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C-reactive protein and complement factor H in aged human eyes and eyes with age-related macular degeneration
Open accessAbstract
BACKGROUND: There is increasing evidence that inflammation and immune-mediated processes (complement activation) play an important role in age-related macular degeneration (AMD) pathogenesis. A genetic variation in the gene encoding complement factor H (CFH) and plasma levels of C-reactive protein (CRP), a systemic marker of subclinical inflammation, have consistently been shown to be associated with an increased risk for AMD. In the present study, we examined the immunolocalisation of CRP and CFH in aged control human donor eyes (n=10; mean age 79 years) and eyes with AMD (n=18; mean age 83 years). METHODS: Alkaline phosphatase immunohistochemistry was performed using polyclonal antibodies against CRP and CFH on cryopreserved tissue sections from disc/macular blocks. Three independent masked observers scored the reaction product (0-8). RESULTS: In aged control eyes, the retinal pigment epithelium/Bruch's membrane/choriocapillaris (RPE/BrM/CC) complex including intercapillary septa (ICS) had the most prominent immunostaining for CRP and CFH. CRP was significantly higher than controls in BrM/CC/ICS and choroidal stroma in early and wet AMD eyes (p<0.05). In contrast, CFH was significantly lower in BrM/CC/ICS complex of AMD choroids than in controls (p<0.05). Interestingly, CRP and CFH were significantly reduced in BrM/CC/ICS complex in atrophic area of macula in geographical atrophy (p<0.05). Drusen and basal laminar deposits were intensely positive for CRP and CFH. CONCLUSION: These immunohistochemical findings show that changes in distribution and relative levels of CRP and CFH were evident in early and late AMD eyes. This suggests that high levels of CRP and insufficient CFH at the retina/choroid interface may lead to uncontrolled complement activation with associated cell and tissue damage. This study supports the hypothesis that inflammation and immune-mediated mechanisms are involved in the pathogenesis of AMD.
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“Reduced expression of FH and CD46 by RPE cells is observed in AMD, and this coincides with increased deposition of the MAC and cell lysis [132,133].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [132]
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Cites
Pearson, T. A., Mensah, G. A., Alexander, R. W., Anderson, J. L., Cannon, R. O., Criqui, M., Fadl, Y. Y., Fortmann, S. P., Hong, Y., Myers, G. L., et al. (2003) · Circulation · doi:10.1161/01.cir.0000052939.59093.45 · Cited by 6,401
C-reactive protein: a critical update
Pepys, M. B., & Hirschfield, G. M. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18921 · Cited by 4,694 · cited 1×
“C-reactive protein (CRP) is an acute-phase reactant that is synthesised predominantly in the liver and adipocytes,”
BackgroundComplement 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
PearsonT, A., MensahG, A., & AlexanderR, W. (2003) · Journal of Cardiopulmonary Rehabilitation · doi:10.1097/00008483-200305000-00016 · Cited by 2,937
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
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
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
Drusen proteome analysis: an approach to the etiology of age-related macular degeneration
Crabb, J. W., Miyagi, M., Gu, X., Shadrach, K., West, K. A., Sakaguchi, H., Kamei, M., Hasan, A., Yan, L., Rayborn, M. E., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.222551899 · Cited by 1,208
A 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 · cited 1×
“and other molecules that mediate local inflammation.”
Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies
Ambati, J., Ambati, B. K., Yoo, S. H., Ianchulev, S., & Adamis, A. P. (2003) · Survey of Ophthalmology · doi:10.1016/s0039-6257(03)00030-4 · Cited by 959 · cited 1×
“INTRODUCTION Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly population worldwide.(1) Recent studies provide increasing evidence that inflammation and immune-mediated processes play an important role in AMD pathogenesis.”
BackgroundMullins, 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
Venugopal, S. K., Devaraj, S., Yuhanna, I. S., Shaul, P. W., & Jialal, I. (2002) · Circulation · doi:10.1161/01.cir.0000033116.22237.f9 · Cited by 849 · cited 1×
“In addition, CRP can reduce endothelial nitric oxide synthase (eNOS) expression,”
BackgroundAnderson, 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 · cited 11×
“Acknowledgements The authors are grateful to the eye donors and their relatives for their generosity and also to Janet Sunness and Carol Applegate at the Greater Baltimore Medical Center (Baltimore, Maryland, USA) for helping us acquire eyes from subjects with AMD.”
