receptor polymorphisms and age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49(4):1652–9. Zhou P, et al. Toll-like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity. Faseb J. 2011;25(10):3489–95. Yang Z, et al. Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med. 2008;359(14):1456–63. • Klein ML, et al. Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology. 2010;117(8):1554–9, 1559 e1. In this longitudinal progression study, patients with geographic atrophy were analyzed for rate of RPE cell loss and association with various SNPs in complement and innate immune pathways. Cho Y, et al. Toll-like receptor polymorphisms and age-related macular degeneration: replication in three case-control samples. Invest Ophthalmol Vis Sci. 2009;50(12):5614–8. Arbour NC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25(2):187–91. Zareparsi S, et al. Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet. 2005;14(11):1449–55. Kaur I, et al. Analysis of CFH, TLR4, and APOE polymorphism in India suggests the Tyr402His variant of CFH to be a global marker for age-related macular degeneration. Invest Ophthalmol Vis Sci. 2006;47(9):3729–35. • Yu Y, et al. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet. 2011;20(18):3699–709. This paper identified 7 new genes associated with AMD in a large collaborative GWAS. Zhao L, et al. Common variant in VEGFA and response to anti-VEGF therapy for neovascular age-related macular degeneration. Curr Mol Med. 2013;13(6):929–34. Kleinman ME, et al. Short-interfering RNAs induce retinal degeneration via TLR3 and IRF3. Mol Ther. 2012;20(1):101–8. Murakami Y, et al. Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ. 2013;21(2):270–7. •• Kaneko H, et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature. 2011;471(7338):325–30. A major advance in the pathogenesis of geographic atrophy is revealed in the studies conducted in this paper relating to the identification of endogenous RNAs that are toxic to the RPE. • Tarallo V, et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell. 2012;149(4):847–59. This is a follow-up study to the discovery of Alu RNA induced RPE degeneration in geographic atrophy demonstrating critical involvement of the inflammasome that is NLRP3 dependent. Penfold PL, et al. Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res. 2001;20(3):385–414. Penfold PL, et al. Autoantibodies to retinal astrocytes associated with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 1990;228(3):270–4. Kubicka-Trzaska A, et al. Circulating antiretinal antibodies predict the outcome of anti-VEGF therapy in patients with exudative age-related macular degeneration. Acta Ophthalmol. 2012;90(1):e21–4. • Hollyfield JG, et al. Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med. 2008;14(2):194–8. A new angle on AMD was introduced in this study which reports on an antigenic protein modification known as carboxyethylpyrrole (CEP) leads the formation of anti-retinal antibodies, retinal toxicity and resultant cell death in AMD. Gu X, et al. Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. J Biol Chem. 2003;278(43):42027–35. Sakurai E, et al. Macrophage depletion inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003;44(8):3578–85. Tsutsumi C, et al. The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization. J Leukoc Biol. 2003;74(1):25–32. Grossniklaus HE, et al. Histopathologic and ultrastructural features of surgically excised subfoveal choroidal neovascular lesions: submacular surgery trials report no. 7. Arch Ophthalmol. 2005;123(7):914–21. Huang H, et al. VEGF receptor blockade markedly reduces retinal microglia/macrophage infiltration into laser-induced CNV. PLoS One. 2013;8(8):e71808. Tsutsumi-Miyahara C, et al. The relative contributions of each subset of ocular infiltrated cells in experimental choroidal neovascularisation. Br J Ophthalmol. 2004;88(9):1217–22. Ambati J, et al. An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med. 2003;9(11):1390–7. • Apte RS, et al. Macrophages inhibit neovascularization in a murine model of age-related macular degeneration. PLoS Med. 2006;3(8):e310. An pioneering study into the anti-angiogenic effects of macrophages in a laser-induced model of choroidal neovascularization and macrophage class switching depending on gene expression profiling and cell subtype. Duffield JS. The inflammatory macrophage: a story of Jekyll and Hyde. Clin Sci (Lond). 2003;104(1):27–38. Kelly J, et al. Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J Clin Invest. 2007;117(11):3421–6. • Espinosa-Heidmann DG, et al. Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser-induced choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013;54(12):7439–49. Further foundational work on the effects of aging on bone-marrow cell function and circulating immune cell properties in an animal model of choroidal neovascularization. Wang VM, et al. Suggestive association between PLA2G12A single nucleotide polymorphism rs2285714 and response to anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration. Mol Vis. 2012;18:2578–85. Schick JH, et al. A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. Am J Hum Genet. 2003;72(6):1412–24. Yu Y, et al. Association of variants in the LIPC and ABCA1 genes with intermediate and large drusen and advanced age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52(7):4663–70. Combadiere C, et al. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest. 2007;117(10):2920–8. Tuo J, et al. Murine ccl2/cx3cr1 deficiency results in retinal lesions mimicking human age-related macular degeneration. Invest Ophthalmol Vis Sci. 2007;48(8):3827–36. Tuo J, et al. The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration. Faseb J. 2004;18(11):1297–9. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19(1):71–82. Maller J, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006;38(9):1055–9. Kortvely E, et al. ARMS2 is a constituent of the extracellular matrix providing a link between familial and sporadic age-related macular degenerations. Invest Ophthalmol Vis Sci. 2010;51(1):79–88.