Table of Contents Author Guidelines Submit a Manuscript
International Journal of Inflammation
Volume 2013 (2013), Article ID 348092, 10 pages
http://dx.doi.org/10.1155/2013/348092
Review Article

The Role of the Immune Response in Age-Related Macular Degeneration

1Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA
2The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
3Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA
4Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO 80045, USA
5Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA
6School of Clinical Sciences and School of Cellular and Molecular Medicine, University of Bristol and Bristol Eye Hospital and NIHR, Bristol BS1 2LX, UK
7Biomedical Research Centre at Moorfields Eye Hospital, NHS Foundation Trust, and UCL Institute of Ophthalmology, London EC1V 2PD, UK

Received 7 March 2013; Accepted 9 April 2013

Academic Editor: Robert B. Nussenblatt

Copyright © 2013 Scott M. Whitcup et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. S. Friedman, B. J. O'Colmain, B. Muñoz et al., “Prevalence of age-related macular degeneration in the United States,” Archives of Ophthalmology, vol. 122, no. 4, pp. 564–572, 2004. View at Publisher · View at Google Scholar · View at Scopus
  2. L. S. Lim, P. Mitchell, J. M. Seddon, F. G. Holz, and T. Y. Wong, “Age-related macular degeneration,” The Lancet, vol. 379, no. 9827, pp. 1728–1738, 2012. View at Publisher · View at Google Scholar
  3. P. L. Penfold, M. C. Madigan, M. C. Gillies, and J. M. Provis, “Immunological and aetiological aspects of macular degeneration,” Progress in Retinal and Eye Research, vol. 20, no. 3, pp. 385–414, 2001. View at Publisher · View at Google Scholar · View at Scopus
  4. D. A. Carter and A. D. Dick, “CD200 maintains microglial potential to migrate in adult human retinal explant model,” Current Eye Research, vol. 28, no. 6, pp. 427–436, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. C. Broderick, R. M. Hoek, J. V. Forrester, J. Liversidge, J. D. Sedgwick, and A. D. Dick, “Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis,” The American Journal of Pathology, vol. 161, no. 5, pp. 1669–1677, 2002. View at Google Scholar · View at Scopus
  6. K. Saijo and C. K. Glass, “Microglial cell origin and phenotypes in health and disease,” Nature Reviews Immunology, vol. 11, no. 11, pp. 775–787, 2011. View at Publisher · View at Google Scholar
  7. C. Broderick, L. Duncan, N. Taylor, and A. D. Dick, “IFN-γ and LPS-mediated IL-10-dependent suppression of retinal microglial activation,” Investigative Ophthalmology and Visual Science, vol. 41, no. 9, pp. 2613–2622, 2000. View at Google Scholar · View at Scopus
  8. E. H. Hughes, F. C. Schlichtenbrede, C. C. Murphy et al., “Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism,” Experimental Eye Research, vol. 78, no. 6, pp. 1077–1084, 2004. View at Publisher · View at Google Scholar · View at Scopus
  9. A. D. Dick, D. Carter, M. Robertson et al., “Control of myeloid activity during retinal inflammation,” Journal of Leukocyte Biology, vol. 74, no. 2, pp. 161–166, 2003. View at Publisher · View at Google Scholar · View at Scopus
  10. R. Medzhitov, “Origin and physiological roles of inflammation,” Nature, vol. 454, no. 7203, pp. 428–435, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. H. Xu, M. Chen, and J. V. Forrester, “Para-inflammation in the aging retina,” Progress in Retinal and Eye Research, vol. 28, no. 5, pp. 348–368, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Raychaudhuri, O. Iartchouk, K. Chin et al., “A rare penetrant mutation in CFH confers high risk of age-related macular degeneration,” Nature Genetics, vol. 43, no. 12, pp. 1232–1236, 2011. View at Publisher · View at Google Scholar
  13. A. Richards, D. Kavanagh, and J. P. Atkinson, “Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory statesthe examples of vascular damage in atypical hemolytic uremic syndrome and debris accumulation in age-related macular degeneration,” Advances in Immunology, vol. 96, pp. 141–177, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. T. H. J. Goodship, “Factor H genotype-phenotype correlations: lessons from aHUS, MPGN II, and AMD,” Kidney International, vol. 70, no. 1, pp. 12–13, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. P. J. Lachmann and R. A. G. Smith, “Taking complement to the clinic—has the time finally come?” Scandinavian Journal of Immunology, vol. 69, no. 6, pp. 471–478, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. J. Tuo, S. Grob, K. Zhang, and C. C. Chan, “Genetics of immunological and inflammatory components in age-related macular degeneration,” Ocular Immunology and Inflammation, vol. 20, no. 1, pp. 27–36, 2012. View at Publisher · View at Google Scholar