BackgroundInfluentialJohnson, L. V., Leitner, W. P., Staples, M. K., & Anderson, D. H. (2001) · Experimental Eye Research · doi:10.1006/exer.2001.1094 · Cited by 621 · cited 1×
“Recent studies provide increasing evidence that inflammation and immune-mediated processes play an important role in AMD pathogenesis. Immunohistochemical studies demonstrate that ocular drusen, in the sub-retinal pigment epithelial (RPE) space, and the capillary pillars of the choroid contain complement components in…”
BackgroundThe human complement factor H: functional roles, genetic variations and disease associations
de Córdoba, S. R., Esparza-Gordillo, J., GOICOECHEADEJORGE, E., López‐Trascasa, M., & Sánchez‐Corral, P. (2004) · Molecular Immunology · doi:10.1016/j.molimm.2004.02.005 · Cited by 574 · cited 1×
“Complement factor H (CFH) is a major inhibitor of the alternate complement pathway and indirectly inhibits the lectin pathway. CFH mainly functions to control the alternate complement activation in plasma, host cells and tissue, and sites of tissue inflammation. It binds to cells and circulates freely. CFH performs th…”
BackgroundRelationship between RPE and Choriocapillaris in Age-Related Macular Degeneration
McLeod, D. S., Grebe, R. R., Bhutto, I. A., Merges, C. A., Baba, T., & Lutty, G. A. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-3639 · Cited by 568 · cited 13×
“Acknowledgements The authors are grateful to the eye donors and their relatives for their generosity and also to Janet Sunness and Carol Applegate at the Greater Baltimore Medical Center (Baltimore, Maryland, USA) for helping us acquire eyes from subjects with AMD.”
BackgroundInfluentialSelf-citationKaplan, M. H., & Volanakis, J. E. (1974) · PubMed · Cited by 563
Seddon, J. M. (2005) · Archives of Ophthalmology · doi:10.1001/archopht.123.6.774 · Cited by 354
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 · cited 1×
“Recent studies provide increasing evidence that inflammation and immune-mediated processes play an important role in AMD pathogenesis. Immunohistochemical studies demonstrate that ocular drusen, in the sub-retinal pigment epithelial (RPE) space, and the capillary pillars of the choroid contain complement components in…”
BackgroundVolanakis, J. E., & Kaplan, M. H. (1974) · PubMed · Cited by 267
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 · cited 1×
“Furthermore, recent compelling evidence indicates that the AMD-associated CFH variant CFH-Y402H in the SCR7 domain of CFH confers reduced binding of CFH to CRP, resulting in high levels of unbound CRP in the choroid, and could thus be permissive for chronic inflammation.”
BackgroundHageman, 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 · cited 1×
“CRP is a known constituent of drusen,(6) 7 and the accumulation of drusen and sub-RPE deposits in early AMD are regarded as an indication of chronic local inflammation at the RPEechoroid interface.(5) 7 Thus, the elevated levels of CRP in eyes with early AMDmay be interpreted as evidence for local inflammation and cel…”
BackgroundYeh, E. T. H. (2004) · Circulation · doi:10.1161/01.cir.0000129507.12719.80 · Cited by 192 · cited 1×
“CRP is a multifunctional, non-specific marker of systemic inflammation. It has pro-inflammatory and pro-thrombotic roles in the pathogenesis of atherosclerosis.”
BackgroundChen, M., Forrester, J. V., & Xu, H. (2007) · Experimental Eye Research · doi:10.1016/j.exer.2006.11.015 · Cited by 184 · cited 2×
“CFH has been detected immunohistochemically in the choroid, and at low levels in the RPE cell and interphotoreceptor matrix, but appeared to be concentrated in dense patches in BrM.(31) Reverse transcriptionpolymerase chain reaction (RT-PCR) studies have shown that the RPE can synthesis CFH locally.”
BackgroundHeterogeneity in localization of isoforms of TGF-beta in human retina, vitreous, and choroid.
Lutty, G. A., Merges, C., Threlkeld, A. B., Crone, S., & McLeod, D. S. (1993) · PubMed · Cited by 183
Self-citationDevaraj, S., Clos, T. W. D., & Jialal, I. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000168573.10844.ae · Cited by 178 · cited 1×
“Thus, the elevated levels of CRP in eyes with early AMD may be interpreted as evidence for local inflammation and cellular injury in the RPE–choroid. Elevated CRP in CC has many implications. When CRP binds the Fc gamma receptors, nuclear factor κB (NF-κB) activation occurs,”
BackgroundBhutto, I. A. (2004) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.03-0862 · Cited by 105 · cited 1×
“Sections were incubated at 4°C overnight with rabbit monoclonal antibody directed against CRP diluted 1:80 000 (1568-1; Epitomics, Inc., Burlingame, California, USA), 1:10 000 goat anti-human CFH antibody (AF4779; RD Signet Laboratory, Dedham, Massachusetts, USA) antibody in adjacent sections to label blood vessels. A…”
MethodSelf-citationDevaraj, S., Davis, B., Simon, S. I., & Jialal, I. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00150.2006 · Cited by 99
Low nitric oxide synthases (NOSs) in eyes with age-related macular degeneration (AMD)
Bhutto, I. A., Baba, T., Merges, C. A., McLeod, D. S., & Lutty, G. A. (2009) · Experimental Eye Research · doi:10.1016/j.exer.2009.10.004 · Cited by 81 · cited 1×
“In addition, CRP can reduce endothelial nitric oxide synthase (eNOS) expression,(29) which we have observed in CC AMD subjects.(30) One of the major and most rigorously defined biological functions of CRP in humans is activation of the complement system via the classical pathway.”
