Skip to main content

A Role for Complement in Glaucoma?

  • Conference paper
  • First Online:
Inflammation and Retinal Disease: Complement Biology and Pathology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 703))

Abstract

Chronic open angle glaucoma is a degenerative optic neuropathy that can lead to blindness. We have shown that one of the major genes with altered expression in the glaucomatous retina is complement component C1q in both animal models of the disease as well as in humans. These observations together with evidence of upregulation of other complement components within the retina suggest a role for complement in the pathogenesis of this disease. We review the current evidence that supports such a role and discuss possible mechanisms through which complement may act. A thorough understanding of these mechanisms is important in allowing us to rationally design new therapeutic approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Anderson DR (2003) Collaborative normal tension glaucoma study. Curr Opin Ophthalmol 14(2):86–90

    Article  PubMed  Google Scholar 

  • Anderson MG, Smith RS, Hawes NL, Zabaleta A, Chang B, Wiggs JL, John SW (2002) Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat Genet 30(1):81–85

    Article  PubMed  CAS  Google Scholar 

  • Anderson MG, Libby RT, Mao M, Cosma IM, Wilson LA, Smith RS, John SW (2006) Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma. BMC Biol 4:20

    Article  PubMed  Google Scholar 

  • Bayer AU, Danias J, Brodie S, Maag KP, Chen B, Shen F, Podos SM, Mittag TW (2001) Electroretinographic abnormalities in a rat glaucoma model with chronic elevated intraocular pressure. Exp Eye Res 72(6):667–677

    Article  PubMed  CAS  Google Scholar 

  • Beck AD (2003) Review of recent publications of the Advanced Glaucoma Intervention Study. Curr Opin Ophthalmol 14(2):83–85

    Article  PubMed  Google Scholar 

  • Bohana-Kashtan O, Ziporen L, Donin N, Kraus S, Fishelson Z (2004) Cell signals transduced by complement. Mol Immunol 41(6–7):583–597

    Article  PubMed  CAS  Google Scholar 

  • Cedrone C, Mancino R, Cerulli A, Cesareo M, Nucci C (2008) Epidemiology of primary glaucoma: prevalence, incidence, and blinding effects. Prog Brain Res 173:3–14

    Article  PubMed  Google Scholar 

  • Coleman AL, Brigatti L (2001) The glaucomas. Minerva Med 92(5):365–379

    PubMed  CAS  Google Scholar 

  • Cordeiro MF, Guo L, Luong V, Harding G, Wang W, Jones HE, Moss SE, Sillito AM, Fitzke FW (2004) Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc Natl Acad Sci U S A 101(36):13352–13356

    Article  PubMed  CAS  Google Scholar 

  • Danias J, Lee KC, Zamora MF, Chen B, Shen F, Filippopoulos T, Su Y, Goldblum D, Podos SM, Mittag T (2003) Quantitative analysis of retinal ganglion cell (RGC) loss in aging DBA/2NNia glaucomatous mice: comparison with RGC loss in aging C57/BL6 mice. Invest Ophthalmol Vis Sci 44(12):5151–5162

    Article  PubMed  Google Scholar 

  • Downs JC, Yang H, Girkin C, Sakata L, Bellezza A, Thompson H, Burgoyne CF (2007) Three-dimensional histomorphometry of the normal and early glaucomatous monkey optic nerve head: neural canal and subarachnoid space architecture. Invest Ophthalmol Vis Sci 48(7):3195–3208

    Article  PubMed  Google Scholar 

  • Gaipl US, Kuhn A, Sheriff A, Munoz LE, Franz S, Voll RE, Kalden JR, Herrmann M (2006) Clearance of apoptotic cells in human SLE. Curr Dir Autoimmun 9:173–187

    PubMed  CAS  Google Scholar 

  • Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK II, Wilson MR, Kass MA (2002) The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 120(6):714–720, discussion 829–830