  17. J. R. Sparrow, K. Ueda, and J. Zhou, “Complement dysregulation in AMD: RPE-Bruch's membrane-choroid,” Molecular Aspects of Medicine, vol. 33, no. 4, pp. 436–445, 2012. View at Publisher · View at Google Scholar
  18. P. F. Zipfel, N. Lauer, and C. Skerka, “The role of complement in AMD,” Advances in Experimental Medicine and Biology, vol. 703, pp. 9–24, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. K. M. Gehrs, J. R. Jackson, E. N. Brown, R. Allikmets, and G. S. Hageman, “Complement, age-related macular degeneration and a vision of the future,” Archives of Ophthalmology, vol. 128, no. 3, pp. 349–358, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. D. H. Anderson, M. J. Radeke, N. B. Gallo et al., “The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited,” Progress in Retinal and Eye Research, vol. 29, no. 2, pp. 95–112, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. S. Khandhadia, V. Cipriani, J. R. Yates, and A. J. Lotery, “Age-related macular degeneration and the complement system,” Immunobiology, vol. 217, no. 2, pp. 127–146, 2012. View at Publisher · View at Google Scholar
  22. I. Bhutto and G. Lutty, “Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex,” Molecular Aspects of Medicine, vol. 33, no. 4, pp. 295–317, 2012. View at Publisher · View at Google Scholar
  23. D. D. G. Despriet, C. C. W. Klaver, J. C. M. Witteman et al., “Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration,” Journal of the American Medical Association, vol. 296, no. 3, pp. 301–309, 2006. View at Publisher · View at Google Scholar · View at Scopus
  24. A. L. Fett, M. M. Hermann, P. S. Muether, B. Kirchhof, and S. Fauser, “Immunohistochemical localization of complement regulatory proteins in the human retina,” Histol Histopathol, vol. 27, no. 3, pp. 357–364, 2012. View at Google Scholar
  25. R. Sofat, J. P. Casas, A. R. Webster et al., “Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype,” International Journal of Epidemiology, vol. 41, no. 1, pp. 250–262, 2012. View at Publisher · View at Google Scholar
  26. J. L. Haines, M. A. Hauser, S. Schmidt et al., “Complement factor H variant increases the risk of age-related macular degeneration,” Science, vol. 308, no. 5720, pp. 419–421, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. A. O. Edwards, R. Ritter, K. J. Abel, A. Manning, C. Panhuysen, and L. A. Farrer, “Complement factor H polymorphism and age-related macular degeneration,” Science, vol. 308, no. 5720, pp. 421–424, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. R. J. Klein, C. Zeiss, E. Y. Chew et al., “Complement factor H polymorphism in age-related macular degeneration,” Science, vol. 308, no. 5720, pp. 385–389, 2005. View at Publisher · View at Google Scholar · View at Scopus
  29. G. S. Hageman, D. H. Anderson, L. V. Johnson et al., “A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 20, pp. 7227–7232, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. T. Montes, A. Tortajada, B. P. Morgan, S. R. De Córdoba, and C. L. Harris, “Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 11, pp. 4366–4371, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. A. P. Sjöberg, L. A. Trouw, S. J. Clark et al., “The factor H variant associated with age-related macular degeneration (His-384) and the non-disease-associated form bind differentially to C-reactive protein, fibromodulin, DNA, and necrotic cells,” Journal of Biological Chemistry, vol. 282, no. 15, pp. 10894–10900, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. R. J. Ormsby, S. Ranganathan, J. C. Tong et al., “Functional and structural implications of the complement factor H Y402H polymorphism associated with age-related macular degeneration,” Investigative Ophthalmology and Visual Science, vol. 49, no. 5, pp. 1763–1770, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. S. J. Clark, R. Perveen, S. Hakobyan et al., “Impaired binding of the age-related macular degeneration-associated complement factor H 402H allotype to Bruch's membrane in human retina,” The Journal of Biological Chemistry, vol. 285, no. 39, pp. 30192–30202, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Laine, H. Jarva, S. Seitsonen et al., “Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein,” The Journal of Immunology, vol. 178, no. 6, pp. 3831–3836, 2007. View at Google Scholar · View at Scopus
