Evidence of complement dysregulation in outer retina of Stargardt disease donor eyes
Jane Hu,
Gayle J. Pauer,
Stephanie A. Hagstrom,
Dean Bok,
Meghan J. DeBenedictis,
Vera L. Bonilha,
Joe G. Hollyfield,
Roxana A. Radu
Affiliations
Jane Hu
UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, 90095, USA
Gayle J. Pauer
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
Stephanie A. Hagstrom
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA
Dean Bok
UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, 90095, USA
Meghan J. DeBenedictis
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
Vera L. Bonilha
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA
Joe G. Hollyfield
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA; Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA
Roxana A. Radu
UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, 90095, USA; Corresponding author. UCLA Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California at Los Angeles, 100 Stein Plaza, Los Angeles, CA, 90095, USA.
Stargardt macular degeneration (STGD) is a central blinding disease caused by loss of or dysfunctional ABCA4 transporter in both photoreceptors and retinal pigment epithelial (RPE) cells. Toxic bisretinoid-lipofuscin buildup in the RPE cells is a pathological hallmark of STGD patients and its mouse model, the Abca4−/−. These vitamin A-derived fluorophores have been shown to induce oxidative stress, stimulate complement activity, and cause chronic inflammation of the RPE. In vivo modulation of complement regulatory pathway in the STGD mouse model has partially rescued the STGD phenotype suggesting that complement attack on the RPE is an important etiologic factor in disease pathogenesis. While bisretinoid-dependent complement activation was further evidenced in cultured RPE cells, this pathway has never been investigated directly in the context of RPE from STGD donor eyes. In the current study, we evaluate the complement reactivity in postmortem donor eyes of clinically diagnosed STGD patients. All three STGD donor eyes RPE displayed strong immunoreactivity for an antibody specific to 4-Hydroxynonenal, a lipid peroxidation byproduct. Also, unlike the control eyes, all three STGD donor eyes showed significantly increased membrane attack complex deposition on the RPE cells. In STGD eyes, increased MAC accumulation was mirrored by elevated C3 fragments internalized by the RPE and inversely correlated with the levels of complement factor H, a major complement regulatory protein. Here, we report the first direct evidence of RPE complement dysregulation as a causative factor in developing Stargardt phenotype.
