A Hapten Generated from an Oxidation Fragment of Docosahexaenoic Acid Is Sufficient to Initiate Age-Related Macular Degeneration
- 337 Downloads
The protein adduct carboxyethylpyrrole (CEP) is present in age-related macular degeneration (AMD) eye tissue and in the blood of AMD patients at higher levels than found in age-matched non-AMD tissues. Autoantibodies to CEP are also higher in AMD blood samples than in controls. To test the hypothesis that this hapten is causally involved in initiating an inflammatory response in AMD, we immunized C57BL/6J mice with mouse serum albumin (MSA) adducted with CEP. Immunized mice develop antibodies to CEP, fix complement component-3 in Bruch’s membrane, accumulate drusen below the retinal pigment epithelium during aging, show decreased a- and b-wave amplitudes in response to light, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. Inflammatory cells are present in the region of lesions and may be actively involved in the pathology observed. We conclude that early immunization of mice with CEP-adducted MSA sensitizes these animals to the ongoing production of CEP adducts in the outer retina where DHA is abundant and the conditions for oxidative damage are permissive. In response to this early sensitization, the immune system mounts a complement-mediated attack on the cells of the outer retina where CEP adducts are formed. This animal model for AMD is the first that was developed from an inflammatory signal discovered in eye tissue and blood from AMD patients. It provides a novel opportunity for dissecting the early pathology of AMD and the immune response contributing to this disorder. The availability of a mouse with a mechanistically based AMD-like disease that progresses rapidly is highly desirable. Such a model will allow for the efficient preclinical testing of the much-needed therapeutics quickly and inexpensively.
KeywordInflammation Retina Oxidative damage Age-related macular degeneration Fatty acid
Supported by the State of Ohio BRTT Program, Columbus, Ohio; a Research Center Grant from the Foundation Fighting Blindness, Owings Mills, Maryland; a Challenge Grant from Research to Prevent Blindness, New York, NY; and by grants from the National Institutes of Health, Bethesda, Maryland, [EY014240 (JGH), EY015638 (JGH), EY014912 (VLP), and GM21249 (RGS)]. We thank Xiaoping (Annie) Yang, Mary E. Rayborn, Karen G. Shadrach, Vera L. Bonilha, and Yong Li for their help with the microscopy and immunology performed in these studies. We also thank Lisa Kuttner-Kondo, John W. Crabb, Bela Anand-Apte, and Neal S. Peachey for discussions and valuable comments during the course of these studies.
- 21.Doyne RW (1989) Trans Ophthalmol Soc U K 19:71–71Google Scholar
- 22.Gass JDM (1987) Stereoscopic atlas of macular diseases. CV Mosby, St. LouisGoogle Scholar
- 27.Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang G, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R (2005) Proc Natl Acad Sci U S A 102:7227–7232CrossRefPubMedGoogle Scholar
- 37.AREDS RG (2001) Arch Ophthalmol 119:1439–1452Google Scholar