Serum cytokines as biomarkers for age-related macular degeneration

  • Khaled NassarEmail author
  • Salvatore Grisanti
  • Elshaymaa Elfar
  • Julia Lüke
  • Matthias Lüke
  • Swaantje Grisanti
Retinal Disorders



This study evaluates the potential of serum pro-inflammatory cytokines as AMD biomarkers.


Serum samples from 30 age-related macular degeneration (AMD) patients and 15 age-matched controls were examined for 16 inflammatory cytokines using multiplex ELISA. Patients were divided into three subgroups (improvement/no change/deterioration during anti-VEGF treatment) by OCT and funduscopy, and correlated to the cytokine levels.


Serum concentrations of IL-1α, IL-1β, IL-4, IL-5, IL-10, IL-13, and IL-17 were significantly higher in AMD patients than in controls. None of the co-variables expressed a significant effect on the tested cytokines. Only IL-1a and IL-17 showed a statistically significant difference between groups (improved, unchanged, deteriorated) as determined by one-way ANOVA. Patients with increased macular thickness during treatment showed significantly lower levels of IL-17 compared to improved cases and to unchanged cases (p = 0.004, 0.03 respectively, Dunnett’s T3 post hoc multiple test). TNF-α was significantly higher in improved cases compared to deteriorated cases (p =0.03, Dunnett’s T3 post hoc multiple test). IL-17 was a significant predictor for macular oedema using linear regression (β = −0.888, p <0.05).


Elevation of IL-1α, IL-1β, IL-4, IL-5, IL-10, IL-13, and IL-17 in the serum of AMD patients supports the hypothesis of AMD as an inflammatory disease. Patients with high IL-17 and TNF-α serum levels were more likely to have a favourable course under VEGF therapy. These cytokines may be used as easy-to-obtain biomarkers.


Age-related macular degeneration (AMD) Biomarker Choroidal neovascular membrane Cytokines Macular oedema Inflammation 



We thank Mrs. Christine Oeruen for her technical assistance. We thank Dr. Reinhard Vonthein, Luebeck University, Institute for Medical Biometry and Statistics (IMBS), Centre for Clinical Trials for his valuable advice during statistical evaluation. The work was supported by Novartis Pharma GmbH, Nürnberg, Germany.

Conflict of interest



  1. 1.
    Yehoshua Z, Rosenfeld PJ, Gregori G, Penha F (2010) Spectral domain optical coherence tomography imaging of dry age-related macular degeneration. Ophthalmic Surg Lasers Imaging 41(Suppl):S6–S14CrossRefPubMedGoogle Scholar
  2. 2.
    Wong TY, Wong T, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, Fahrbach K, Probst C, Sledge I (2008) The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology 115:116–126CrossRefPubMedGoogle Scholar
  3. 3.
    Ambati J, Anand A, Fernandez S, Sakurai E, Lynn BC, Kuziel WA, Rollins BJ, Ambati BK (2003) An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice. Nat Med 9:1390–1397CrossRefPubMedGoogle Scholar
  4. 4.
    Penfold PL, Provis JM, Billson FA (1987) Age-related macular degeneration: ultrastructural studies of the relationship of leucocytes to angiogenesis. Graefes Arch Clin Exp Ophthalmol 225:70–76CrossRefPubMedGoogle Scholar
  5. 5.
    Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424CrossRefPubMedGoogle Scholar
  6. 6.
    Mo FM, Proia AD, Johnson WH, Cyr D, Lashkari K (2010) Interferon gamma-inducible protein-10 (IP-10) and eotaxin as biomarkers in age-related macular degeneration. Invest Ophthalmol Vis Sci 51:4226–4236CrossRefPubMedGoogle Scholar
  7. 7.
    Chau KY, Sivaprasad S, Patel N, Donaldson TA, Luthert PJ, Chong NV (2008) Plasma levels of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) in age-related macular degeneration. Eye (Lond) 22:855–859CrossRefGoogle Scholar
  8. 8.
    Sivaprasad S, Adewoyin T, Bailey TA, Dandekar SS, Jenkins S, Webster AR, Chong NV (2007) Estimation of systemic complement C3 activity in age-related macular degeneration. Arch Ophthalmol 125:515–519CrossRefPubMedGoogle Scholar
  9. 9.
    Reynolds R, Rosner B, Seddon JM (2010) Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology 117:1989–1995CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Klein R, Myers CE, Cruickshanks KJ, Gangnon RE, Danforth LG, Sivakumaran TA, Iyengar SK, Tsai MY, Klein BEK (2014) Markers of inflammation, oxidative stress, and endothelial dysfunction and the 20-year cumulative incidence of early age-related macular degeneration: the Beaver Dam Eye Study. JAMA Ophthalmol 132:446–455CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Wu KHC, Tan AG, Rochtchina E, Favaloro EJ, Williams A, Mitchell P, Wang JJ (2007) Circulating inflammatory markers and hemostatic factors in age-related maculopathy: a population-based case-control study. Invest Ophthalmol Vis Sci 48:1983–1988CrossRefPubMedGoogle Scholar
  12. 12.
    Cha DM, Woo SJ, Kim H-J, Lee C, Park KH (2013) Comparative analysis of aqueous humor cytokine levels between patients with exudative age-related macular degeneration and normal controls. Invest Ophthalmol Vis Sci 54:7038–7044CrossRefPubMedGoogle Scholar
  13. 13.
    Martin DF, Maguire MG, Ying G, Grunwald JE, Fine SL, Jaffe GJ (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med 364:1897–1908CrossRefPubMedGoogle Scholar
  14. 14.
    Gasperini JL, Fawzi AA, Khondkaryan A, Lam L, Chong LP, Eliott D, Walsh AC, Hwang J, Sadda SR (2012) Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol 96:14–20CrossRefPubMedGoogle Scholar
  15. 15.
    Schaal S, Kaplan HJ, Tezel TH (2008) Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 115:2199–2205CrossRefPubMedGoogle Scholar
  16. 16.
    Zimmermann J, Krauthausen M, Hofer MJ, Heneka MT, Campbell IL, Müller M (2013) CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia. PLoS One 8:e57307CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Toussirot E (2012) The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. Inflamm. Allergy Drug Targets 11:159–168CrossRefGoogle Scholar
  18. 18.
    Siakavellas SI, Bamias G (2012) Role of the IL-23/IL-17 Axis in Crohn’s Disease. Discov Med 14:253–262PubMedGoogle Scholar
  19. 19.
    Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550CrossRefPubMedGoogle Scholar
  20. 20.
    Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, Mineau F, Pelletier JP (1998) IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160:3513–3521PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Khaled Nassar
    • 1
    • 2
    Email author
  • Salvatore Grisanti
    • 1
  • Elshaymaa Elfar
    • 1
    • 3
  • Julia Lüke
    • 1
  • Matthias Lüke
    • 1
  • Swaantje Grisanti
    • 1
  1. 1.Department of OphthalmologyUniversity of LuebeckLuebeckGermany
  2. 2.Department of OphthalmologyFayoum UniversityFayoumEgypt
  3. 3.Department of Rheumatology and RehabilitationCairo UniversityCairoEgypt

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