May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Identification of an Inflammatory Signal From the Outer Retina Causing Age-Related Macular Degeneration
Author Affiliations & Notes
  • J. G. Hollyfield
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • M. E. Rayborn
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • X. Yang
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • R. Ufret
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • L. Liang
    Chemistry, Case Western Reserve University, Cleveland, Ohio
  • M. Yu
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • K. G. Shadrach
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • N. S. Peachey
    Cole Eye Institute / Research, Cleveland Clinic / Cleveland VA Medical Center, Cleveland, Ohio
  • R. G. Salomon
    Chemistry, Case Western Reserve University, Cleveland, Ohio
  • V. L. Perez
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • Footnotes
    Commercial Relationships J.G. Hollyfield, Cleveland Clinic has protected the intellectual property described in this new animal model for AMD, P; M.E. Rayborn, None; X. Yang, Cleveland Clinic has protected the intellectual property discribed in this new animal model of AMD, P; R. Ufret, None; L. Liang, None; M. Yu, None; K.G. Shadrach, None; N.S. Peachey, None; R.G. Salomon, Cleveland Clinic has protected the intellectual property disclosed in this new animal model of AMD., P; V.L. Perez, Cleveland Clinic has protected the intellectual property discribed in this new animal model of AMD., P.
  • Footnotes
    Support NIH EY015638 HIGHWIRE EXLINK_ID="48:5:2356:1" VALUE="EY015638" TYPEGUESS="GEN" /HIGHWIRE , EY014240 HIGHWIRE EXLINK_ID="48:5:2356:2" VALUE="EY014240" TYPEGUESS="GEN" /HIGHWIRE , KO8-EY014912 HIGHWIRE EXLINK_ID="48:5:2356:3" VALUE="EY014912" TYPEGUESS="GEN" /HIGHWIRE -03, GM21249,Research to Prevent Blindness, State of Ohio-BRTT 05-29 & The Foundation Fighting Blindness
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 2356. doi:
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    • Get Citation

      J. G. Hollyfield, M. E. Rayborn, X. Yang, R. Ufret, L. Liang, M. Yu, K. G. Shadrach, N. S. Peachey, R. G. Salomon, V. L. Perez; Identification of an Inflammatory Signal From the Outer Retina Causing Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2356.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: AMD eye tissues contain proteins chemically modified with adducts generated by the oxidative fragmentation of the long chain polyunsaturated fatty acid, docosahexaenoic acid (DHA). Proteins modified with these adducts are found in drusen and Bruch’s membrane. Additionally, autoantibodies against a unique carboxyethylpyrrole (CEP) adduct that can only be generated from DHA are more abundant in the circulation (plasma) of individuals with AMD than in age-matched individuals without AMD. To demonstrate the linkage between oxidative modifications of proteins, their recognition by the immune system and the vulnerability of the outer retina to immune attack leading to age-related macular degeneration (AMD) we conducted the following experiment.

Methods:: Normal mice were systemically immunized with CEP-adducted mouse serum albumin (MSA). We used two immunization protocols: one with multiple boosts over a three month period, and the other with a single boost and maintenance of the mice for up to one year. ERGs were used to examine overall retinal function and eye tissues were recovered and analyzed with microscopy.

Results:: In single boost animals, focal drusen deposits in the fundus were present along with thinning of the RPE. In multiple boost mice, dramatic lesions of the RPE involving lysis of individual cells were evident along with the invasion of macrophages and debris removal. The focal nature of these changes were confirmed by generally normal ERGs. None of these changes were observed in immunized rag-/- mice that are missing mature T and B cells, or in mice immunized with non-adducted MSA.

Conclusions:: Mice immunized with CEP-MSA develop lesions in the outer retina that mimic those present in humans with AMD. The high concentration of DHA in the photoreceptor-RPE complex, coupled with the vulnerability of DHA to oxidative damage in this location results in the slow generation of CEP-adducts that accumulate over time in the outer retina. These CEP-adducts represent new epitopes foreign to the immune system. Mice immunized with CEP-MSA become sensitized to the CEP-adduct and respond to the endogenous source of CEP with an immune attack on the the outer retina and the development of AMD-like changes. This new model for AMD in the mouse is an important new resource for preclinical testing of therapeutics designed to prevent or limit the progression of AMD.

Keywords: age-related macular degeneration • drusen • Bruch's membrane 
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