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judging from the finding of their second study, in time period varied widely among and within studies,
which IgG was more densely deposited towards the including one of the studies in which samples varied from
outer aneurysm wall, it is unclear whether this graded 4 h to 47 days. [101] However, although this is a consideration
IgG concentration could be the primary factor in the for judging the quality of the immunologically analyzed
greater MAC activity in the outer wall. specimens, they were generally flash-frozen in liquid
nitrogen so as to minimize degradation and preserve
Studies on genetic expression profiles have also their immunohistological staining characteristics. In
identified the role of complement-related genes in addition, the aneurysm samples represent patients
aneurysmal tissue. In a small study, [103] which compared requiring surgical, but not endovascular intervention,
aneurysm samples to control superficial temporal artery which imparts a selection bias to patients with certain
tissue, there was upregulated expression of three genes clinical and aneurysmal morphological characteristics.
for C1q, the deposition of which was found in the The results of the Tulamo studies from Finland may also
aforementioned study by Tulamo et al., [84] as well as have limitations in their external validity because Finland
those for complement Factor D, Factor H, Factor B, and represents a relatively homogenous population, and the
C3a. The authors pointed out that these alterations prevalence of intracranial aneurysms is twice as high as
in the expression profile of these genes represent a other comparable countries. [1]
change in equilibrium of the complement system in the
perianeurysmal environment. There has also been an A larger issue with interpreting the results of the
animal study by Aoki et al., [104] in which the investigators analyses, in which authors have attributed the aneurysm
used a DNA microarray to compare intimal and medial pathogenesis to complement activation, are confounding
gene expression in cerebral aneurysms versus normal causes of the observed immunohistological properties of
cerebral arteries. It was found that in the media there was aneurysm tissue. In several of the human studies there
upregulation of Factor H and C4 expression, although were statistically significant differences in the proportions
downregulation of C3 and C6. By contrast, C3 and C6 of patients with characteristics known to affect aneurysm
were upregulated in the intima. The authors argue that pathology (including smoking history, hypertension,
their differing results from the initial study by Tulamo and family history of aneurysms) as well as differences
et al., [100] may be explained by different regulation of in the gross aneurysm morphology. Furthermore, it is
complement mRNA expression between the endothelial unclear whether the increased complement activation
cells and the SMCs in cerebral aneurysms. in ruptured compared with unruptured samples (as
was reported in the studies by Tulamo et al. [84,100,101] )
Although the genetic and histopathological studies contributed to the acute mechanism of rupture, or
mentioned were no doubt pioneering, there are certain whether the resulting rupture and SAH hemorrhage
points of discussion. Among the studies assessing the occurred for other reasons (i.e. hemodynamic factors,
role of the complement in aneurysms, the experimental etc.) and then initiated a secondary complement and
design often differed significantly. In general, the study inflammatory response as a result of the injury. Indeed,
sizes were small, although this is what would be expected as mentioned, there is evidence that the complement
given the limits of intraoperative sample collection. In system is upregulated in patients with SAH. [60,65,66] In
addition, one study was an animal model. [104] Whereas response to this concern, Tulamo et al. [84,100,101] have
some of the studies compared aneurysmal tissue to argued that the increased density of macrophage
control samples (such as the superficial temporal infiltration in ruptured versus unruptured aneurysms
artery), [48,103,104] the three studies by Tulamo et al. [84,100,101] argues for a more chronic inflammatory process, as dense
only compared ruptured to unruptured aneurysms. In accumulation of macrophages typically occurs over days
effect, although several studies provide compelling to weeks following an acute injury. In addition, they
evidence that there is more complement deposition and point out that although less concentrated, complement
activation in aneurysms than in healthy cerebrovascular deposits were found in unruptured aneurysms. Their
tissue, those by Tulamo et al. [84,100,101] generally cannot argument is also supported by the numerous animal and
make this comparison since these studies lacked controls human studies that have shown inflammatory infiltrate
from nonaneurysmal vascular tissue. in aneurysms that have not ruptured. [22,32,36,37] Tulamo
et al. [84,100,101] suggest that the hemorrhagic insult and
In general, the method of specimen collection involved physical factors may have contributed to complement
taking a sample of aneurysm tissue, intraoperatively, that activation but that more studies will be needed.
was distal to the placement of a surgical clip and then
running immunhistological analyses. There is a possibility, CONCLUSION
therefore, that the pathology of the sample and/or its
immunological characteristics may have changed between There is mounting evidence that the complement cascade
the time that the sample was collected and analyzed. This plays a role in the chronic as well as acute inflammation

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