    Article  PubMed  Google Scholar 

  • Gullstrand B, Martensson U, Sturfelt G, Bengtsson AA, Truedsson L (2009) Complement classical­ pathway components are all important in clearance of apoptotic and secondary necrotic cells. Clin Exp Immunol 156(2):303–311

    Article  PubMed  CAS  Google Scholar 

  • Gupta N, Ly T, Zhang Q, Kaufman PL, Weinreb RN, Yucel YH (2007) Chronic ocular hypertension induces dendrite pathology in the lateral geniculate nucleus of the brain. Exp Eye Res 84(1):176–184

    Article  PubMed  CAS  Google Scholar 

  • Gupta N, Greenberg G, de Tilly LN, Gray B, Polemidiotis M, Yucel YH (2009) Atrophy of the lateral geniculate nucleus in human glaucoma detected by magnetic resonance imaging. Br J Ophthalmol 93(1):56–60

    Article  PubMed  CAS  Google Scholar 

  • Howell GR, Libby RT, Jakobs TC, Smith RS, Phalan FC, Barter JW, Barbay JM, Marchant JK, Mahesh N, Porciatti V, Whitmore AV, Masland RH, John SW (2007a) Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J Cell Biol 179(7):1523–1537

    Article  PubMed  CAS  Google Scholar 

  • Howell GR, Libby RT, Marchant JK, Wilson LA, Cosma IM, Smith RS, Anderson MG, John SW (2007b) Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1. BMC Genet 8:45

    Article  PubMed  Google Scholar 

  • Jakobs TC, Libby RT, Ben Y, John SW, Masland RH (2005) Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. J Cell Biol 171(2):313–325

    Article  PubMed  CAS  Google Scholar 

  • Jha P, Bora PS, Sohn JH, Kaplan HJ, Bora NS (2006) Complement system and the eye. Adv Exp Med Biol 586:53–62

    Article  PubMed  CAS  Google Scholar 

  • John SW, Smith RS, Savinova OV, Hawes NL, Chang B, Turnbull D, Davisson M, Roderick TH, Heckenlively JR (1998) Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci 39(6):951–962

    PubMed  CAS  Google Scholar 

  • Johnson EC, Morrison JC, Farrell S, Deppmeier L, Moore CG, McGinty MR (1996) The effect of chronically elevated intraocular pressure on the rat optic nerve head extracellular matrix. Exp Eye Res 62(6):663–674

    Article  PubMed  CAS  Google Scholar 

  • Kerrigan LA, Zack DJ, Quigley HA, Smith SD, Pease ME (1997) TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol 115(8):1031–1035

    Article  PubMed  CAS  Google Scholar 

  • Khalyfa A, Chlon T, Qiang H, Agarwal N, Cooper NG (2007) Microarray reveals complement components are regulated in the serum-deprived rat retinal ganglion cell line. Mol Vis 13:293–308

    PubMed  CAS  Google Scholar 

  • Kim SJ, Gershov D, Ma X, Brot N, Elkon KB (2003) Opsonization of apoptotic cells and its effect on macrophage and T cell immune responses. Ann N Y Acad Sci 987:68–78

    Article  PubMed  CAS  Google Scholar 

  • Kuehn MH, Kim CY, Ostojic J, Bellin M, Alward WL, Stone EM, Sakaguchi DS, Grozdanic SD, Kwon YH (2006) Retinal synthesis and deposition of complement components induced by ocular hypertension. Exp Eye Res 83(3):620–628

    Article  PubMed  CAS  Google Scholar 

  • Lautenschlager I, Hockerstedt K, Meri S (1999) Complement membrane attack complex and protectin (CD59) in liver allografts during acute rejection. J Hepatol 31(3):537–541

    Article  PubMed  CAS  Google Scholar 

  • Leske MC (2007) Open-angle glaucoma – an epidemiologic overview. Ophthalmic Epidemiol 14(4):166–172