  35. G. S. Hageman, P. J. Luthert, N. H. Victor Chong, L. V. Johnson, D. H. Anderson, and R. F. Mullins, “An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration,” Progress in Retinal and Eye Research, vol. 20, no. 6, pp. 705–732, 2001. View at Publisher · View at Google Scholar · View at Scopus
  36. D. H. Anderson, R. F. Mullins, G. S. Hageman, and L. V. Johnson, “A role for local inflammation in the formation of drusen in the aging eye,” American Journal of Ophthalmology, vol. 134, no. 3, pp. 411–431, 2002. View at Publisher · View at Google Scholar · View at Scopus
  37. R. F. Mullins, N. Aptsiauri, and G. S. Hageman, “Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis,” Eye, vol. 15, no. 3, pp. 390–395, 2001. View at Google Scholar · View at Scopus
  38. L. V. Johnson, W. P. Leitner, M. K. Staples, and D. H. Anderson, “Complement activation and inflammatory processes in drusen formation and age related macular degeneration,” Experimental Eye Research, vol. 73, no. 6, pp. 887–896, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. R. D. Horstmann, H. J. Sievertsen, J. Knobloch, and V. A. Fischetti, “Antiphagocytic activity of streptococcal M protein: selective binding of complement control protein factor H,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 5, pp. 1657–1661, 1988. View at Google Scholar · View at Scopus
  40. J. D. Lambris, D. Ricklin, and B. V. Geisbrecht, “Complement evasion by human pathogens,” Nature Reviews Microbiology, vol. 6, no. 2, pp. 132–142, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. N. Lauer, M. Mihlan, A. Hartmann et al., “Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-H His402 risk variant,” The Journal of Immunology, vol. 187, no. 8, pp. 4374–4383, 2011. View at Publisher · View at Google Scholar
  42. S. J. Clark, V. A. Higman, B. Mulloy et al., “His-384 allotypic variant of factor H associated with age-related macular degeneration has different heparin binding properties from the non-disease-associated form,” The Journal of Biological Chemistry, vol. 281, no. 34, pp. 24713–24720, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. J. G. Hollyfield, V. L. Bonilha, M. E. Rayborn et al., “Oxidative damage-induced inflammation initiates age-related macular degeneration,” Nature Medicine, vol. 14, no. 2, pp. 194–198, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. P. T. Johnson, K. E. Betts, M. J. Radeke, G. S. Hageman, D. H. Anderson, and L. V. Johnson, “Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 46, pp. 17456–17461, 2006. View at Publisher · View at Google Scholar · View at Scopus
  45. P. J. Lachmann, “The amplification loop of the complement pathways,” Advances in Immunology, vol. 104, pp. 115–149, 2009. View at Google Scholar · View at Scopus
  46. J. M. Seddon, R. Reynolds, J. Maller, J. A. Fagerness, M. J. Daly, and B. Rosner, “Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables,” Investigative Ophthalmology and Visual Science, vol. 50, no. 5, pp. 2044–2053, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. R. Reynolds, M. E. Hartnett, J. P. Atkinson, P. C. Giclas, B. Rosner, and J. M. Seddon, “Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes,” Investigative Ophthalmology and Visual Science, vol. 50, no. 12, pp. 5818–5827, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. H. P. N. Scholl, P. C. Issa, M. Walier et al., “Systemic complement activation in age-related macular degeneration,” PLoS ONE, vol. 3, no. 7, Article ID e2593, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. J. Wang, K. Ohno-Matsui, T. Yoshida et al., “Amyloid-β up-regulates complement factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: another mechanism of complement activation in age-related macular degeneration,” Journal of Cellular Physiology, vol. 220, no. 1, pp. 119–128, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. I. Droz, I. Mantel, A. Ambresin, M. Faouzi, D. F. Schorderet, and F. L. Munier, “Genotype-phenotype correlation of age-related macular degeneration: influence of complement factor H polymorphism,” British Journal of Ophthalmology, vol. 92, no. 4, pp. 513–517, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. T. Sepp, J. C. Khan, D. A. Thurlby et al., “Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers,” Investigative Ophthalmology and Visual Science, vol. 47, no. 2, pp. 536–540, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. J. M. Seddon, S. George, B. Rosner, and N. Rifai, “Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers,” Archives of Ophthalmology, vol. 123, no. 6, pp. 774–782, 2005. View at Publisher · View at Google Scholar · View at Scopus
