Bisretinoid-mediated complement activation on retinal pigment epithelial cells is dependent on complement factor H haplotype
Open accessAbstract
Age-related macular degeneration (AMD) is a common central blinding disease of the elderly. Homozygosity for a sequence variant causing Y402H and I62V substitutions in the gene for complement factor H (CFH) is strongly associated with risk of AMD. CFH, secreted by many cell types, including those of the retinal pigment epithelium (RPE), is a regulatory protein that inhibits complement activation. Recessive Stargardt maculopathy is another central blinding disease caused by mutations in the gene for ABCA4, a transporter in photoreceptor outer segments (OS) that clears retinaldehyde and prevents formation of toxic bisretinoids. Photoreceptors daily shed their distal OS, which are phagocytosed by the RPE cells. Here, we investigated the relationship between the CFH haplotype of human RPE (hRPE) cells, exposure to OS containing bisretinoids, and complement activation. We show that hRPE cells of the AMD-predisposing CFH haplotype (HH402/VV62) are attacked by complement following exposure to bisretinoid-containing Abca4(-/-) OS. This activation was dependent on factor B, indicating involvement of the alternative pathway. In contrast, hRPE cells of the AMD-protective CFH haplotype (YY402/II62) showed no complement activation following exposure to either Abca4(-/-) or wild-type OS. The AMD-protective YY402/II62 hRPE cells were more resistant to the membrane attack complex, whereas HH402/VV62 hRPE cells showed significant membrane attack complex deposition following ingestion of Abca4(-/-) OS. These results suggest that bisretinoid accumulation in hRPE cells stimulates activation and dysregulation of complement. Cells with an intact complement negative regulatory system are protected from complement attack, whereas cells with reduced CFH synthesis because of the Y402H and I62V substitutions are vulnerable to disease.
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Human fetal RPE cultures carrying a complement factor H risk haplotype have increased susceptibility to oxidative stress and complement attack when fed OSs from Abca4−/− mice.
“Human fetal RPE cultures carrying a complement factor H risk haplotype were found to have an increased susceptibility to oxidative stress and complement attack when fed OSs from Abca4−/− mice (Radu et al., 2011, 2014)”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Radu et al., 2014
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Cites
Complement factor H polymorphism in age-related macular degeneration
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J.-Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., et al. (2005) · Science · doi:10.1126/science.1109557 · Cited by 4,492 · see citing works
Prevalence of Age-Related Macular Degeneration in the United States
The Eye Diseases Prevalence Research Group* (2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.4.564 · Cited by 2,742 · see citing works
Complement factor H polymorphism and age-related macular degeneration
Edwards, A. O., Ritter, R., Abel, K. J., Manning, A., Panhuysen, C., & Farrer, L. A. (2005) · Science · doi:10.1126/science.1110189 · Cited by 2,449 · see citing works
Complement factor H variant increases the risk of age-related macular degeneration
Haines, J. L., Hauser, M. A., Schmidt, S., Scott, W. K., Olson, L. M., Gallins, P., Spencer, K. L., Kwan, S. Y., Noureddine, M., Gilbert, J. R., et al. (2005) · Science · doi:10.1126/science.1110359 · Cited by 2,424 · see citing works
Hageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., Hardisty, L. I., Hageman, J. L., Stockman, H. A., Borchardt, J. D., Gehrs, K. M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501536102 · Cited by 1,961 · see citing works
The AMD Genetics Clinical Study Group, Gold, B., Merriam, J. E., Zernant, J., Hancox, L. S., Taiber, A. J., Gehrs, K., Cramer, K., Neel, J., Bergeron, J., et al. (2006) · Nature Genetics · doi:10.1038/ng1750 · Cited by 1,075 · see citing works
Weng, J., Mata, N. L., Azarian, S. M., Tzekov, R. T., Birch, D. G., & Travis, G. H. (1999) · Cell · doi:10.1016/s0092-8674(00)80602-9 · Cited by 881 · cited 1× · see citing works
“Similar to STGD1 patients, mice with a knockout mutation in the Abca4 gene accumulate fluorescent lipofuscin granules and bisretinoids, such as A2E, in the RPE (24, 25).”
