Complement system becomes activated by the classical pathway in intracranial aneurysm walls

Lab Invest. 2010 Feb;90(2):168-79. doi: 10.1038/labinvest.2009.133. Epub 2009 Dec 7.


Inflammation and activation of the complement system in the intracranial aneurysm (IA) wall predispose to IA rupture. We have previously shown that increased C5b-9 accumulation correlates with IA rupture and wall degeneration. To elucidate the underlying mechanisms, we investigated initiators and the pathway of complement activation in unruptured and ruptured IAs. Unruptured and ruptured IA wall samples were studied in parallel sections by immunohistochemical and immunofluorescence stainings for the location and relations of classical and alternative pathway complement components (C1q, C3b/iC3b, C3d, C4b/iC4b; n=35 and properdin, n=10), putative complement activators IgG (n=90), IgM, CRP and OxLDL (n=10), and complement activation endproduct C5b-9. Classical pathway components were seen in all IAs, and they were located mostly in the extracellular matrix. The early pathway complement components colocalized with each other, but were present in larger areas than C5b-9. The areas positive for complement component accumulation were significantly broader in ruptured than in unruptured IAs. The potential complement activators IgG, IgM, CRP and OxLDL were found mostly in the extracellular matrix and in partial overlap with C5b-9. Lipids were seen in Oil-Red-O staining in colocalization with C5b-9. Complement becomes activated by the classical pathway in the IA wall. The activation appears to be induced by multiple factors, which, in addition to the traditional activators (immunoglobulins, CRP, OxLDL), could involve vascular pressure-induced tissue damage. Despite wide early pathway activation, the terminal pathway is focused on a distinct lipid-rich layer. The profile of the complement components and the association of C5b-9 with lipids in the extracellular matrix indicate a long-term chronic inflammatory process rather than an acute targeted inflammatory reaction. The observed pattern of complement activation may be the consequence of local stress-induced insufficiency of complement regulation in IA walls.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aneurysm, Ruptured / immunology*
  • C-Reactive Protein / analysis
  • Complement Pathway, Classical / immunology*
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Immunoglobulin G / immunology
  • Immunohistochemistry
  • Inflammation / immunology*
  • Intracranial Aneurysm / immunology*
  • Lipoproteins, LDL / immunology
  • Male
  • Middle Aged


  • Immunoglobulin G
  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • C-Reactive Protein