Expression of innate immune complement regulators on brain epithelial cells during human bacterial meningitis

Canova, Cécile; Neal, J. W.; Gasque, Philippe

doi:10.1186/1742-2094-3-22

Cited by 31 publications

(16 citation statements)

References 37 publications

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“…Gasque and colleagues reported CR1 localization in astrocytes in human brains from normal or multiple sclerosis patients as well as in human primary astrocyte cell cultures or cell lines [ 54 ]. However, others have reported CR1 mRNA expression in phagocytic Kolmer cells of the choroid plexus (by in situ hybridization) [ 55 ], anti-CR1 reactivity on brain Kolmer and ependymal cells though only during bacterial meningitis [ 56 ], and anti-CR1 staining of microglia and neurons [ 57 , 58 ], none of which we were able to replicate in our normal, MCI or AD brains or in human brain derived microglial cultures. The differences in results seen among the studies could be due to differences in Ab reactivity or levels of detection.…”

Section: Discussionmentioning

confidence: 60%

Analysis of the Putative Role of CR1 in Alzheimer’s Disease: Genetic Association, Expression and Function

et al. 2016

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Chronic activation of the complement system and induced inflammation are associated with neuropathology in Alzheimer’s disease (AD). Recent large genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the C3b/C4b receptor (CR1 or CD35) that are associated with late onset AD. Here, anti-CR1 antibodies (Abs) directed against different epitopes of the receptor, were used to localize CR1 in brain, and relative binding affinities of the CR1 ligands, C1q and C3b, were assessed by ELISA. Most Abs tested stained red blood cells in blood vessels but showed no staining in brain parenchyma. However, two monoclonal anti-CR1 Abs labeled astrocytes in all of the cases tested, and this reactivity was preabsorbed by purified recombinant human CR1. Human brain-derived astrocyte cultures were also reactive with both mAbs. The amount of astrocyte staining varied among the samples, but no consistent difference was conferred by diagnosis or the GWAS-identified SNPs rs4844609 or rs6656401. Plasma levels of soluble CR1 did not correlate with diagnosis but a slight increase was observed with rs4844609 and rs6656401 SNP. There was also a modest but statistically significant increase in relative binding activity of C1q to CR1 with the rs4844609 SNP compared to CR1 without the SNP, and of C3b to CR1 in the CR1 genotypes containing the rs6656401 SNP (also associated with the larger isoform of CR1) regardless of clinical diagnosis. These results suggest that it is unlikely that astrocyte CR1 expression levels or C1q or C3b binding activity are the cause of the GWAS identified association of CR1 variants with AD. Further careful functional studies are needed to determine if the variant-dictated number of CR1 expressed on red blood cells contributes to the role of this receptor in the progression of AD, or if another mechanism is involved.

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Section: Discussionmentioning

confidence: 60%

Analysis of the Putative Role of CR1 in Alzheimer’s Disease: Genetic Association, Expression and Function

et al. 2016

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“…However, initial studies suggest that primary human pericytes in vitro produce C1q (Verbeek et al , 1999) and that cultured endothelial cells from human brain microvessels produce soluble regulators fH and C1-inh and components of both the classical (C4), and the alternative (fB) complement pathway (Vastag et al , 1998). Ependymal cells, ciliated epithelial cells that line the lumen of the brain ventricular system, express Cregs CD59 and at a low level CD55, but no CD46 or CD35, however in inflammatory conditions (meningitis) CD46 and CD35 are highly expressed on epithelial cells of the ependymal lining, as well as in the choroid plexus (Canova et al , 2006). To what extent these cell types contribute to the levels of C factors in the brain parenchyma and of the CSF is unknown.…”

Section: Local Synthesis Of Complement and Complement Regulators Imentioning

confidence: 99%

Complement in the brain

Veerhuis

Nielsen

Tenner

2011

Molecular Immunology

356

333

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The brain is considered to be an immune privileged site, because the blood-brain barrier limits entry of blood borne cells and proteins into the central nervous system (CNS). As a result, the detection and clearance of invading microorganisms and senescent cells as well as surplus neurotransmitters, aged and glycated proteins, in order to maintain a healthy environment for neuronal and glial cells, is largely confined to the innate immune system. In recent years it has become clear that many factors of innate immunity are expressed throughout the brain. Neuronal and glial cells express Toll like receptors as well as complement receptors, and virtually all complement components can be locally produced in the brain, often in response to injury or developmental cues. However, as inflammatory reactions could interfere with proper functioning of the brain, tight and fine tuned regulatory mechanisms are warranted. In age related diseases, such as Alzheimer’s disease (AD), accumulating amyloid proteins elicit complement activation and a local, chronic inflammatory response that leads to attraction and activation of glial cells that, under such activation conditions, can produce neurotoxic substances, including pro-inflammatory cytokines and oxygen radicals. This process may be exacerbated by a disturbed balance between complement activators and complement regulatory proteins such as occurs in AD, as the local synthesis of these proteins is differentially regulated by pro-inflammatory cytokines. Much knowledge about the role of complement in neurodegenerative diseases has been derived from animal studies with transgenic overexpressing or knockout mice for specific complement factors or receptors. These studies have provided insight into the potential therapeutic use of complement regulators and complement receptor antagonists in chronic neurodegenerative diseases as well as in acute conditions, such as stroke. Interestingly, recent animal studies have also indicated that complement activation products are involved in brain development and synapse formation. Not only are these findings important for the understanding of how brain development and neural network formation is organized, it may also give insights into the role of complement in processes of neurodegeneration and neuroprotection in the injured or aged and diseased adult central nervous system, and thus aid in identifying novel and specific targets for therapeutic intervention.

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“…Expression of the complement regulatory proteins is decreased in a model of multiple sclerosis (57), and appears to be increased in the brains of patients with Huntington’s disease (58). Bacterial meningitis is associated with increased expression of CD55 and CD59 (59). On the other hand, CD59 expression was decreased in the brains of two patients with diabetic ketoacidosis who died of cerebral edema (60).…”

Section: Altered Complement Regulatory Proteins Expression By Viable mentioning

confidence: 99%

Dynamic control of the complement system by modulated expression of regulatory proteins

Thurman

Renner

2011

Laboratory Investigation

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The complement system serves many biologic functions, including the eradication of invasive pathogens and the removal of damaged cells and immune-complexes. Uncontrolled complement activation causes injury to host cells, however, so adequate regulation of the system is essential. Control of the complement system is maintained by a group of cell surface and circulating proteins referred to as complement regulatory proteins. The expression of the cell surface complement regulatory proteins varies from tissue to tissue. Furthermore, specific cell types can up-regulate or down-regulate the expression of these proteins in response to a variety of signals or insults. Altered regulation of the complement regulatory proteins can have important effects on local complement activation. In some circumstances this can be beneficial, such as in the setting of certain infections. In other circumstances, however, this can be a cause of complement-mediated injury of the tissue. A full understanding of the mechanisms by which the complement system is modulated at the local level can have important implications for how we diagnose and treat a wide range of inflammatory diseases.

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Expression of innate immune complement regulators on brain epithelial cells during human bacterial meningitis

Cited by 31 publications

References 37 publications

Analysis of the Putative Role of CR1 in Alzheimer’s Disease: Genetic Association, Expression and Function

Analysis of the Putative Role of CR1 in Alzheimer’s Disease: Genetic Association, Expression and Function

Complement in the brain

Dynamic control of the complement system by modulated expression of regulatory proteins

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