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Complement Activation by Bisretinoid Constituents of RPE Lipofuscin

¹From the Departments of Ophthalmology and ²Pathology and Cell Biology, Columbia University, New York, New York.

PURPOSE. Studies implicate activation of complement among the processes involved in the pathogenesis of age-related macular degeneration (AMD). Questions pertain to the trigger(s) responsible for the complement-associated events. The authors previously reported that photooxidation products of A2E can activate complement. Here they have further explored these events.

METHODS. In vitro assays using human serum as a source of complement were used, and the C3 split product iC3b was measured by enzyme immunoassay. Serum was placed in contact with ARPE-19 cells and polarized human fetal retinal pigment epithelium that had accumulated A2E and were irradiated (430 nm). Serum was also incubated in wells precoated with bisretinoid pigments of lipofuscin and their oxidized forms. iC3b generation in normal human serum (NHS) was compared with that in factor B-depleted and C1q-depleted human serum.

RESULTS. iC3b levels were elevated in NHS placed in contact with A2E-laden retinal pigment epithelium that were irradiated to generate A2E photooxidation products. iC3b was also increased in serum incubated in wells precoated with peroxy-A2E, the lipofuscin pigment all-trans-retinal dimer, and oxidized forms of all-trans-retinal dimer. Substitution of NHS with factor B-depleted sera abrogated these increases in iC3b. Complement activation was also suppressed by the addition of C-reactive protein and by a C3 cleavage inhibitor.

CONCLUSIONS. The authors suggest that bisretinoid pigments of retinal pigment epithelial lipofuscin, subsequent to photoactivation and cleavage, serve to activate complement. Complement activation by this mechanism is dependent on the alternative pathway and can be modulated by an inhibitor of C3 cleavage. These events in the setting of complement dysregulation could contribute to the chronic inflammation that underlies AMD pathogenesis.

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				J. R. Sparrow, Y. Wu, C. Y. Kim, and J. Zhou Phospholipid meets all-trans-retinal: the making of RPE bisretinoids J. Lipid Res., February 1, 2010; 51(2): 247 - 261. [Abstract] [Full Text] [PDF]