BackgroundMutation of the Stargardt Disease Gene ( ABCR ) in Age-Related Macular Degeneration
Allikmets, R. L., Shroyer, N. F., Singh, N., Seddon, J. M., Lewis, R. A., Bernstein, P. S., Peiffer, A. P., Zabriskie, N. A., Li, Y., Hutchinson, A. A., et al. (1997) · Science · doi:10.1126/science.277.5333.1805 · Cited by 879 · see citing works
Complement C3 variant and the risk of age-related macular degeneration
Yates, J. R. W., Sepp, T., Matharu, B. K., Khan, J. C., Thurlby, D. A., Shahid, H., Clayton, D. G., Hayward, C., Morgan, J., Wright, A. F., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa072618 · Cited by 829 · see citing works
Anderson, D. H., Radeke, M. J., Gallo, N. B., Chapin, E. A., Johnson, P. T., Curletti, C. R., Hancox, L. S., Hu, J., Ebright, J. N., Malek, G., et al. (2010) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2009.11.003 · Cited by 727 · see citing works
Self-citationRPE lipofuscin and its role in retinal pathobiology
Sparrow, J. R., & Boulton, M. (2005) · Experimental Eye Research · doi:10.1016/j.exer.2005.01.007 · Cited by 644 · see citing works
The role of mannose-binding lectin in health and disease
Turner, M. W. (2003) · Molecular Immunology · doi:10.1016/s0161-5890(03)00155-x · Cited by 637 · see citing works
Sparrow, J. R., Nakanishi, K., & Parish, C. A. (2000) · PubMed · Cited by 566 · see citing works
Complement factor H binds malondialdehyde epitopes and protects from oxidative stress
Weismann, D., Hartvigsen, K., Lauer, N., Bennett, K. L., Scholl, H. P. N., Issa, P. C., Cano, M., Brandstätter, H., Tsimikas, S., Skerka, C., et al. (2011) · Nature · doi:10.1038/nature10449 · Cited by 533 · cited 1× · see citing works
“Y402H-substituted CFH has been shown recently to bind malondialdehyde with greatly reduced affinity (13).”
BackgroundThe Role of Inflammation in the Pathogenesis of Age-related Macular Degeneration
Donoso, L. A., Kim, D. S., Frost, A. T., Callahan, A., & Hageman, G. S. (2006) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2005.12.001 · Cited by 480 · see citing works
Hughes, A. E., Orr, N., Esfandiary, H., Diaz-Torres, M., Goodship, T., & Chakravarthy, U. (2006) · Nature Genetics · doi:10.1038/ng1890 · Cited by 467 · see citing works
Mata, N. L., Weng, J., & Travis, G. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130110497 · Cited by 456 · see citing works
Variation in complement factor 3 is associated with risk of age-related macular degeneration
Maller, J. B., Fagerness, J. A., Reynolds, R. C., Neale, B. M., Daly, M. J., & Seddon, J. M. (2007) · Nature Genetics · doi:10.1038/ng2131 · Cited by 437 · see citing works
Zhou, J., Jang, Y. P., Kim, S. R., & Sparrow, J. R. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604255103 · Cited by 358 · see citing works
Forecasting Age-Related Macular Degeneration Through the Year 2050
Rein, D. B. (2009) · Archives of Ophthalmology · doi:10.1001/archophthalmol.2009.58 · Cited by 345 · see citing works
Mannose‐binding lectin in innate immunity: past, present and future
Dommett, R. M., Klein, N. J., & TURNER, M. W. (2006) · Tissue Antigens · doi:10.1111/j.1399-0039.2006.00649.x · Cited by 342 · see citing works
A rare penetrant mutation in CFH confers high risk of age-related macular degeneration
Raychaudhuri, S., Iartchouk, O., Chin, K., Tan, P. L., Tai, A. K., Ripke, S., Gowrisankar, S., Vemuri, S., Montgomery, K., Yu, Y., et al. (2011) · Nature Genetics · doi:10.1038/ng.976 · Cited by 323 · see citing works
Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin.
Schütt, F., Davies, S., Kopitz, J., Holz, F. G., & Boulton, M. (2000) · PubMed · Cited by 292 · see citing works
Finnemann, S. C., Leung, L. W., & Rodriguez-Boulan, E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052025899 · Cited by 283 · see citing works
ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer
Quazi, F., Lenevich, S., & Molday, R. S. (2012) · Nature Communications · doi:10.1038/ncomms1927 · Cited by 276 · see citing works
PARTICIPATION OF THE RETINAL PIGMENT EPITHELIUM IN THE ROD OUTER SEGMENT RENEWAL PROCESS
Young, R. W., & Bok, D. (1969) · Journal of Cell Biology · doi:10.1083/jcb.42.2.392 · Cited by 271 · see citing works
Self-citationLiu, J., Itagaki, Y., Ben-Shabat, S., Nakanishi, K., & Sparrow, J. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m910191199 · Cited by 255 · see citing works
Johnson, P. T., Betts, K. E., Radeke, M. J., Hageman, G. S., Anderson, D. H., & Johnson, L. V. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606234103 · Cited by 223 · see citing works
Fritsche, L. G., Lauer, N., Hartmann, A., Stippa, S., Keilhauer, C. N., Oppermann, M., Pandey, M. K., Köhl, J., Zipfel, P. F., Weber, B. H. F., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq399 · Cited by 203 · see citing works
Johnson, L. V., Forest, D. L., Banna, C. D., Radeke, C. M., Maloney, M. A., Hu, J. G., Spencer, C. N., Walker, A. M., Tsie, M. S., Bok, D., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109703108 · Cited by 196 · see citing works
