Structure and composition of drusen associated with glomerulonephritis: Implications for the role of complement activation in drusen biogenesis
Abstract
Purpose The ocular fundi of many patients with membranoproliferative glomerulonephritis type II (MPGN-II) are characterised by the presence of deposits within Bruch's membrane that resemble drusen, hallmark lesions associated with age-related macular degeneration (AMD). Glomerulonephritis (GN)-associated drusen appear at a younger age, however, than do drusen in individuals with AMD. In light of recent evidence that immune-mediated events participate in drusen biogenesis and AMD, we examined the structure and composition of drusen in eyes obtained from human donors with two distinct glomerulopathies, both of which involve complement deposition within glomeruli. These features were compared with those of drusen from patients with clinically documented AMD.Methods Eyes obtained from two human human donors diagnosed with membranous and post-streptococcal GN, respectively, were analysed histochemically, immunohistochemically and ultrastructurally.Results Subretinal pigment epithelial (RPE) deposits in both types of GN are numerous and indistinguishable, both structurally and compositionally, from drusen in donors with AMD. GN-associated drusen exhibit sudanophilia, bind filipin, and react with antibodies directed against vitronectin, complement C5 and C5b-9 complexes, TIMP-3 and amyloid P component. Drusen from the membranous GN donor, but not the post-streptococcal GN donor, reacted with peanut agglutinin and antibodies directed against MHC class II antigens and IgG. The ultrastructural characteristics of these deposits were also identical with those of AMD-associated drusen.Conclusions The composition and structure of ocular drusen associated with membranous and post-streptococcal/segmental GN are generally similar to those of drusen in individuals with AMD. In view of the recent data supporting the involvement of complement activation in drusen biogenesis and the pathobiology of AMD, further studies of the biological relationships between AMD and diseases associated with complement activation are warranted.
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Biochemical analysis of drusen has identified complement components and inflammatory modulators.
“Biochemical analysis of drusen have indeed resulted in identification of complement components and inflammatory modulators [2–8].”
From CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD (2005) · cites this paper as [5]
Cites
Bird, A. C., Bressler, N. M., Bressler, S. B., Chisholm, I. H., Coscas, G., Davis, M. D., de Jong, P. T. V. M., Klaver, C. C. W., Klein, B. E. K., Klein, R., et al. (1995) · Survey of Ophthalmology · doi:10.1016/s0039-6257(05)80092-x · Cited by 1,926 · see citing works
Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment
(1990) · Archives of Ophthalmology · doi:10.1001/archopht.1990.01070060042026 · Cited by 1,014 · see citing works
Mullins, R. F., Russell, S. R., Anderson, D. H., & Hageman, G. S. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.7.835 · Cited by 937 · see citing works
Self-citationStone, E. M., Lotery, A. J., Munier, F. L., Héon, E., Piguet, B., Guymer, R. H., Vandenburgh, K., Cousin, P., Nishimura, D. Y., Swiderski, R. E., et al. (1999) · Nature Genetics · doi:10.1038/9722 · Cited by 488 · see citing works
Self-citationAccumulation of cholesterol with age in human Bruch's membrane.
Curcio, C. A., Millican, C. L., Bailey, T. A., & Kruth, H. S. (2001) · PubMed · Cited by 442 · see citing works
A potential role for immune complex pathogenesis in drusen formation
JOHNSON, L. V., OZAKI, S., STAPLES, M. K., ERICKSON, P. A., & ANDERSON, D. H. (2000) · Experimental Eye Research · doi:10.1006/exer.1999.0798 · Cited by 353 · see citing works
Bressler, S. B. (1990) · Archives of Ophthalmology · doi:10.1001/archopht.1990.01070120090035 · Cited by 325 · see citing works
Kilgore, K. S., Schmid, E., Shanley, T. P., Flory, C. M., Maheswari, V., Tramontini, N. L., Cohen, H. C., Ward, P. A., Friedl, H. P., & Warren, J. S. (1997) · Europe PMC (PubMed Central) · Cited by 230 · see citing works
Bilateral Macular Drusen in Age-related Macular Degeneration
Holz, F. G., Wolfensberger, T. J., Piguet, B., Gross‐Jendroska, M., Wells, J. A., Minassian, D. C., Chisholm, I. H., & Bird, A. C. (1994) · Ophthalmology · doi:10.1016/s0161-6420(94)31139-0 · Cited by 221 · see citing works
Hageman, G. S., Mullins, R. F., Russell, S. R., Johnson, L. V., & Anderson, D. H. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.3.477 · Cited by 206 · see citing works
Self-citationRussell, S. R., Mullins, R. F., Schneider, B. L., & Hageman, G. S. (2000) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(99)00345-1 · Cited by 170 · see citing works
Self-citationMolecular composition of drusen as related to substructural phenotype.