  53. K. M. Gehrs, D. H. Anderson, L. V. Johnson, and G. S. Hageman, “Age-related macular degeneration—emerging pathogenetic and therapeutic concepts,” Annals of Medicine, vol. 38, no. 7, pp. 450–471, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. G. S. Hageman, L. S. Hancox, A. J. Taiber et al., “Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications,” Annals of Medicine, vol. 38, no. 8, pp. 592–604, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. J. Maller, S. George, S. Purcell et al., “Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration,” Nature Genetics, vol. 38, no. 9, pp. 1055–1059, 2006. View at Publisher · View at Google Scholar · View at Scopus
  56. K. M. Nishiguchi, T. R. Yasuma, D. Tomida et al., “C9-R95X polymorphism in patients with neovascular age-related macular degeneration,” Investigative Ophthalmology & Visual Science, vol. 53, no. 1, pp. 508–512, 2012. View at Publisher · View at Google Scholar
  57. J. B. Maller, J. A. Fagerness, R. C. Reynolds, B. M. Neale, M. J. Daly, and J. M. Seddon, “Variation in complement factor 3 is associated with risk of age-related macular degeneration,” Nature Genetics, vol. 39, no. 10, pp. 1200–1201, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Heurich, R. Martínez-Barricarte, N. J. Francis et al., “Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 21, pp. 8761–8766, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. J. A. Fagerness, J. B. Maller, B. M. Neale, R. C. Reynolds, M. J. Daly, and J. M. Seddon, “Variation near complement factor I is associated with risk of advanced AMD,” European Journal of Human Genetics, vol. 17, no. 1, pp. 100–104, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Nozaki, B. J. Raisler, E. Sakurai et al., “Drusen complement components C3a and C5a promote choroidal neovascularization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 7, pp. 2328–2333, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. B. Rohrer, B. Coughlin, K. Kunchithapautham et al., “The alternative pathway is required, but not alone sufficient, for retinal pathology in mouse laser-induced choroidal neovascularization,” Molecular Immunology, vol. 48, no. 6-7, pp. e1–e8, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. N. S. Bora, S. Kaliappan, P. Jha et al., “Complement activation via alternative pathway is critical in the development of laser-induced choroidal neovascularization: role of factor B and factor H,” The Journal of Immunology, vol. 177, no. 3, pp. 1872–1878, 2006. View at Google Scholar · View at Scopus
  63. N. S. Bora, S. Kaliappan, P. Jha et al., “CD59, a complement regulatory protein, controls choroidal neovascularization in a mouse model of wet-type age-related macular degeneration,” The Journal of Immunology, vol. 178, no. 3, pp. 1783–1790, 2007. View at Google Scholar · View at Scopus
  64. N. S. Bora, P. Jha, V. V. Lyzogubov et al., “Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice,” The Journal of Biological Chemistry, vol. 285, no. 44, pp. 33826–33833, 2010. View at Google Scholar
  65. S. M. Cashman, K. Ramo, and R. Kumar-Singh, “A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration,” PLoS ONE, vol. 6, no. 4, Article ID e19078, 2011. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. Huang, F. Qiao, C. Atkinson, V. M. Holers, and S. Tomlinson, “A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury,” The Journal of Immunology, vol. 181, no. 11, pp. 8068–8076, 2008. View at Google Scholar · View at Scopus
  67. B. Rohrer, Q. Long, B. Coughlin et al., “A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration,” Investigative Ophthalmology and Visual Science, vol. 50, no. 7, pp. 3056–3064, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. S. B. Bressler, “Introduction: understanding the role of angiogenesis and antiangiogenic agents in age-related macular degeneration,” Ophthalmology, vol. 116, no. 10, pp. S1–S7, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. O. Gross, C. J. Thomas, G. Guarda, and J. Tschopp, “The inflammasome: an integrated view,” Immunological Reviews, vol. 243, no. 1, pp. 136–151, 2011. View at Publisher · View at Google Scholar
  70. J. K. Dowling and L. A. O'Neill, “Biochemical regulation of the inflammasome,” Critical Reviews in Biochemistry and Molecular Biology, vol. 47, no. 5, pp. 424–443, 2012. View at Publisher · View at Google Scholar
  71. P. Menu and J. E. Vince, “The NLRP3 inflammasome in health and disease: the good, the bad and the ugly,” Clinical & Experimental Immunology, vol. 166, no. 1, pp. 1–15, 2011. View at Publisher · View at Google Scholar
