Complement activation and inflammatory processes in Drusen formation and age related macular degeneration

Exp Eye Res. 2001 Dec;73(6):887-96. doi: 10.1006/exer.2001.1094.


Recent studies implicate inflammation and complement mediated attack as early events in drusen biogenesis. The investigations described here sought to determine whether primary sites of complement activation could be identified within drusen substructure, and whether known inhibitors of the terminal pathway of complement are present in drusen and/or retinal pigmented epithelial (RPE) cells that lie in close proximity to drusen. Immunohistochemical examination shows two fluid phase regulators of the terminal pathway, vitronectin (Vn, S-protein) and clusterin (apolipoprotein J), to be present in drusen; Vn also accumulates in the cytoplasm of RPE cells that are closely associated with drusen. The membrane associated complement inhibitor, complement receptor 1, is also localized in drusen, but it is not detected in RPE cells immunohistochemically. In contrast, a second membrane associated complement inhibitor, membrane cofactor protein, is present in drusen associated RPE cells, as well as in small, spherical substructural elements within drusen. These previously unidentified elements also show strong immunoreactivity for proteolytic fragments of complement component C3 that are characteristically deposited at sites of complement activation. It is proposed that these structures represent residual debris from degenerating RPE cells that are the targets of complement attack. It is likely that RPE cell debris entrapped between the RPE monolayer and Bruch's membrane serves as a chronic inflammatory stimulus and a potential nucleation site for drusen formation. Thus, the process of drusen biogenesis may be envisaged as a secondary manifestation of primary RPE pathology that is exacerbated by consequences of local inflammatory processes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / immunology
  • Clusterin
  • Complement Activation / physiology*
  • Complement Inactivator Proteins / physiology
  • Glycoproteins / immunology
  • Humans
  • Macular Degeneration / immunology*
  • Membrane Cofactor Protein
  • Membrane Glycoproteins / immunology
  • Microscopy, Confocal
  • Middle Aged
  • Molecular Chaperones / immunology
  • Pigment Epithelium of Eye / immunology
  • Retinal Drusen / immunology*
  • Vitronectin / immunology


  • Antigens, CD
  • CD46 protein, human
  • CLU protein, human
  • Clusterin
  • Complement Inactivator Proteins
  • Glycoproteins
  • Membrane Cofactor Protein
  • Membrane Glycoproteins
  • Molecular Chaperones
  • Vitronectin