Hageman, G. S., & Mullins, R. F. (1999) · PubMed · Cited by 167 · see citing works
Self-citationCorrelation between Biochemical Composition and Fluorescein Binding of Deposits in Bruch's Membrane
Pauleikhoff, D., Zuels, S., Sheraidah, G. S., Marshall, J., WESSING, A., & Bird, A. C. (1992) · Ophthalmology · doi:10.1016/s0161-6420(92)31768-3 · Cited by 161 · see citing works
Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye.
Fariss, R. N., Apte, S., Olsen, B. R., Iwata, K., & Milam, A. H. (1997) · Europe PMC (PubMed Central) · Cited by 151 · see citing works
Duvall-Young, J., MacDonald, M. K., & McKechnie, N. M. (1989) · British Journal of Ophthalmology · doi:10.1136/bjo.73.4.297 · Cited by 124 · see citing works
Couser, W. G. (1999) · The Lancet · doi:10.1016/s0140-6736(98)06195-9 · Cited by 120 · see citing works
Farkas, T. G., Sylvester, V., Archer, D., & Altona, M. (1971) · American Journal of Ophthalmology · doi:10.1016/0002-9394(71)90964-0 · Cited by 112 · see citing works
Hellmark, T., Burkhardt, H., & Wieslander, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.36.25862 · Cited by 104 · see citing works
Bressler, N. M., Bressler, S. B., Seddon, J. M., et al. (1988) · Retina · doi:10.1097/00006982-198808020-00005 · Cited by 85 · see citing works
DRUSEN PATTERNS PREDISPOSING TO GEOGRAPHIC ATROPHY OF THE RETINAL PIGMENT EPITHELIUM
Sarks, S. H. (1982) · Australian Journal of Opthalmology · doi:10.1111/j.1442-9071.1982.tb00366.x · Cited by 83 · see citing works
Duvall-Young, J., Short, C. D., Raines, M. F., Gokal, R., & Lawler, W. (1989) · British Journal of Ophthalmology · doi:10.1136/bjo.73.11.900 · Cited by 74 · see citing works
Characterization of Drusen-associated Glycoconjugates
Mullins, R. F., Johnson, L. V., Anderson, D. H., & Hageman, G. S. (1997) · Ophthalmology · doi:10.1016/s0161-6420(97)30322-4 · Cited by 72 · see citing works
Self-citationGorin, M. B., Jackson, K. E., Ferrell, R. E., et al. (1995) · Ophthalmology · doi:10.1016/s0161-6420(95)31029-9 · Cited by 68 · see citing works
Human Ocular Drusen Possess Novel Core Domains with a Distinct Carbohydrate Composition
Mullins, R. F., & Hageman, G. S. (1999) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215549904701205 · Cited by 65 · see citing works
Self-citationDiscrete expression and distribution pattern of TIMP-3 in the human retina and choroid
Vranka, J. A., Johnson, E. C., Zhu, X., Shepardson, A., Alexander, J. P., Bradley, J. M. B., Wirtz, M. K., Weleber, R. G., Klein, M. L., & Acott, T. S. (1997) · Current Eye Research · doi:10.1076/ceyr.16.2.102.5086 · Cited by 62 · see citing works
Piguet, B., Héon, E., Munier, F. L., Grounauer, P. A., Niemeyer, G., Butler, N. S., Schorderet, D. F., Sheffield, V. C., & Stone, E. M. (1996) · Ophthalmic Genetics · doi:10.3109/13816819609057891 · Cited by 61 · see citing works
Leys, A., Vanrenterghem, Y., Van Damme, B., Snyers, B., Pirson, Y., & Leys, M. (1991) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/bf00166300 · Cited by 57 · see citing works
Vitronectin gene expression in the adult human retina.
Anderson, D. H., Hageman, G. S., Mullins, R. F., Neitz, M., Jay Neitz, A., Ozaki, S., Preissner, K. T., & Johnson, L. V. (1999) · PubMed · Cited by 49 · see citing works
Self-citationWOLTER, J. R., & Falls, H. F. (1962) · Archives of Ophthalmology · doi:10.1001/archopht.1962.00960030223013 · Cited by 42 · see citing works
LEYS, A. M., Michielsen, B., Leys, M. J. J., Vanrenterghem, Y. F. C., Missotten, L., & Damme, B. V. (1990) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/bf00918479 · Cited by 36 · see citing works
O'Brien, C., Duvall-Young, J., Brown, M. M., et al. (1993) · British Journal of Ophthalmology · doi:10.1136/bjo.77.12.778 · Cited by 27 · see citing works
Jahn, B., von Kempis, J., Krämer, K. L., et al. (1993) · PubMed · Cited by 18 · see citing works
Pauleikhoff, D. (1992) · PubMed · Cited by 17 · see citing works
Fundus changes in mesangiocapillary glomerulonephritis type II: vitreous fluorophotometry
Raines, M. F., Duvall-Young, J., & Short, C. D. (1989) · British Journal of Ophthalmology · doi:10.1136/bjo.73.11.907 · Cited by 11 · see citing works
Subretinale Neovaskularisationsmembranen bei Membranoproliferativer Glomerulonephritis Typ II
Framme, C., Herboth, T., Roider, J. B., & Laqua, H. (1998) · Klinische Monatsblätter für Augenheilkunde · doi:10.1055/s-2008-1034983 · Cited by 10 · see citing works
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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
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
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
Self-citationHageman, G. (2001) · Progress in Retinal and Eye Research · doi:10.1016/s1350-9462(01)00010-6 · Cited by 1,265 · see citing works
Self-citationA role for local inflammation in the formation of drusen in the aging eye
Anderson, D. H., Mullins, R. F., Hageman, G. S., & Johnson, L. V. (2002) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(02)01624-0 · Cited by 1,087 · see citing works
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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
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Ambati, J., Anand, A., Fernandez, S., Sakurai, E., Lynn, B. C., Kuziel, W. A., Rollins, B. J., & Ambati, B. K. (2003) · Nature Medicine · doi:10.1038/nm950 · Cited by 631 · see citing works
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Ding, X., Patel, M., & Chan, C.-C. (2009) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2008.10.001 · Cited by 582 · see citing works
“…components and complement regulatory proteins in drusen and nearby RPE of AMD patients (Crabb et al., 2002; Hageman et al., 1999; Johnson et al., 2001; Johnson et al., 2000; Mullins et al., 2001; Nozaki et al., 2006), suggesting a role for complement in AMD pathogenesis (Bora et al., 2008).”