BackgroundSelf-citationRisk of Type 2 Diabetes Attributable to C-Reactive Protein and Other Risk Factors
Dehghan, A., van Hoek, M., Sijbrands, E. J. G., Stijnen, T., Albert Hofman, D., & Witteman, J. C. M. (2007) · Diabetes Care · doi:10.2337/dc07-0348 · Cited by 77
Macular and peripheral distribution of ICAM-1 in the human choriocapillaris and retina.
Mullins, R. F., Skeie, J. M., Malone, E. A., & Kuehn, M. H. (2006) · PubMed · Cited by 66
Barna, B. P., Deodhar, S. D., Gautam, S., Yen‐Lieberman, B., & Roberts, D. (1984) · PubMed · Cited by 57
Prognosis of Atrial Fibrillation in Congestive Heart Failure
Folkeringa, J. R., Crijns, H. J. G. M., & van Veldhuisen, D. J. (2004) · Circulation · doi:10.1161/01.cir.0000111134.23909.db · Cited by 43
Platelet agonist synergism by the acute phase reactant C-reactive protein
Fiedel, B. A. (1985) · Blood · doi:10.1182/blood.v65.2.264.264 · Cited by 23
Platelet agonist synergism by the acute phase reactant C-reactive protein
Fiedel, B. (1985) · Blood · doi:10.1182/blood.v65.2.264.bloodjournal652264 · Cited by 19 · cited 1×
“7 Several biological activities have been attributed to CRP, such as complement activation,(12) macrophage activation(13) and platelet activation.(14) Complement factor H (CFH) is a major inhibitor of the alternate complement pathway and indirectly inhibits the lectin pathway.”
Background
Cited by
Sorted by citations
Bhutto, I. A., & Lutty, G. A. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.04.005 · Cited by 1,028
“In contrast, immunostaining for CFH was significantly reduced in the BrMb/CC complex including the ICS in eyes with early and wet AMD (Bhutto et al., 2011).”
BackgroundInfluentialSelf-citationThe impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD
Datta, S., Cano, M., Ebrahimi, K. B., Wang, L., & Handa, J. T. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.03.002 · Cited by 843
“…altered pattern is protective or pathologic is unclear at this time, but studies on CFH immunolabeling indicate that CFH, which is normally confined to the choriocapillaris, intercapillary pillars, and Bruch’s membrane, is decreased in both early AMD and geographic atrophy (Bhutto et al., 2011).”
BackgroundLuan, Y., & Yao, Y.-M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01302 · Cited by 418
“It was found that mCRP played a role in choroidal vascular dysfunction in AMD by influencing endothelial cell phenotypes in vitro and ex vivo (63).”
BackgroundParainflammation, Chronic Inflammation and Age-Related Macular Degeneration
Chen, M., & Xu, H. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.3ri0615-239r · Cited by 381
“The expression of CFH [137], CD46, and CD59 [138]”
BackgroundRisk factors and biomarkers of age-related macular degeneration
Lambert, N. G., Elshelmani, H., Singh, M. K., Mansergh, F. C., Wride, M. A., Padilla, M., Keegan, D., Hogg, R. E., & Ambati, B. K. (2016) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2016.04.003 · Cited by 367
“elevated levels of CRP, there is an increased interaction between CRP and CFH (Bhutto et al., 2011).”
Influential
Metadata
- Authors
- Bhutto, I. A., Baba, T., Merges, C., Juriasinghani, V., McLeod, D. S., & Lutty, G. A.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Lutty, G. A.
- Venue
- British Journal of Ophthalmology
- Publisher
- BMJ
- Published
- 2011-06-01
- Volume
- 95
- Issue
- 9
- Pages
- 1323-1330
- ISSN
- 0007-1161 (ISSN-L)
- PMC
- PMC4916773
- OpenAlex
- W1974343663
- Cited by
- 126
- References
- 34
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 11 · 2023: 4 · 2022: 9 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 11 · 2017: 8 · 2016: 15 · 2015: 9 · 2014: 13 · 2013: 9 · 2012: 5
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- British Journal of Ophthalmology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Johns Hopkins University
- National Eye Institute (R01EY016151, #EY01765, P30EY001765)
- 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
- age-related macular degeneration, C-reactive protein, complement factor H, complement activation, retinal inflammation, choroid, Bruch's membrane, choroidal stroma, drusen, retinal pigment epithelium, choriocapillaris, immunolocalization
- MeSH terms
- Aged, Aged, 80 and over, Aging, C-Reactive Protein, Female, Humans, Immunohistochemistry, Macular Degeneration, Male, Prognosis, Biomarkers, Complement Factor H, Disease Progression, Retinal Pigment Epithelium
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