  72. A. K. Mankan, A. Kubarenko, and V. Hornung, “Immunology in clinic review series, focus on autoinflammatory diseases: inflammasomes: mechanisms of activation,” Clinical & Experimental Immunology, vol. 167, no. 3, pp. 369–381, 2012. View at Publisher · View at Google Scholar
  73. S. L. Doyle, M. Campbell, E. Ozaki et al., “NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components,” Nature Medicine, vol. 18, no. 5, pp. 791–798, 2012. View at Publisher · View at Google Scholar
  74. V. Tarallo, Y. Hirano, B. D. Gelfand et al., “DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88,” Cell, vol. 149, no. 4, pp. 847–859, 2012. View at Google Scholar
  75. M. E. Benoit, E. V. Clarke, P. Morgado, D. A. Fraser, and A. J. Tenner, “Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells,” The Journal of Immunology, vol. 188, no. 11, pp. 5682–5693, 2012. View at Publisher · View at Google Scholar
  76. W. A. Tseng, T. Thein, K. Kinnunen et al., “NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration,” Investigative Ophthalmology & Visual Science, vol. 54, no. 1, pp. 110–120, 2013. View at Publisher · View at Google Scholar
  77. K. Nakahira, J. A. Haspel, V. A. Rathinam et al., “Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome,” Nature Immunology, vol. 12, no. 3, pp. 222–230, 2011. View at Google Scholar
  78. C. S. Shi, K. Shenderov, N. N. Huang et al., “Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction,” Nature Immunology, vol. 13, no. 3, pp. 255–263, 2012. View at Publisher · View at Google Scholar
  79. M. C. Kenney, M. Chwa, S. R. Atilano et al., “Mitochondrial DNA variants mediate energy production and expression levels for CFH, C3 and EFEMP1 genes: implications for age-related macular degeneration,” PLoS ONE, vol. 8, no. 1, Article ID e54339, 2013. View at Google Scholar
  80. N. Patel, M. Ohbayashi, A. K. Nugent et al., “Circulating anti-retinal antibodies as immune markers in age-related macular degeneration,” Immunology, vol. 115, no. 3, pp. 422–430, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Cherepanoff, P. Mitchell, J. J. Wang, and M. C. Gillies, “Retinal autoantibody profile in early age-related macular degeneration: preliminary findings from the blue mountains eye study,” Clinical and Experimental Ophthalmology, vol. 34, no. 6, pp. 590–595, 2006. View at Publisher · View at Google Scholar · View at Scopus
  82. K. Morohoshi, A. M. Goodwin, M. Ohbayashi, and S. J. Ono, “Autoimmunity in retinal degeneration: autoimmune retinopathy and age-related macular degeneration,” Journal of Autoimmunity, vol. 33, no. 3-4, pp. 247–254, 2009. View at Publisher · View at Google Scholar · View at Scopus
  83. K. Morohoshi, M. Ohbayashi, N. Patel, V. Chong, A. C. Bird, and S. J. Ono, “Identification of anti-retinal antibodies in patients with age-related macular degeneration,” Experimental and Molecular Pathology, vol. 93, no. 2, pp. 193–199, 2012. View at Publisher · View at Google Scholar
  84. K. Morohoshi, N. Patel, M. Ohbayashi et al., “Serum autoantibody biomarkers for age-related macular degeneration and possible regulators of neovascularization,” Experimental and Molecular Pathology, vol. 92, no. 1, pp. 64–73, 2012. View at Publisher · View at Google Scholar
  85. B. Dhillon, A. F. Wright, A. Tufail et al., “Complement factor H autoantibodies and age-related macular degeneration,” Investigative Ophthalmology and Visual Science, vol. 51, no. 11, pp. 5858–5863, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. J. G. Hollyfield, V. L. Perez, and R. G. Salomon, “A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration,” Molecular Neurobiology, vol. 41, no. 2-3, pp. 290–298, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. B. Liu, L. Wei, C. Meyerle et al., “Complement component C5a promotes expression of IL-22 and IL-17 from human T cells and its implication in age-related macular degeneration,” Journal of Translational Medicine, vol. 9, p. 111, 2011. View at Publisher · View at Google Scholar · View at Scopus
  88. L. Wei, B. Liu, J. Tuo et al., “Hypomethylation of the IL17RC promoter associates with age-related macular degeneration,” Cell Reports, vol. 2, no. 5, pp. 1151–1158, 2012. View at Publisher · View at Google Scholar
  89. T. W. Olsen and X. Feng, “The minnesota grading system of eye bank eyes for age-related macular degeneration,” Investigative Ophthalmology and Visual Science, vol. 45, no. 12, pp. 4484–4490, 2004. View at Publisher · View at Google Scholar · View at Scopus