BackgroundHughes, 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
Yehoshua, Z., Alexandre de Amorim Garcia Filho, C., Nunes, R. P., Gregori, G., Penha, F. M., Moshfeghi, A. A., Zhang, K., Sadda, S., Feuer, W., & Rosenfeld, P. J. (2014) · Ophthalmology · doi:10.1016/j.ophtha.2013.09.044 · Cited by 299 · see citing works
CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD
Magnusson, K. P., Duan, S., Sigurdsson, H., Petursson, H., Yang, Z., Zhao, Y., Bernstein, P. S., Ge, J., Jonasson, F., Stefansson, E., et al. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0030005 · Cited by 226 · see citing works
Sepp, T., Khan, J. C., Thurlby, D. A., Shahid, H., Clayton, D. G., Moore, A. T., Bird, A. C., & Yates, J. R. W. (2006) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.05-1143 · Cited by 186 · see citing works
Cameron, D. J., Yang, Z., Gibbs, D., Chen, H., Kaminoh, Y., Jorgensen, A., Zeng, J., Luo, L., Brinton, E., Brinton, G., et al. (2007) · Cell Cycle · doi:10.4161/cc.6.9.4157 · Cited by 114 · see citing works
Toll-like receptor polymorphisms and age-related macular degeneration
Edwards, A. O., Chen, D., Fridley, B. L., James, K. M., Wu, Y., Abecasis, G., Swaroop, A., Othman, M., Branham, K., Iyengar, S. K., et al. (2008) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.07-1378 · Cited by 84 · see citing works
A local complement response by RPE causes early-stage macular degeneration
Fernandez-Godino, R., Garland, D. L., & Pierce, E. A. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv287 · Cited by 73 · see citing works
Vogt, S. D., Barnum, S. R., Curcio, C. A., & Read, R. W. (2006) · Experimental Eye Research · doi:10.1016/j.exer.2006.04.002 · Cited by 71 · see citing works
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Murinello, S., Mullins, R. F., Lotery, A. J., Perry, V. H., & Teeling, J. L. (2014) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.13-11821 · Cited by 51 · see citing works
Self-citationMontes, T., Goicoechea de Jorge, E., Ramos, R., Gomà, M., Pujol, O., Sánchez-Corral, P., & Rodríguez de Córdoba, S. (2008) · Molecular Immunology · doi:10.1016/j.molimm.2008.01.027 · Cited by 47 · see citing works
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- Authors
- Mullins, R. F., Aptsiauri, N., & Hageman, G. S.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Hageman, Gregory S
- Venue
- Eye
- Published
- 2001-05
- Volume
- 15
- Issue
- 3
- Pages
- 390-395
- ISSN
- 0078-5334 (ISSN-L)
- 0950-222X
- 1476-5454
- OpenAlex
- W1966318341
- Cited by
- 231
- References
- 36
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 3 · 2023: 5 · 2022: 10 · 2021: 7 · 2020: 8 · 2019: 3 · 2018: 11 · 2017: 6 · 2016: 16 · 2015: 9 · 2014: 11 · 2013: 12 · 2012: 11
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Eye (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG 00214)
- National Eye Institute (EY11515, R01EY011515)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- drusen, membranoproliferative glomerulonephritis type II, membranous nephropathy, post-streptococcal glomerulonephritis, age-related macular degeneration, complement activation, complement C5, membrane attack complex, vitronectin, TIMP-3, serum amyloid P component, Bruch's membrane
- MeSH terms
- Complement Activation, Glomerulonephritis, Humans, Immunoenzyme Techniques, Macular Degeneration, Microscopy, Electron, Middle Aged, Pigment Epithelium of Eye, Streptococcal Infections, Glomerulonephritis, Membranous, Retinal Drusen
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