Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction

Divisions of *Cellular Therapy,
^†Pathology,
^‡Visual Science, and
^‖Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom;
^§Molecular Genetics and Rheumatology Section, Imperial College London, London W12 0NN, United Kingdom; and
^¶Moorfields Eye Hospital, City Road, London EC1V 2PD, United Kingdom

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 22, 2007 (received for review June 1, 2007)

Abstract

Age-related macular degeneration is the most common form of legal blindness in westernized societies, and polymorphisms in the gene encoding complement factor H (CFH) are associated with susceptibility to age-related macular degeneration in more than half of affected individuals. To investigate the relationship between complement factor H (CFH) and retinal disease, we performed functional and anatomical analysis in 2-year-old CFH-deficient (cfh ^−/−) mice. cfh ^−/− animals exhibited significantly reduced visual acuity and rod response amplitudes on electroretinography compared with age-matched controls. Retinal imaging by confocal scanning laser ophthalmoscopy revealed an increase in autofluorescent subretinal deposits in the cfh ^−/− mice, whereas the fundus and vasculature appeared normal. Examination of tissue sections showed an accumulation of complement C3 in the neural retina of the cfh ^−/− mice, together with a decrease in electron-dense material, thinning of Bruch's membrane, changes in the cellular distribution of retinal pigment epithelial cell organelles, and disorganization of rod photoreceptor outer segments. Collectively, these data show that, in the absence of any specific exogenous challenge to the innate immune system, CFH is critically required for the long-term functional health of the retina.

Footnotes

**To whom correspondence should be addressed. E-mail: j.greenwood{at}ucl.ac.uk
Author contributions: P.J.C., A.B., F.W.F., G.E.H., P.J.L., T.E.S., S.E.M., and J.G. designed research; P.J.C., C.G., C.J.M., P.L., C.S., A.M., L.L.C., and J.G. performed research; M.C.P. contributed new reagents/analytic tools; P.J.C., C.G., C.J.M., P.L., A.B., F.W.F., G.E.H., P.J.L., T.E.S., S.E.M., and J.G. analyzed data; and M.C.P., S.E.M., and J.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0705079104/DC1.
Abbreviations:

AMD,

age-related macular degeneration;

AP,

alternative pathway;

BM,

Bruch's membrane;

c/d,

cycles per degree;

EDM,

electron-dense material;

ERG,

electroretinography;

MPGN2,

membranoproliferative glomerulonephritis type II;

OS,

outer segment;

RPE,

retinal pigmented epithelium.