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  1. Article ; Online: Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia.

    Zelek, Wioleta M / Bevan, Ryan J / Morgan, Bryan Paul

    Brain, behavior, and immunity

    2024  Volume 118, Page(s) 355–363

    Abstract: Complement is dysregulated in the brain in Alzheimer's Disease and in mouse models of Alzheimer's disease. Each of the complement derived effectors, opsonins, anaphylatoxins and membrane attack complex (MAC), have been implicated as drivers of disease ... ...

    Abstract Complement is dysregulated in the brain in Alzheimer's Disease and in mouse models of Alzheimer's disease. Each of the complement derived effectors, opsonins, anaphylatoxins and membrane attack complex (MAC), have been implicated as drivers of disease but their relative contributions remain unclarified. Here we have focussed on the MAC, a lytic and pro-inflammatory effector, in the App
    MeSH term(s) Mice ; Animals ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Cognitive Dysfunction/metabolism ; Mice, Transgenic ; Plaque, Amyloid/metabolism ; Brain/metabolism ; Cognition/physiology ; Complement Activation ; Disease Models, Animal
    Chemical Substances Amyloid beta-Peptides ; Amyloid beta-Protein Precursor
    Language English
    Publishing date 2024-03-12
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 639219-2
    ISSN 1090-2139 ; 0889-1591
    ISSN (online) 1090-2139
    ISSN 0889-1591
    DOI 10.1016/j.bbi.2024.03.017
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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: The role of complement in neurological and neuropsychiatric diseases.

    Morgan, Bryan Paul

    Expert review of clinical immunology

    2015  Volume 11, Issue 10, Page(s) 1109–1119

    Abstract: The complement system is a major component of innate immunity and a potent driver of inflammation. It has key roles in host defense against pathogens but can also contribute to pathology by driving inflammation and cell damage in diverse diseases. ... ...

    Abstract The complement system is a major component of innate immunity and a potent driver of inflammation. It has key roles in host defense against pathogens but can also contribute to pathology by driving inflammation and cell damage in diverse diseases. Complement has emerged as an important factor in the pathogenesis of numerous diseases of the CNS and PNS, including infectious, autoimmune and degenerative disorders, and is increasingly implicated in neuropsychiatric disease. Establishing the roles and relevance of complement in disease pathogenesis has become ever more important in recent years as new drugs targeting the complement system have reached the clinic, and the potential for using complement analytes as disease biomarkers has been recognized. In this brief review, the author summarizes the evidence implicating complement in these diseases and outlines ways in which this new understanding can be used to aid diagnosis and improve outcome.
    MeSH term(s) Animals ; Central Nervous System ; Complement System Proteins/physiology ; Humans ; Immunity, Innate ; Inflammation ; Nervous System Diseases/immunology ; Peripheral Nervous System
    Chemical Substances Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2015
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2274260-8
    ISSN 1744-8409 ; 1744-666X
    ISSN (online) 1744-8409
    ISSN 1744-666X
    DOI 10.1586/1744666X.2015.1074039
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  3. Article ; Online: Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System.

    Carpanini, Sarah M / Torvell, Megan / Morgan, Bryan Paul

    Frontiers in immunology

    2019  Volume 10, Page(s) 362

    Abstract: The complement system plays critical roles in development, homeostasis, and regeneration in the central nervous system (CNS) throughout life; however, complement dysregulation in the CNS can lead to damage and disease. Complement proteins, regulators, ... ...

