Lack of complement inhibitors in the outer intracranial artery aneurysm wall associates with complement terminal pathway activation.
Inflammation and activation of the complement system predispose to intracranial artery aneurysm (IA) rupture. Because disturbances in complement regulation may lead to increased susceptibility to complement activation and inflammation, we looked for evidence for dysregulation of the complement system in 26 unruptured and 26 ruptured IAs resected intraoperatively. Immunohistochemical and immunofluorescence results of parallel IA sections showed that deposition of the complement activation end-product C5b-9 was lacking from the luminal part of the IA wall that contained complement inhibitors factor H, C4b binding protein, and protectin as well as glycosaminoglycans. In contrast, the outer, less cellular part of the IA wall lacked protectin and had enabled full complement activation and C5b-9 formation. Decay accelerating factor and membrane cofactor protein had less evident roles in complement regulation. The Factor H Y402H variant, studied in 97 IA patients, was seen as often in aneurysm patients with or without aneurysm rupture as in the control population. The regulatory capacity of the complement system thus appears disturbed in the outer part of the IA wall, allowing full proinflammatory complement activation to occur before aneurysm rupture. Insufficient complement control might be due to matrix remodeling and cell loss by mechanical hemodynamics and/or inflammatory stress. Apparently, disturbed complement regulation leads to an increased susceptibility to complement activation, inflammation, and tissue damage in the IA wall.
Tulamo
Riikka
R
Neurosurgery Research Group, Room B408a2, Biomedicum Helsinki 1, P.O. Box 700, FI-00029 Huch, Finland. riikka.tulamo@hus.fi
Frösen
Juhana
J
Paetau
Anders
A
Seitsonen
Sanna
S
Hernesniemi
Juha
J
Niemelä
Mika
M
Järvelä
Irma
I
Meri
Seppo
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017542:Aneurysm, Ruptured / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002536:Cerebral Arteries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D003167:Complement Activation / Q000276:immunology; D003169:Complement Inactivator Proteins / Q000276:immunology / Q000378:metabolism*; D003171:Complement Pathway, Classical / Q000276:immunology* / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D003169:Complement Inactivator Proteins