    Article  PubMed  Google Scholar 

  • Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E (2003) Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 121(1):48–56

    Article  PubMed  Google Scholar 

  • Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z (2007a) Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology 114(11):1965–1972

    Article  PubMed  Google Scholar 

  • Leske MC, Wu SY, Honkanen R, Nemesure B, Schachat A, Hyman L, Hennis A (2007b) Nine-year incidence of open-angle glaucoma in the Barbados Eye Studies. Ophthalmology 114(6):1058–1064

    Article  PubMed  Google Scholar 

  • Levkovitch-Verbin H, Quigley HA, Kerrigan-Baumrind LA, D’Anna SA, Kerrigan D, Pease ME (2001) Optic nerve transection in monkeys may result in secondary degeneration of retinal ganglion cells. Invest Ophthalmol Vis Sci 42(5):975–982

    PubMed  CAS  Google Scholar 

  • Libby RT, Anderson MG, Pang IH, Robinson ZH, Savinova OV, Cosma IM, Snow A, Wilson LA, Smith RS, Clark AF, John SW (2005a) Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. Vis Neurosci 22(5):637–648

    Article  PubMed  Google Scholar 

  • Libby RT, Li Y, Savinova OV, Barter J, Smith RS, Nickells RW, John SW (2005b) Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet 1(1):17–26

    Article  PubMed  CAS  Google Scholar 

  • Mevorach D (2000) Opsonization of apoptotic cells. Implications for uptake and autoimmunity. Ann N Y Acad Sci 926:226–235

    Article  PubMed  CAS  Google Scholar 

  • Mittag TW, Danias J, Pohorenec G, Yuan HM, Burakgazi E, Chalmers-Redman R, Podos SM, Tatton WG (2000) Retinal damage after 3 to 4 months of elevated intraocular pressure in a rat glaucoma model. Invest Ophthalmol Vis Sci 41(11):3451–3459

    PubMed  CAS  Google Scholar 

  • Miyahara T, Kikuchi T, Akimoto M, Kurokawa T, Shibuki H, Yoshimura N (2003) Gene microarray analysis of experimental glaucomatous retina from cynomologous monkey. Invest Ophthalmol Vis Sci 44(10):4347–4356

    Article  PubMed  Google Scholar 

  • Morrison JC, Moore CG, Deppmeier LM, Gold BG, Meshul CK, Johnson EC (1997) A rat model of chronic pressure-induced optic nerve damage. Exp Eye Res 64(1):85–96

    Article  PubMed  CAS  Google Scholar 

  • Muller-Eberhard HJ (1986) The membrane attack complex of complement. Annu Rev Immunol 4:503–528

    Article  PubMed  CAS  Google Scholar 

  • Nemesure B, Honkanen R, Hennis A, Wu SY, Leske MC (2007) Incident open-angle glaucoma and intraocular pressure. Ophthalmology 114(10):1810–1815

    Article  PubMed  CAS  Google Scholar 

  • Oliver JE, Hattenhauer MG, Herman D, Hodge DO, Kennedy R, Fang-Yen M, Johnson DH (2002) Blindness and glaucoma: a comparison of patients progressing to blindness from glaucoma with patients maintaining vision. Am J Ophthalmol 133(6):764–772

    Article  PubMed  Google Scholar 

  • Parrish RK II, Feuer WJ, Schiffman JC, Lichter PR, Musch DC (2009) Five-year follow-up optic disc findings of the Collaborative Initial Glaucoma Treatment Study. Am J Ophthalmol 147(4):717–724.e1

    Article  PubMed  Google Scholar 

  • Pasinetti GM, Tocco G, Sakhi S, Musleh WD, DeSimoni MG, Mascarucci P, Schreiber S, Baudry M, Finch CE (1996) Hereditary deficiencies in complement C5 are associated with intensified neurodegenerative responses that implicate new roles for the C-system in neuronal and astrocytic functions. Neurobiol Dis 3(3):197–204

