Bruch’s Membrane Compartmentalizes Complement Regulation in the Eye with Implications for Therapeutic Design in Age-Related Macular Degeneration
Open accessAbstract
Age-related macular degeneration (AMD) is the leading cause of blindness in the western world and affects nearly 200 million people globally. Local inflammation driven by complement system dysregulation is currently a therapeutic target. Bruch's membrane (BrM) is a sheet of extracellular matrix that separates the retina from the underlying choroid, a highly vascularized layer that supplies oxygen and nutrition to the outer retina. Here, we show that most complement proteins are unable to diffuse through BrM, although FHL-1, factor D and C5a can. AMD-associated lipid deposition in BrM decreases FHL-1 diffusion. We show that this impermeability of BrM creates two separate semi-independent compartments with respect to complement activation and regulation. Complement proteins synthesized locally on either side of BrM, or on the choroidal side if derived from the circulation, predominantly remain on their side of origin. As previous studies suggest that complement activation in AMD is confined to the choroidal side of BrM, we propose a model whereby complement activation in the choriocapillaris layer of the choroid generates C5a, which crosses BrM to interact with its specific receptor on RPE cells to initiate an inflammatory response in the retina. Understanding mechanisms underpinning AMD is essential for developing therapeutics that target the right molecule in the right anatomical compartment.
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Post-translational modifications such as N-linked glycosylation may impede diffusion of Factor I through BrM, although these are not sufficient to explain the lack of diffusion of Factor H and Factor B.
“Post-translational modifications, such as N-linked glycosylation, may also impede diffusion of complement proteins such as Factor I (FI) through BrM, although these are not considered sufficient to explain the lack of diffusion of Factor H (FH) and Factor B (FB) [35,39].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [35]
Some complement proteins such as FHL-1, FD, and C5a have been found to pass through BrM, while C3a is not able to do so despite its small molecular weight.
“While some complement proteins such as Factor H-like protein 1 (FHL-1), Factor D (FD), and C5a have been found to pass through BrM [35,36], it has been reported that C3a, despite its small molecular weight, is not able to do so.”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [35]
The inability of C3a to pass through BrM may reflect its higher positive net charge at neutral pH, causing it to be trapped within the negatively charged BrM due to glycosaminoglycans.
“This observation may reflect the higher positive net charge of C3a at neutral pH [35], causing it to be trapped within the BrM, which is negatively charged due to the presence of glycosaminoglycans [35,37,38].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [35]
Certain complement proteins, such as C3/C3b, FH, FB, and FI, are unable to penetrate the BrM even at small quantities.
“certain complement proteins, such as C3/C3b, FH, FB, and FI, are unable to penetrate the BrM even at small quantities”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [35]
FHL-1 may play a specialised role in controlling complement activation locally.
“suggests that it may play a specialised role in controlling complement activation locally [35,36].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [35]
Other complement proteins, such as Factor D, FHL-1, and C5a, can cross the BrM but at reduced concentrations.
“while others, such as Factor D, Factor H-like protein 1 (FHL-1), and C5a, can cross the BrM but at reduced concentrations [35].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [35]
FHL-1 (49 kDa), a splice variant of CFH, has better tissue penetration than full-length glycosylated FH (155 kDa).
“The fact that FHL-1 (49 kDa), a splice variant of the CFH gene, has better tissue penetration than the full-length, glycosylated FH protein (155 kDa)”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [35]
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- Authors
- Clark, S. J., McHarg, S., Tilakaratna, V., Brace, N., & Bishop, P. N.
- Affiliations
- University of Manchester (GB)
- Manchester Academic Health Science Centre (GB)
- Corresponding author
- Clark, Simon J.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2017-12-19
- Volume
- 8
- Pages
- 1778-1778
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC5742201
- OpenAlex
- W2781073743
- Cited by
- 71
- References
- 33
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 6 · 2023: 10 · 2022: 7 · 2021: 10 · 2020: 11 · 2019: 5 · 2018: 1
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Medical Research Council (MR/K024418/1)
- Fight for Sight UK (1517/1518)
- Macular Society (12928)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- Bruch's membrane, age-related macular degeneration, complement regulation, complement activation, FHL1, factor D, C5a, membrane permeability, choroid, choriocapillaris, retinal pigment epithelium, lipid accumulation, inflammation, complement receptors, therapeutic targeting
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