Innate immunity and brain inflammation: the key role of complement

Abstract

The complement inflammatory cascade is an essential component of the phylogenetically ancient innate immune response and is crucial to our natural ability to ward off infection. Complement is involved in host defence by triggering the generation of a membranolytic complex (the C5b-9 complex) at the surface of the pathogen. Complement fragments (opsonins; C1q, C3b and iC3b) interact with complement cell-surface receptors (C1qRp, CR1, CR3 and CR4) to promote phagocytosis and a local pro-inflammatory response that, ultimately, contributes to the protection and healing of the host. Complement is of special importance in the brain, where entrance of elements of the adaptive immune system is restricted by a blood–brain barrier. There is now compelling evidence that complement is produced locally in response to an infectious challenge. Moreover, complement biosynthesis and activation also occurs in neurodegenerative disorders such as Alzheimer's, Huntington's and Pick's diseases, and the cytolytic/cytotoxic activities of complement are thought to contribute to neuronal loss and brain tissue damage. However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways. The emerging paradigm is that complement is involved in the clearance of toxic cell debris (e.g. amyloid fibrils) and apoptotic cells, as well as in promoting tissue repair through the anti-inflammatory activities of C3a. Knowledge of the unique molecular and cellular innate immunological interactions that occur in the development and resolution of pathology in the brain should facilitate the design of effective therapeutic strategies.

A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins

“…80 This may be important in autism as neurons are notably sensitive to complement and specifically C1q mediated cell death. 81 Fibronectin 1. Fibronectin proteins are also involved in the classical pathway and appear to be increased in serum of children with autism.…”

“…81,85 Most of the complement proteins found in blood are also expressed in the brain, mainly by microglia and to a lesser extent by stressed or damaged astrocytes and neurons. 81,86,87 C1q, C3, C4, C5, C6, C9, CR1, C1qRp, CR3, CR4, Factor H and others have been shown to be upregulated in brain in humans and experimental animals with infection, ischemia and stroke, Alzheimer's disease, prion disease, Huntington's chorea and many other CNS diseases. 81,85,86 C1q-deficient mice have less injury following cerebral ischemia and have less neuropathology in transgenic mouse models of Alzheimer's disease.…”

“…81,86,87 C1q, C3, C4, C5, C6, C9, CR1, C1qRp, CR3, CR4, Factor H and others have been shown to be upregulated in brain in humans and experimental animals with infection, ischemia and stroke, Alzheimer's disease, prion disease, Huntington's chorea and many other CNS diseases. 81,85,86 C1q-deficient mice have less injury following cerebral ischemia and have less neuropathology in transgenic mouse models of Alzheimer's disease. 88,89 Factor H is found in brain and may contribute to intracerebral complement system.…”

Soluble membrane attack complex is diagnostic for intraventricular shunt infection in children

“…Interestingly, while 33% of uninfected patients with symptomatic hydrocephalus had undetectable sMAC levels, the remaining patients had, on average, low sMAC levels (44.6 ± 7.4 ng/ml), suggesting a previously undescribed relationship between ventricular stretch and complement activation. Under the inflammatory conditions of a bacterial infection, local complement production by glial cells (ependymal cells, astrocytes, and microglia) and neurons may contribute substantially to intrathecal complement levels (14,(60)(61)(62). Furthermore, regional blood brain barrier disruption due to inflammation allows blood-derived complement to reach the ventricles.…”

In vitro blood brain barrier models as a screening tool for colloidal drug delivery systems and other nanosystems

“…These include a lack of fenestration, a paucity of pinocytic vesicles, a greater number of mitochondria, expression of specific transport and efflux systems, and the presence of complex tight-junctions in addition to the cell-cell adherens junctions that are responsible for the specific 'tightness' of the BCECs (Persidsky et al, 2006). Most of these properties are partly induced and maintained by the close association with astrocyte foot processes, which release environmental factors and cover close to 99% of the abluminal surface area of the capillary endothelium (Francis et al, 2003;Pardridge, 2005) (Figure 2). Tight junctions are composed of transmembrane proteins (occludin, claudins, and junction-associated membrane proteins), which are the main contributors that interact together to seal the paracellular pathway, as well as several cytoplasmic accessory proteins (zonula occludens (ZO) 1, 2, and cingulin) linked to the actin cytoskeleton to allow permeability modulation in response to stimuli (Hawkins and Davis, 2005).…”