    Article  PubMed  CAS  Google Scholar 

  • Pederson JE, Gaasterland DE (1984) Laser-induced primate glaucoma. I. Progression of cupping. Arch Ophthalmol 102(11):1689–1692

    Article  PubMed  CAS  Google Scholar 

  • Quigley HA (1995) Ganglion cell death in glaucoma: pathology recapitulates ontogeny. Aust N Z Ophthalmol 23(2):85–91

    Article  CAS  Google Scholar 

  • Rasmussen CA, Kaufman PL (2005) Primate glaucoma models. J Glaucoma 14(4):311–314

    Article  PubMed  Google Scholar 

  • Rudnicka AR, Mt-Isa S, Owen CG, Cook DG, Ashby D (2006) Variations in primary open-angle glaucoma prevalence by age, gender, and race: a Bayesian meta-analysis. Invest Ophthalmol Vis Sci 47(10):4254–4261

    Article  PubMed  Google Scholar 

  • Schlamp CL, Li Y, Dietz JA, Janssen KT, Nickells RW (2006) Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric. BMC Neurosci 7:66

    Article  PubMed  Google Scholar 

  • Schwartz M (2004) Vaccination for glaucoma: dream or reality? Brain Res Bull 62(6):481–484

    Article  PubMed  CAS  Google Scholar 

  • Schwartz M (2005) T-cell-based vaccination against neurodegeneration: a new therapeutic approach. Retina 25(8 Suppl):S33–S35

    Article  PubMed  Google Scholar 

  • Schwartz M (2007) Modulating the immune system: a vaccine for glaucoma? Can J Ophthalmol 42(3):439–441

    Article  PubMed  Google Scholar 

  • Schwartz M, Kipnis J (2005) Therapeutic T cell-based vaccination for neurodegenerative disorders: the role of CD4+CD25+ regulatory T cells. Ann N Y Acad Sci 1051:701–708

    Article  PubMed  CAS  Google Scholar 

  • Shareef SR, Garcia-Valenzuela E, Salierno A, Walsh J, Sharma SC (1995) Chronic ocular hypertension following episcleral venous occlusion in rats. Exp Eye Res 61(3):379–382

    Article  PubMed  CAS  Google Scholar 

  • Sheldon WG, Warbritton AR, Bucci TJ, Turturro A (1995) Glaucoma in food-restricted and ad libitum-fed DBA/2NNia mice. Lab Anim Sci 45(5):508–518

    PubMed  CAS  Google Scholar 

  • Shields MB (2008) Normal-tension glaucoma: is it different from primary open-angle glaucoma? Curr Opin Ophthalmol 19(2):85–88

    Article  PubMed  Google Scholar 

  • Sohn JH, Kaplan HJ, Suk HJ, Bora PS, Bora NS (2000) Chronic low level complement activation within the eye is controlled by intraocular complement regulatory proteins. Invest Ophthalmol Vis Sci 41(11):3492–3502

    PubMed  CAS  Google Scholar 

  • Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt J, Singh K (1991) Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol 109(8):1090–1095

    Article  PubMed  CAS  Google Scholar 

  • Stasi K, Nagel D, Yang X, Wang RF, Ren L, Podos SM, Mittag T, Danias J (2006) Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest Ophthalmol Vis Sci 47(3):1024–1029

    Article  PubMed  Google Scholar 

  • Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131(6):1164–1178

    Article  PubMed  CAS  Google Scholar 

  • Tezel G (2009) The role of glia, mitochondria, and the immune system in glaucoma. Invest Ophthalmol Vis Sci 50(3):1001–1012

    Article  PubMed  Google Scholar 

  • Tezel G, Seigel GM, Wax MB (1998) Autoantibodies to small heat shock proteins in glaucoma. Invest Ophthalmol Vis Sci 39(12):2277–2287

