Format

Send to

Choose Destination
J Immunol. 2014 Nov 15;193(10):4962-70. doi: 10.4049/jimmunol.1401613. Epub 2014 Oct 10.

Identification of factor H-like protein 1 as the predominant complement regulator in Bruch's membrane: implications for age-related macular degeneration.

Author information

1
Centre for Hearing and Vision Research, Institute of Human Development, University of Manchester, Manchester M13 9PT, United Kingdom; Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom; simon.clark-3@manchester.ac.uk.
2
Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081 Ulm, Germany;
3
Centre for Hearing and Vision Research, Institute of Human Development, University of Manchester, Manchester M13 9PT, United Kingdom; Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom;
4
Complement Biology Group, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; and.
5
Centre for Hearing and Vision Research, Institute of Human Development, University of Manchester, Manchester M13 9PT, United Kingdom; Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom; Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, United Kingdom.

Abstract

The tight regulation of innate immunity on extracellular matrix (ECM) is a vital part of immune homeostasis throughout the human body, and disruption to this regulation in the eye is thought to contribute directly to the progression of age-related macular degeneration (AMD). The plasma complement regulator factor H (FH) is thought to be the main regulator that protects ECM against damaging complement activation. However, in the present study we demonstrate that a truncated form of FH, called FH-like protein 1 (FHL-1), is the main regulatory protein in the layer of ECM under human retina, called Bruch's membrane. Bruch's membrane is a major site of AMD disease pathogenesis and where drusen, the hallmark lesions of AMD, form. We show that FHL-1 can passively diffuse through Bruch's membrane, whereas the full sized, glycosylated, FH cannot. FHL-1 is largely bound to Bruch's membrane through interactions with heparan sulfate, and we show that the common Y402H polymorphism in the CFH gene, associated with an increased risk of AMD, reduces the binding of FHL-1 to this heparan sulfate. We also show that FHL-1 is retained in drusen whereas FH coats the periphery of the lesions, perhaps inhibiting their clearance. Our results identify a novel mechanism of complement regulation in the human eye, which highlights potential new avenues for therapeutic strategies.

PMID:
25305316
PMCID:
PMC4225158
DOI:
10.4049/jimmunol.1401613
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center