Self-citationRadu, R. A., Yuan, Q., Hu, J., Peng, J. H., Lloyd, M., Nusinowitz, S., Bok, D., & Travis, G. H. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.07-1470 · Cited by 188 · see citing works
Self-citationMannose-Binding Lectin (MBL) in Health and Disease
TURNER, M. W. (1998) · Immunobiology · doi:10.1016/s0171-2985(98)80037-5 · Cited by 180 · see citing works
Hu, J. G., & Bok, D. (2001) · PubMed · Cited by 165 · see citing works
Self-citationDNA Is a Target of the Photodynamic Effects Elicited in A2E-Laden RPE by Blue-Light Illumination
Sparrow, J. R., Zhou, J., & Cai, B. (2003) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.02-0746 · Cited by 161 · see citing works
Radu, R. A., Hu, J., Yuan, Q., Welch, D. L., Makshanoff, J., Lloyd, M., McMullen, S., Travis, G. H., & Bok, D. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.191866 · Cited by 157 · see citing works
Self-citationSohn, J.-H., Kaplan, H. J., Suk, H.-J., Bora, P. S., & Bora, N. S. (2000) · PubMed · Cited by 142 · see citing works
The role of ficolins in the lectin pathway of innate immunity
Endo, Y., Matsushita, M., & Fujita, T. (2011) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2011.02.003 · Cited by 141 · see citing works
Complement Activation by Bisretinoid Constituents of RPE Lipofuscin
Zhou, J., Kim, S. R., Westlund, B. S., & Sparrow, J. R. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-2868 · Cited by 138 · see citing works
Toward a structure-based comprehension of the lectin pathway of complement
Kjær, T. R., Thiel, S., & Andersen, G. R. (2013) · Molecular Immunology · doi:10.1016/j.molimm.2013.05.220 · Cited by 113 · see citing works
Wu, Y., Fishkin, N. E., Pande, A., Pande, J., & Sparrow, J. R. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.021345 · Cited by 103 · see citing works
De, S., & Sakmar, T. P. (2002) · The Journal of General Physiology · doi:10.1085/jgp.20028566 · Cited by 91 · see citing works
Fritsche, L. G., Fleckenstein, M., Fiebig, B. S., Schmitz-Valckenberg, S., Bindewald-Wittich, A., Keilhauer, C. N., Renner, A. B., Mackensen, F., Mößner, A., Pauleikhoff, D., et al. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-8785 · Cited by 87 · see citing works
Toward a structure-based comprehension of the lectin pathway of complement
Kjær, T. R., Thiel, S., & Andersen, G. R. (2013) · Molecular Immunology · doi:10.1016/j.molimm.2013.05.007 · Cited by 86 · see citing works
Lueck, K., Wasmuth, S., Williams, J., Hughes, T. R., Morgan, B. P., Lommatzsch, A., Greenwood, J., Moss, S. E., & Pauleikhoff, D. (2011) · Eye · doi:10.1038/eye.2011.109 · Cited by 80 · see citing works
Expression and Modulation of RPE Cell Membrane Complement Regulatory Proteins
Yang, P., Tyrrell, J., Han, I. C., & Jaffe, G. J. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-3202 · Cited by 77 · see citing works
Complement in age-related macular degeneration: a focus on function
Bradley, D., Zipfel, P. F., & Hughes, A. E. (2011) · Eye · doi:10.1038/eye.2011.37 · Cited by 75 · see citing works
Joseph, K., Kulik, L. N., Coughlin, B. A., Kunchithapautham, K., Bandyopadhyay, M., Thiel, S., Thielens, N. M., Holers, V. M., & Rohrer, B. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.421891 · Cited by 66 · see citing works
Hu, J., & Bok, D. (2010) · Methods in Molecular Biology · doi:10.1007/978-1-60327-325-1_2 · Cited by 24 · see citing works
Self-citationHu, J. G., & Bok, D. (2013) · Experimental Eye Research · doi:10.1016/j.exer.2013.09.009 · Cited by 23 · see citing works
Self-citationAll- trans -Retinal Sensitizes Human RPE Cells to Alternative Complement Pathway–Induced Cell Death
Berchuck, J. E., Yang, P., Toimil, B. A., Ma, Z., Baciu, P. C., & Jaffe, G. J. (2013) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-11020 · Cited by 16 · see citing works
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The cell biology of the retinal pigment epithelium
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- Authors
- Radu, R. A., Hu, J., Jiang, Z., & Bok, D.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Radu, Roxana A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 289
- Issue
- 13
- Pages
- 9113-9120
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3979386
- OpenAlex
- W2107997598
- Cited by
- 44
- References
- 50
- Citations by year
- 2025: 3 · 2024: 3 · 2022: 3 · 2021: 2 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 6
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Macula Vision Research Foundation
- University of California, Santa Barbara
- National Eye Institute (EY-000331, P30EY000331)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- complement activation, complement factor H, bisretinoids, retinal pigment epithelium, age-related macular degeneration, ABCA4, photoreceptor outer segments, alternative complement pathway, factor B, membrane attack complex, complement regulation
- MeSH terms
- Animals, Cell Membrane, Complement C3b, Haplotypes, Humans, Macular Degeneration, Retinoids, Complement Factor H, ATP-Binding Cassette Transporters, Genetic Predisposition to Disease, Mice, Retinal Pigment Epithelium, Retinal Photoreceptor Cell Outer Segment
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