    PubMed  CAS  Google Scholar 

  • Tezel G, Yang X, Luo C, Peng Y, Sun SL, Sun D (2007) Mechanisms of immune system activation in glaucoma: oxidative stress-stimulated antigen presentation by the retina and optic nerve head glia. Invest Ophthalmol Vis Sci 48(2):705–714

    Article  PubMed  Google Scholar 

  • Thylefors B, Negrel AD (1994) The global impact of glaucoma. Bull World Health Organ 72(3):323–326

    PubMed  CAS  Google Scholar 

  • Tielsch JM, Sommer A, Katz J, Royall RM, Quigley HA, Javitt J (1991) Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey. JAMA 266(3):369–374

    Article  PubMed  CAS  Google Scholar 

  • Urcola JH, Hernandez M, Vecino E (2006) Three experimental glaucoma models in rats: comparison of the effects of intraocular pressure elevation on retinal ganglion cell size and death. Exp Eye Res 83(2):429–437

    Article  PubMed  CAS  Google Scholar 

  • Villalba JM, Navas P (2000) Plasma membrane redox system in the control of stress-induced apoptosis. Antioxid Redox Signal 2(2):213–230

    Article  PubMed  CAS  Google Scholar 

  • Wax MB (2000) Is there a role for the immune system in glaucomatous optic neuropathy? Curr Opin Ophthalmol 11(2):145–150

    Article  PubMed  CAS  Google Scholar 

  • Wax MB, Tezel G (2002) Neurobiology of glaucomatous optic neuropathy: diverse cellular events in neurodegeneration and neuroprotection. Mol Neurobiol 26(1):45–55

    Article  PubMed  CAS  Google Scholar 

  • Weinreb RN, Lindsey JD (2005) The importance of models in glaucoma research. J Glaucoma 14(4):302–304

    Article  PubMed  Google Scholar 

  • Wilson MR, Kosoko O, Cowan CL Jr, Sample PA, Johnson CA, Haynatzki G, Enger C, Crandall D (2002) Progression of visual field loss in untreated glaucoma patients and glaucoma suspects in St. Lucia, West Indies. Am J Ophthalmol 134(3):399–405

    Article  PubMed  Google Scholar 

  • Xiong ZQ, Qian W, Suzuki K, McNamara JO (2003) Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration. J Neurosci 23(3):955–960

    PubMed  CAS  Google Scholar 

  • Yang H, Downs JC, Bellezza A, Thompson H, Burgoyne CF (2007a) 3-D histomorphometry of the normal and early glaucomatous monkey optic nerve head: prelaminar neural tissues and cupping. Invest Ophthalmol Vis Sci 48(11):5068–5084

    Article  PubMed  Google Scholar 

  • Yang H, Downs JC, Girkin C, Sakata L, Bellezza A, Thompson H, Burgoyne CF (2007b) 3-D histomorphometry of the normal and early glaucomatous monkey optic nerve head: lamina cribrosa and peripapillary scleral position and thickness. Invest Ophthalmol Vis Sci 48(10):4597–4607

    Article  PubMed  Google Scholar 

  • Yucel Y, Gupta N (2008) Glaucoma of the brain: a disease model for the study of transsynaptic neural degeneration. Prog Brain Res 173:465–478

    Article  PubMed  Google Scholar 

  • Yucel YH, Zhang Q, Gupta N, Kaufman PL, Weinreb RN (2000) Loss of neurons in magnocellular and parvocellular layers of the lateral geniculate nucleus in glaucoma. Arch Ophthalmol 118(3):378–384

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John Danias .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this paper

Cite this paper

Ren, L., Danias, J. (2010). A Role for Complement in Glaucoma?. In: Lambris, J., Adamis, A. (eds) Inflammation and Retinal Disease: Complement Biology and Pathology. Advances in Experimental Medicine and Biology, vol 703. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5635-4_7

Download citation

Publish with us

Policies and ethics