Systemic Complement Activation in Ischemic Stroke
To the Editor:
Activation of the complement system has been reported in a variety of inflammatory diseases and neurodegenerative processes of the central nervous system, and recent evidence indicates that complement proteins and receptors are synthesized on or by glial cells and, surprisingly, neurons.1
In their study, Xi and colleagues2 furnish new indirect data on the activation of complement system after intracerebral hemorrhage (ICH) in rats and suggest a possible pharmacological manipulation preventing complement activation to reduce the brain edema in ICH. However, despite the large number of therapeutic interventions that decrease damage in experimental animals, many negative results have been produced in the history of therapy in cerebrovascular disease when the same agent is tested in clinical trials. Experimental studies are conducted on healthy, young animals under rigorously controlled laboratory conditions. However, the typical stroke patient is elderly with numerous risk factors and complicating disease (for example, diabetes, arterial hypertension, and heart disease). Therefore, we must have more strong data on complement activation in stroke patients from observational epidemiological studies before suggesting a possible pharmacological manipulation of the complement system in stroke.
The complement system has an important role in innate and specific immune responses with functions that include the augmentation of the acute phase response.1 It can be activated via two reaction pathways: the classic pathway, which is triggered primarily by cell-bound immune complexes, and the alternative pathway, which is activated primarily by foreign bodies, such as microorganisms. The complement component C3 is a key protein in both reaction pathways, whereas C4 belongs to the classic pathway of complement activation. Complement activation is associated with consumption of components of C3 and/or C4 so that a reduction in their concentrations can allow diagnostic conclusions to reached. In the presence of an inflammatory response, both complement components react as acute-phase proteins and may therefore show elevated serum concentrations. Unfortunately, our group and I do not have exhaustive epidemiological data on complement activation in ICH, but I would like to present to you our preliminary results on complement system in ischemic stroke.
Previously, our group found a strong inflammatory response after ischemic stroke detected by circulating levels of C-reactive protein (CRP).3 4 CRP increases in patients with ischemic stroke,3 may remain elevated after stroke, and is correlated with clinical outcome.4 Furthermore, CRP is also able to activate the classic pathway of complement.5 These data also encourage the study of the role of complement activation after ischemic stroke.
From this viewpoint, I have recently analyzed the data on complement activation in our previously described stroke cohort.3 4 We measured serum levels of C3c and C4 complement component together with CRP levels within 24 hours after stroke. Continuous variables are described as median value with 25th and 75th percentiles. Comparisons between groups were evaluated by the Mann-Whitney or Kruskall-Wallis test, when appropriate. To avoid possible confounding factors, no patients with evidence of possible elevations of inflammation markers due to other causes except for stroke were included in this series. A systemic complement activation was evident in only 30 patients (15.5%) within 24 hours after stroke. Median (25th to 75th percentiles) serum levels of C3c and C4 complement components and CRP were 1.32 (1.14 to 1.55) g/L, 0.31 (0.27 to 0.39) g/L, and 13 (6 to 33) mg/L, respectively, in 193 first-ever ischemic stroke patients. Log-transformed C3c levels were modestly correlated with CRP (Pearson correlation coefficient r=0.12, P=0.049) and fibrinogen (r=0.25, P<0.0001) levels, while C4 was correlated with fibrinogen (r=0.20, P=0.003) but not with CRP (r=0.08, P=0.145).
Significantly reduced median serum concentrations of C3c (P=0.0052, Kruskall-Wallis test) and C4 (P=0.0007) were primarily observed in cardioembolic strokes when compared with atherothrombotic and lacunar strokes. In the case of cardioembolic stroke, the serum concentrations of the complement factors reflected the stroke severity (r=0.18, P=0.007, and r=0.22, P=0.001, respectively) assessed by Canadian Neurological Stroke Scale Score. Lower levels of C3c (P=0.0450, Mann Whitney U test) and C4 (P=0.0385) were also significantly associated with the presence of leukoaraiosis (diffuse or patchy lucencies of the white matter or centrum ovale) and large infarcts (when the sum of the largest transverse and sagittal diameter divided by 2 was >1.5 cm, P=0.0468 and P=0.0408, respectively). Isolated increased C3 values (P=0.0101) occurred in the presence of cortical involvement (>50%) whereas increased levels of C4 were found in spontaneous hemorrhagic transformation of the infarction (P=0.0403). Apparently, the presence of edema did not induce an systemic activation of complement system within the first 24 hours after stroke.
Our preliminary results show a variable response of complement system after ischemic stroke. Prevalently, the complement activation in ischemic stroke occurs via the classic pathway. A systemic activation of the classic pathway in the first 24 hours after ischemic stroke is apparently present in cardioembolic stroke, in larger infarcts, and in the presence of leukoaraiosis. Thus, complement activation could be a key event mediating the deleterious effects of the local inflammatory response occurring in the infarcted area. The nature of the substances in the infarcted area that start activation of complement by binding and activating the first component of complement is unknown. However, our results indicate that CRP could be involved as an activator. Yet, we cannot exclude the possibility that other substances able to activate complement are generated in the infarcted area during the first 24 hours because we found only a modest correlation with CRP.
In conclusion, our data suggest that the activation of complement enhances inflammation and hence promotes more severe strokes. Moreover, these observations might have pathophysiological implications in ischemic stroke, because in other similar conditions, such as myocardial infarction, very similar responses are seen.6 Future studies to investigate the complement role in ischemic stroke are warranted.
- Copyright © 2001 by American Heart Association
Xi G, Hua Y, Keep RF, Younger JG, Hoff JT. Systemic complement depletion diminishes perihematomal brain edema in rats. Stroke. 2001;32:162–167.
Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001;32:133–138.
Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke.. 2001;32:917-924.
Lagrand WK, Niessen HWM, Wolbink G-J, Jaspars LH, Visser CA, Verheugt FWA, Meijer CJLM, Hack CE. C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation. 1997;95:97–103.
We would like to thank Dr Di Napoli for his thoughtful letter. We agree with his comments about the difficulties in translating basic research on animals to the clinic and the need for further studies into the role of complement in brain injury. Our dataR1 R2 and those of othersR3 suggest that complement does play a role in brain injury following stroke and in other similar conditions, such as myocardial infarction.R4 Dr Di Napoli’s data are intriguing in providing data indicating that complement system activation occurs in human stroke as well as in animal models. As he points out, human stroke is very heterogeneous, and this variability may account for differences in the degree of complement activation seen in his patients. It should also be noted that measurements of systemic complement activation may not fully reflect complement activation within the brain. One of the advantages of performing animal experiments is access to brain tissues to assess such activation. Indeed, we have found that complement C9 protein content is increased in the brain after middle cerebral artery occlusion in rats.
Finally, we would encourage him and his colleagues to look at evidence for complement activation in his patients with intracerebral hemorrhage. Apart from the results presented in our article,R2 there is evidence that there is a greater inflammatory response after intracerebral hemorrhage compared with ischemic stroke,R5 and the direct influx of blood components into brain after an intracerebral hemorrhage may be a particularly potent stimulant of complement activation.
Xi G, Hua Y, Keep RF, Younger JG, Hoff JT. Systemic complement depletion diminishes perihematomal brain edema. Stroke. 2001;32:162–167.
Del Bigio MR, Yan HJ, Buist R, Peeling J. Experimental intracerebral hemorrhage in rats: Magnetic resonance imaging and histopathological correlates. Stroke. 1996;27:2312–2319; discussion 2319–2320.