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The significance of the complement system for the pathogenesis of age-related macular degeneration - current evidence and translation into clinical application.
Graefes Arch Clin Exp Ophthalmol. 2011 Feb; 249(2):163-74.GA

Abstract

BACKGROUND

Dysregulation of the complement system has been shown to play a major role in the pathogenesis of age-related macular degeneration (AMD).

METHODS

The current evidence from human studies derives from immunohistochemical and proteomic studies in donor eyes, genetic association studies, and studies of blood complement protein levels. These lines of evidence are corroborated by in vitro and animal studies.

RESULTS

In AMD donor eyes, detection of complement proteins in drusen suggested local inflammatory processes involving the complement system. Moreover, higher levels of complement proteins in the Bruch's membrane/choroid complex could be detected in AMD donor eyes compared to controls. A large number of independent genetic studies have consistently confirmed the association of AMD with risk or protective variants in genes coding for complement proteins, including complement factor H (CFH), CFH-related proteins 1 and 3, factor B/C2, C3 and factor I. Another set of independent studies detected increased levels of complement activation products in plasma of AMD patients, suggesting that AMD may be a systemic disease and the macula a vulnerable anatomic site of minimal resistance to complement activation. Genotype-phenotype correlations, including the impact of genetic variants on disease progression, gene-environment and pharmacogenetic interactions, have been investigated. There is evidence that complement gene variants may be associated with the progression from early to late forms of AMD, whereas they do not appear to play a significant role when late atrophic AMD has already developed. There are indications for an interaction between genetic variants and supplementation and dietary factors. Also, there is some evidence that variants in the CFH gene influence treatment effects in patients with neovascular AMD.

CONCLUSIONS

Such data suggest that the complement system may have a significant role for developing new prophylactic and therapeutic interventions in AMD. In fact, several compounds acting on the complement pathway are currently in clinical trials. Therapeutics that modulate the complement system need to balance inhibition with preservation of sufficient functional activity in order to maintain adequate immune responses and tissue homeostasis. Specifically, targeting the dysfunction appears more adequate than a global suppression of complement activation in chronic diseases such as AMD.

Authors+Show Affiliations

Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, UK.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

21127893

Citation

Charbel Issa, Peter, et al. "The Significance of the Complement System for the Pathogenesis of Age-related Macular Degeneration - Current Evidence and Translation Into Clinical Application." Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie, vol. 249, no. 2, 2011, pp. 163-74.
Charbel Issa P, Chong NV, Scholl HP. The significance of the complement system for the pathogenesis of age-related macular degeneration - current evidence and translation into clinical application. Graefes Arch Clin Exp Ophthalmol. 2011;249(2):163-74.
Charbel Issa, P., Chong, N. V., & Scholl, H. P. (2011). The significance of the complement system for the pathogenesis of age-related macular degeneration - current evidence and translation into clinical application. Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie, 249(2), 163-74. https://doi.org/10.1007/s00417-010-1568-6
Charbel Issa P, Chong NV, Scholl HP. The Significance of the Complement System for the Pathogenesis of Age-related Macular Degeneration - Current Evidence and Translation Into Clinical Application. Graefes Arch Clin Exp Ophthalmol. 2011;249(2):163-74. PubMed PMID: 21127893.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The significance of the complement system for the pathogenesis of age-related macular degeneration - current evidence and translation into clinical application. AU - Charbel Issa,Peter, AU - Chong,N Victor, AU - Scholl,Hendrik P N, Y1 - 2010/12/03/ PY - 2010/08/26/received PY - 2010/10/29/accepted PY - 2010/10/25/revised PY - 2010/12/4/entrez PY - 2010/12/4/pubmed PY - 2011/5/21/medline SP - 163 EP - 74 JF - Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie JO - Graefes Arch Clin Exp Ophthalmol VL - 249 IS - 2 N2 - BACKGROUND: Dysregulation of the complement system has been shown to play a major role in the pathogenesis of age-related macular degeneration (AMD). METHODS: The current evidence from human studies derives from immunohistochemical and proteomic studies in donor eyes, genetic association studies, and studies of blood complement protein levels. These lines of evidence are corroborated by in vitro and animal studies. RESULTS: In AMD donor eyes, detection of complement proteins in drusen suggested local inflammatory processes involving the complement system. Moreover, higher levels of complement proteins in the Bruch's membrane/choroid complex could be detected in AMD donor eyes compared to controls. A large number of independent genetic studies have consistently confirmed the association of AMD with risk or protective variants in genes coding for complement proteins, including complement factor H (CFH), CFH-related proteins 1 and 3, factor B/C2, C3 and factor I. Another set of independent studies detected increased levels of complement activation products in plasma of AMD patients, suggesting that AMD may be a systemic disease and the macula a vulnerable anatomic site of minimal resistance to complement activation. Genotype-phenotype correlations, including the impact of genetic variants on disease progression, gene-environment and pharmacogenetic interactions, have been investigated. There is evidence that complement gene variants may be associated with the progression from early to late forms of AMD, whereas they do not appear to play a significant role when late atrophic AMD has already developed. There are indications for an interaction between genetic variants and supplementation and dietary factors. Also, there is some evidence that variants in the CFH gene influence treatment effects in patients with neovascular AMD. CONCLUSIONS: Such data suggest that the complement system may have a significant role for developing new prophylactic and therapeutic interventions in AMD. In fact, several compounds acting on the complement pathway are currently in clinical trials. Therapeutics that modulate the complement system need to balance inhibition with preservation of sufficient functional activity in order to maintain adequate immune responses and tissue homeostasis. Specifically, targeting the dysfunction appears more adequate than a global suppression of complement activation in chronic diseases such as AMD. SN - 1435-702X UR - https://www.unboundmedicine.com/medline/citation/21127893/The_significance_of_the_complement_system_for_the_pathogenesis_of_age_related_macular_degeneration___current_evidence_and_translation_into_clinical_application_ L2 - https://dx.doi.org/10.1007/s00417-010-1568-6 DB - PRIME DP - Unbound Medicine ER -