    Abstract The complement system plays critical roles in development, homeostasis, and regeneration in the central nervous system (CNS) throughout life; however, complement dysregulation in the CNS can lead to damage and disease. Complement proteins, regulators, and receptors are widely expressed throughout the CNS and, in many cases, are upregulated in disease. Genetic and epidemiological studies, cerebrospinal fluid (CSF) and plasma biomarker measurements and pathological analysis of post-mortem tissues have all implicated complement in multiple CNS diseases including multiple sclerosis (MS), neuromyelitis optica (NMO), neurotrauma, stroke, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Given this body of evidence implicating complement in diverse brain diseases, manipulating complement in the brain is an attractive prospect; however, the blood-brain barrier (BBB), critical to protect the brain from potentially harmful agents in the circulation, is also impermeable to current complement-targeting therapeutics, making drug design much more challenging. For example, antibody therapeutics administered systemically are essentially excluded from the brain. Recent protocols have utilized "Trojan horse" techniques to transport therapeutics across the BBB or used osmotic shock or ultrasound to temporarily disrupt the BBB. Most research to date exploring the impact of complement inhibition on CNS diseases has been in animal models, and some of these studies have generated convincing data; for example, in models of MS, NMO, and stroke. There have been a few recent clinical trials of available anti-complement drugs in CNS diseases associated with BBB impairment, for example the use of the anti-C5 monoclonal antibody (mAb) eculizumab in NMO, but for most CNS diseases there have been no human trials of anti-complement therapies. Here we will review the evidence implicating complement in diverse CNS disorders, from acute, such as traumatic brain or spine injury, to chronic, including demyelinating, neuroinflammatory, and neurodegenerative diseases. We will discuss the particular problems of drug access into the CNS and explore ways in which anti-complement therapies might be tailored for CNS disease.
    MeSH term(s) Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; Blood-Brain Barrier/immunology ; Blood-Brain Barrier/pathology ; Complement Activation/drug effects ; Complement C5/antagonists & inhibitors ; Complement C5/immunology ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/immunology ; Neurodegenerative Diseases/pathology
    Chemical Substances Antibodies, Monoclonal ; Complement C5
    Language English
    Publishing date 2019-03-04
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2019.00362
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Characterizing the original anti-C5 function-blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5.

    Zelek, Wioleta M / Menzies, Georgina E / Brancale, Andrea / Stockinger, Brigitta / Morgan, Bryan Paul

    Immunology

    2020  Volume 161, Issue 2, Page(s) 103–113

    Abstract: The implication of complement in multiple diseases over the last 20 years has fuelled interest in developing anti-complement drugs. To date, the focus has been on C5; blocking cleavage of C5 prevents formation of two pro-inflammatory activities, C5a ... ...

    Abstract The implication of complement in multiple diseases over the last 20 years has fuelled interest in developing anti-complement drugs. To date, the focus has been on C5; blocking cleavage of C5 prevents formation of two pro-inflammatory activities, C5a anaphylatoxin and membrane attack complex. The concept of C5 blockade to inhibit inflammation dates back 30 years to the description of BB5.1, an anti-C5 blocking monoclonal antibody raised in C5-deficient mice. This antibody proved an invaluable tool to demonstrate complement involvement in mouse disease models and catalysed enthusiasm for anti-complement drug development, culminating in the anti-human C5 monoclonal antibody eculizumab, the most successful anti-complement drug to date, already in clinical use for several rare diseases. Despite its key role in providing proof-of-concept for C5 blockade, the mechanism of BB5.1 inhibition remains poorly understood. Here, we characterized BB5.1 cross-species inhibition, C5 binding affinity and chain specificity. BB5.1 efficiently inhibited C5 in mouse serum but not in human or other rodent sera; it prevented C5 cleavage and C5a generation. BB5.1 bound the C5 α-chain with high affinity and slow off-rate. BB5.1 complementarity-determining regions were obtained and docking algorithms were used to predict the likely binding interface on mouse C5.
    MeSH term(s) Animals ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/metabolism ; Antibodies, Monoclonal, Humanized/genetics ; Antibodies, Monoclonal, Humanized/therapeutic use ; Complement C5/genetics ; Complement C5/metabolism ; Computer Simulation ; Cross Reactions ; Guinea Pigs ; Humans ; Hybridomas ; Inflammation/therapy ; Mice ; Mice, Knockout ; Molecular Docking Simulation ; Protein Binding ; Proteolysis ; Rabbits ; Species Specificity
    Chemical Substances Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Complement C5 ; eculizumab (A3ULP0F556)
    Language English
    Publishing date 2020-07-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80124-0
    ISSN 1365-2567 ; 0019-2805 ; 0953-4954
    ISSN (online) 1365-2567
    ISSN 0019-2805 ; 0953-4954
    DOI 10.1111/imm.13228
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  5. Article ; Online: Alzheimer's disease-associated complement gene variants influence plasma complement protein levels.

