A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration

Joe G. Hollyfield, Victor L Perez Quinones, Robert G. Salomon

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)290-298
Number of pages9
JournalMolecular Neurobiology
Volume41
Issue number2-3
DOIs
StatePublished - Jun 1 2010

Fingerprint

Docosahexaenoic Acids
Haptens
Macular Degeneration
Retinal Pigment Epithelium
Serum Albumin
Retina
Geographic Atrophy
Pathology
Complement C3
Inbred C57BL Mouse
Autoantibodies
Immune System
Immunization
Animal Models
Light

Keywords

  • Age-related macular degeneration
  • Fatty acid
  • Inflammation
  • Oxidative damage
  • Retina

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration. / Hollyfield, Joe G.; Perez Quinones, Victor L; Salomon, Robert G.

In: Molecular Neurobiology, Vol. 41, No. 2-3, 01.06.2010, p. 290-298.

Research output: Contribution to journalArticle

Hollyfield, Joe G. ; Perez Quinones, Victor L ; Salomon, Robert G. / A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration. In: Molecular Neurobiology. 2010 ; Vol. 41, No. 2-3. pp. 290-298.
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