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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.”
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Items 101–125 of 125
Maruyama-Inoue, M., Yamane, S., Satoh, H., Sato, S., & Kadonosono, K. (2017) · Journal of VitreoRetinal Diseases · doi:10.1177/2474126417733161 · Cited by 5
Bonyadi, M. J., Mehdizadeh, F., Bonyadi, M. H. J., Soheilian, M., Javadzadeh, A., & Yaseri, M. (2017) · Ophthalmic Genetics · doi:10.1080/13816810.2016.1251947 · Cited by 4
“Various studies have shown that there is a significant association between high serum CRP and late AMD which is related to pro-inflammatory CRP effects.(28) One meta-analysis has shown that a high level of CRP (> 3 mg/L) is associated with a two-fold higher risk of advanced AMD.”
BackgroundChucair‐Elliott, A. J., Pham, K. D., Cleuren, A. C. A., Schafer, C. M., Griffin, C. T., Ocañas, S. R., Freeman, W. M., & Elliott, M. H. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.110101 · Cited by 3
Jensen, E. G., Jakobsen, T. S., Schnabolk, G., Wilson, K., Rask-Pedersen, M., Jensen, N. M., Andersen, G. R., Thiel, S., Aagaard, L., Rohrer, B., et al. (2025) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2025.101620 · Cited by 3
Scotti, F., Milani, P., Setaccioli, M., Maestroni, S., Sidénius, N., Lorenzi, V. D., Massacesi, A., Bergamini, F., & Zerbini, G. (2019) · Graefe s Archive for Clinical and Experimental Ophthalmology · doi:10.1007/s00417-018-04230-w · Cited by 3
The Role of Inflammation in Age-Related Macular Degeneration
Harris, J. M., & Wu, D. M. (2025) · International Ophthalmology Clinics · doi:10.1097/iio.0000000000000578 · Cited by 2
Truncated complement factor H Y402 gene therapy rescues C3 glomerulonephritis
Chew, L. A., Grigsby, D., Hester, C. G., Amason, J., McPherson, W. K., Flynn, E. J., Visel, M., Starr, C. R., Flannery, J. G., Lewis, T. R., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.035 · Cited by 3
Age Related Macular Degeneration: a Complex Pathology
Kumar, S., Fu, Y., & Moran, J. A. (2014) · Cited by 2
Garweg, J. G. (2016) · Der Ophthalmologe · Cited by 2
Retinal Pigment Epithelium in Age-Related Macular Degeneration
Kaarniranta, K., Salminen, A., & Kauppinen, A. (2020) · Springer eBooks · doi:10.1007/978-3-030-28384-1_9 · Cited by 2
Pharmacogenomics & its Application in Ophthalmology
Gupta, S., Kumar, S., & Garg, P. (2015) · Delhi Journal of Ophthalmology · doi:10.7869/djo.136 · Cited by 1
Cebeci, D., Tülüceoğlu, E. E., Gonca, T., Calapoğlu, N. Ş., ÖZTÜRK, Ö., & Calapoğlu, M. (2018) · SDÜ Tıp Fakültesi Dergisi · doi:10.17343/sdutfd.422561 · Cited by 1
Limoli, P. G., Limoli, C., & Nebbioso, M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15717-2.00079-2 · Cited by 1
Relationship among C-reactive protein, iron status, oxidative stress, and pulmonary tuberculosis
Sun, B. H. (2012) · African Journal of Pharmacy and Pharmacology · doi:10.5897/ajpp12.958 · Cited by 1
“However, this value increases in the presence of inflammation, tissue damage, local ischemia, cancer, and other diseases (Liu et al., 2010; Hamidon et al., 2004; Bhutto et al., 2011).”
BackgroundOuter Retinal (Choroidal) Vasculature Structure and Choroidopathies
Lutty, G. A. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-386456-7.04710-9
Self-citationA Revised Hemodynamic Theory of Age-Related
Gelfand, B. D., & Ambati, J. (2016)
Retinales Pigmentepithel bei altersbedingter Makuladegeneration
Kaarniranta, K., Salminen, A., & Kauppinen, A. (2024) · Springer eBooks · doi:10.1007/978-3-031-35055-9_9
Aging Vasculature in the Choroid and Retina
Ghosh, K. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13820-1.00155-9
Truncated Complement Factor H Y402 Gene Therapy Cures C3 GlomerulonephritisPreprint
Chew, L. A., Grigsby, D., Hester, C. G., Amason, J., McPherson, W. K., Flynn, E. J., Visel, M., Flannery, J. G., & Rickman, C. B. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.17.613471
“In particular, the capacity of tCFH to clear C3 deposits from glomeruli in C3G suggests that tCFH may be capable of clearing pro-inflammatory accumulates ( i.e. , high-density lipoproteins 52 , C-reactive protein 53 , and other accumulated molecules) from Bruch’s membrane in AMD.”
BackgroundZhao, S., Voegele, F., Tang, J., Clark, S. J., Tschulakow, A., & Julien, S. (2025) · The FASEB Journal · doi:10.1096/fj.202502226r
“The reactivity for FH did not change throughout the entire observation period in our model, which correlates with the situation observed in GA patients, where the immunoreactivity score for FH was not significantly different compared to that of aged controls [40].”
Jacob, M., Stattin, M., Graf, A. C., Ebner, A., Ahmed-Balestra, D., Krepler, K., & Ansari‐Shahrezaei, S. (2026) · European Journal of Ophthalmology · doi:10.1177/11206721261424054
“16,17 SRF in exudative MNV type 1 has been ascribed to support the viability of the chorio-capillaris and neovascular network, facilitating nutrients and oxygen to the adjacent RPE and potentially preventing atrophy and functional loss.”
CPD: Dry age-related macular degeneration
Green, A. (2026) · Optician · doi:10.12968/opti.2026.273.7058.19
KamaliZonouzi, S., Zadeh, P. B., Popovic, M. M., Gorin, M. B., & Eshkoly-Lior, T. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1799560
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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