Complement activation in the central nervous system following blood–brain barrier damage in man

Abstract

The central nervous system (CNS) is virtually isolated from circulating immunological factors such as complement (C), an important mediator of humoral immunity and inflammation. In circulation, C is constantly inhibited to prevent attack on host cells. Since a host of diseases produce an abnormal blood-brain/cerebrospinal fluid (blood-brain/CSF) permeability allowing C protein extravasation, we investigated if C activation occurs in CSF in vitro and in CNS in vivo during subarachnoid hemorrhage (SAH) or brain infarction. After SAH (n = 15), the terminal complement complex (TCC) concentration on days 0 to 2 was higher in the CSF, 210 +/- 61 ng/ml, than in the plasma, 63 +/- 17 ng/ml, but null in the CSF of controls (n = 8) or patients with an ischemic stroke (n = 7). TCC was eliminated from the CSF after SAH (24 +/- 10 ng/ml on days 7 to 10). Incubation of normal human CSF with serum in vitro also activated the terminal C pathway. In 10 fatal ischemic brain infarctions, immunohistochemical techniques demonstrated neuronal fragment-associated deposition of C9 accompanied by neutrophil infiltration. We conclude that the C system becomes activated intrathecally in SAH and focally in the brain parenchyma in ischemic stroke. By promoting chemotaxis and vascular perturbation, C activation may instigate nonimmune inflammation and aggravate CNS damage in diseases associated with plasma extravasation.

Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells

“…51 As discussed previously, though, this was not sufficient to allow for OV propagation within infected tumors. This suggested that complement had a minimal role in inhibiting OV dissemination within a tumor perhaps due to its low concentrations within normal nervous tissue 67 and due to the expression by human brain tumors of factors that downmodulate complement activity. 68,69 Instead, when CPA was used, both increases in initial infection of tumors and in subsequent propagation of OV within tumors were observed.…”

Complement C1q Is Dramatically Up-Regulated in Brain Microglia in Response to Transient Global Cerebral Ischemia

“…Activation of complement by the classical, the alternative and the recently discovered lectin pathway generates opsonins, inflammatory mediators, and cytolytic protein complexes which play an essential role in clearing microorganisms and tissue damage products (4). It has recently been suggested that local activation of complement in the CNS is of pathophysiological significance in both degenerative and inflammatory neurological diseases including Alzheimer's (2, 5-9) and Parkinson's dementia (10), supranuclear palsy (11), Pick's disease (12), multiple sclerosis (13,14), cerebral malaria (15), meningoencephalitis (16), scrapie (17,18), and cerebrovascular disorders (19). Increased biosynthesis of various complement factors in the CNS has also been reported in experimental animal models of neurodegeneration or neuroinflammation such as peripheral or central axotomy (20 -24), excitotoxic kainic acid lesions (21,25), exposure to neurotoxins (26), and experimental allergic and virus-induced encephalitis (27) and in cultured microglial cells (28 -32).…”

Collectins, C3 complement protein, annexin V and C-reactive protein in acute ischemic stroke: interrelation and implication to upregulated apoptosis and inflammation

“…A number of animal and human studies [29][30][31][32][33][34][35][36][37][38][39] , including our own [40][41][42] , demonstrated that activation of the complement system play a decisive role in the pathophysiology of IS. No study has reported data on functional state of FH and FL in this disorder.…”