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with Bb. This process achieves specificity to protecting including wall degeneration, de-endothelialization,
host cells from complement activation because it and degenerative change of the outer wall, as well as
requires the host membrane-bound cofactors including infiltrates of CD163+ macrophages and T-lymphocytes.
complement receptor-1 (CR-1) and membrane-cofactor Together, these results suggested a role for activated
protein (MCP). [57,75,94-96] CR-1 in particular is a potent complement in saccular aneurysm degeneration and
inhibitor of the classical and alternative pathways, and rupture.
also plays a role in clearing immune complexes and
antigen presentation to B-cells. [10,57] Other inhibitors Using a similar experimental model as their first study,
at the convertase level include decay accelerating Tulamo et al. [84] then sought to determine, which
factor (DAF), which inhibits assembly of C3 convertases, complement pathway was involved in aneurysm rupture
and Factor H, which serves as a cofactor for factor I and by staining for complement components specific to
DAF. Inhibitors of assembly of the MAC include CD59, the alternative and classical pathways, as well as their
vitronectin, and S-protein. [10,95,97] potential activators. It was found that components of the
classical pathway, C1q and C4b/iC4b, as well as the MAC
ROLE OF COMPLEMENT IN ANEURYSMS and C3b/iC3b and C3d, were present in significantly
greater concentrations and were more widely distributed
There has been a growing interest in the role that in ruptured versus unruptured aneurysms, and
complement plays in the pathogenesis of cerebral specifically the staining tended to localize along the
aneurysms, which has paralleled similar work done ECM in a band-like pattern in the outer aneurysm wall.
with aortic aneurysms. [47,98,99] Much of the esteemed In a smaller, separate sample of unruptured aneurysms,
work has been done by the Neurosurgery Research the authors reported heavy immunostaining for CRP,
Group at the Helsinki University Central Hospital, MAC, oxidized LDL, and IgG, which was increased in
Helsinki, Finland, and has taken the research model of concentration from the lumen-to-adventitia direction.
previous studies which have examined ruptured versus Of note, however, although the authors report that
unruptured aneurysms. [32] The studies have largely tissue form human tonsils was used as a positive
been done by standard immunohistological localization control (presumably due to the dense immune elements),
of complement in aneurysm tissue samples taken
intraoperatively immediately after aneurysm clipping. they did not have separate, nonaneurysmal tissue that
served as a negative control. Tulamo et al. concluded
[84]
that these findings most likely represented activation of
The first study to demonstrate complement deposition
in aneurysm walls was by Chyatte et al., [48] who the classical pathway, due to the presence of its potential
compared 25 aneurysm samples taken during activators (including IgG, oxidized LDL, and CRP) and
microsurgical repair to 11 control samples from basilar C1q deposition, which is specific to the classical pathway.
arteries taken at autopsy. Compared to the basilar The alternative pathway was less likely to play a role
samples, they found significantly more deposition of because there was little staining of the specific marker,
immunoreactive C9 and C3c (a breakdown product of Properdin. They suggested these immunoglobulins and
C3), and both C3c and C9 were deposited throughout complement components leak out and accumulated in
the aneurysm wall, often diffusely. They also found the aneurysmal wall due to endothelial dysfunction and
increased presence of immunoglobulins (IgG and impaired clearance mechanisms.
IgM) and leukocytes (CD68 macrophages and
T-lymphocytes). Due to the deposition of earlier (C3c) A third similar study by Tulamo et al. [101] found that
as well as terminal complement products (C9), the deposition of the MAC was greater in the outer wall than
authors concluded that complement activation, in in the lumen of ruptured compared with unruptured
concert with other inflammatory mediators, played a aneurysms. This was associated with increased
role in the pathogenesis of aneurysms. deposition of the complement inhibitors, including
the Factor H polymorphic variant Y402H (associated
In a 2006 study, Tulamo et al. [100] investigated the with age-related macular degeneration [102] ), C4b binding
role of the MAC in aneurysm rupture by comparing protein, and protectin (CD59, a MAC inhibitor);
samples from 26 unruptured to 32 ruptured samples. however, the outer wall lacked inhibitors, especially
Using a monoclonal mouse antibody to stain the protectin. Other inhibitors, such as MCP and DAF,
C5b-9 complex (MAC), the authors found that the were only sparsely expressed by adventitial mural
immunostaining for the MAC was approximately twice as cells. The authors suggested that the increased MAC
dense in ruptured versus unruptured samples (median: activity in the outer wall may be the result of decreased
39% vs. 20%, P < 0.001, respectively). A greater complement inhibitors in that region, and that the outer
concentration of MAC was also significantly associated wall’s decreased ability to inhibit the complement
with structural pathology of the aneurysmal wall cascade may facilitate eventual rupture. However,

Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015 97