Scholars@Duke publication: Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration.

Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration.

Publication , Journal Article

Kelly, U; Yu, L; Kumar, P; Ding, J-D; Jiang, H; Hageman, GS; Arshavsky, VY; Frank, MM; Hauser, MA; Rickman, CB

Published in: J Immunol

November 1, 2010

An imbalance between activation and inhibition of the complement system has been implicated in the etiologies of numerous common diseases. Allotypic variants of a key complement fluid-phase regulatory protein, complement factor H (CFH), are strongly associated with age-related macular degeneration (AMD), a leading cause of worldwide visual dysfunction, although its specific role in AMD pathogenesis is still not clear. CFH was isolated from individuals carrying combinations of two of the nonsynonymous coding variants most strongly associated with AMD risk, V62/H402 (risk haplotype variants), I62/Y402 (nonrisk haplotype variants), and V62/Y402. These proteins were used in two functional assays (cell surface- and fluid-phase-based) measuring cofactor activity of CFH in the factor I-mediated cleavage of C3b. Although no variant-specific differences in the cofactor activity were detected, when heparan sulfate (HS) was added to these assays, it accelerated the rate of C3b cleavage, and this effect could be modulated by degree of HS sulfation. Bruch's membrane/choroid, a site of tissue damage in AMD, contains high concentrations of glycosaminoglycans, including HS. Addition of human Bruch's membrane/choroid to the fluid-phase assay accelerated the C3b cleavage, and this effect was lost posttreatment of the tissue with heparinase III. Binding of CFH variants to Bruch's membrane/choroid isolated from elderly, non-AMD donor eyes, was similar, as was the functional activity of bound CFH. These findings refine our understanding of interactions of HS and complement and support the hypothesis that these interactions play a role in the transition between normal aging and AMD in Bruch's membrane/choroid.

Duke Scholars

Author Vadim Y Arshavsky Ophthalmology, Vitreoretinal Diseases & Surgery

Author Michael Arthur Hauser Medicine, Medical Genetics

Author Catherine Bowes Rickman Ophthalmology, Vitreoretinal Diseases & Surgery

Published In

J Immunol

DOI

10.4049/jimmunol.0903596

EISSN

1550-6606

Publication Date

November 1, 2010

Volume

185

Issue

Start / End Page

5486 / 5494

Location

United States

Related Subject Headings

Protein Isoforms
Middle Aged
Microscopy, Electron, Transmission
Male
Macular Degeneration
Immunology
Humans
Heparitin Sulfate
Female
Complement Pathway, Alternative

Citation

APA

Chicago

ICMJE

MLA

NLM

Kelly, U., Yu, L., Kumar, P., Ding, J.-D., Jiang, H., Hageman, G. S., … Rickman, C. B. (2010). Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration. J Immunol, 185(9), 5486–5494. https://doi.org/10.4049/jimmunol.0903596

Kelly, Una, Ling Yu, Pallavi Kumar, Jin-Dong Ding, Haixiang Jiang, Gregory S. Hageman, Vadim Y. Arshavsky, Michael M. Frank, Michael A. Hauser, and Catherine Bowes Rickman. “Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration.” J Immunol 185, no. 9 (November 1, 2010): 5486–94. https://doi.org/10.4049/jimmunol.0903596.

Kelly U, Yu L, Kumar P, Ding J-D, Jiang H, Hageman GS, et al. Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration. J Immunol. 2010 Nov 1;185(9):5486–94.

Kelly, Una, et al. “Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration.” J Immunol, vol. 185, no. 9, Nov. 2010, pp. 5486–94. Pubmed, doi:10.4049/jimmunol.0903596.

Kelly U, Yu L, Kumar P, Ding J-D, Jiang H, Hageman GS, Arshavsky VY, Frank MM, Hauser MA, Rickman CB. Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration. J Immunol. 2010 Nov 1;185(9):5486–5494.