    Veteleanu, Aurora / Stevenson-Hoare, Joshua / Keat, Samuel / Daskoulidou, Nikoleta / Zetterberg, Henrik / Heslegrave, Amanda / Escott-Price, Valentina / Williams, Julie / Sims, Rebecca / Zelek, Wioleta M / Carpanini, Sarah M / Morgan, Bryan Paul

    Journal of neuroinflammation

    2023  Volume 20, Issue 1, Page(s) 169

    Abstract: Background: Alzheimer's disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin (CLU) and complement receptor 1 (CR1), ... ...

    Abstract Background: Alzheimer's disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin (CLU) and complement receptor 1 (CR1), recognised as key players in AD pathology, and complement proteins have been proposed as biomarkers.
    Main body: To address whether changes in plasma complement protein levels in AD relate to AD-associated complement gene variants we first measured relevant plasma complement proteins (clusterin, C1q, C1s, CR1, factor H) in a large cohort comprising early onset AD (EOAD; n = 912), late onset AD (LOAD; n = 492) and control (n = 504) donors. Clusterin and C1q were significantly increased (p < 0.001) and sCR1 and factor H reduced (p < 0.01) in AD plasma versus controls. ROC analyses were performed to assess utility of the measured complement biomarkers, alone or in combination with amyloid beta, in predicting AD. C1q was the most predictive single complement biomarker (AUC 0.655 LOAD, 0.601 EOAD); combining C1q with other complement or neurodegeneration makers through stepAIC-informed models improved predictive values slightly. Effects of GWS SNPs (rs6656401, rs6691117 in CR1; rs11136000, rs9331888 in CLU; rs3919533 in C1S) on protein concentrations were assessed by comparing protein levels in carriers of the minor vs major allele. To identify new associations between SNPs and changes in plasma protein levels, we performed a GWAS combining genotyping data in the cohort with complement protein levels as endophenotype. SNPs in CR1 (rs6656401), C1S (rs3919533) and CFH (rs6664877) reached significance and influenced plasma levels of the corresponding protein, whereas SNPs in CLU did not influence clusterin levels.
    Conclusion: Complement dysregulation is evident in AD and may contribute to pathology. AD-associated SNPs in CR1, C1S and CFH impact plasma levels of the encoded proteins, suggesting a mechanism for impact on disease risk.
    MeSH term(s) Humans ; Complement Factor H/genetics ; Alzheimer Disease/genetics ; Clusterin/genetics ; Amyloid beta-Peptides ; Complement C1q ; Genome-Wide Association Study ; Complement System Proteins/genetics
    Chemical Substances Complement Factor H (80295-65-4) ; Clusterin ; Amyloid beta-Peptides ; Complement C1q (80295-33-6) ; Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2023-07-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 2156455-3
    ISSN 1742-2094 ; 1742-2094
    ISSN (online) 1742-2094
    ISSN 1742-2094
    DOI 10.1186/s12974-023-02850-6
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  6. Article ; Online: Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer's disease.

    Stevenson-Hoare, Joshua / Heslegrave, Amanda / Leonenko, Ganna / Fathalla, Dina / Bellou, Eftychia / Luckcuck, Lauren / Marshall, Rachel / Sims, Rebecca / Morgan, Bryan Paul / Hardy, John / de Strooper, Bart / Williams, Julie / Zetterberg, Henrik / Escott-Price, Valentina

    Brain : a journal of neurology

    2022  Volume 146, Issue 2, Page(s) 690–699

    Abstract: Plasma biomarkers for Alzheimer's disease-related pathologies have undergone rapid developments during the past few years, and there are now well-validated blood tests for amyloid and tau pathology, as well as neurodegeneration and astrocytic activation. ...

    Abstract Plasma biomarkers for Alzheimer's disease-related pathologies have undergone rapid developments during the past few years, and there are now well-validated blood tests for amyloid and tau pathology, as well as neurodegeneration and astrocytic activation. To define Alzheimer's disease with biomarkers rather than clinical assessment, we assessed prediction of research-diagnosed disease status using these biomarkers and tested genetic variants associated with the biomarkers that may reflect more accurately the risk of biochemically defined Alzheimer's disease instead of the risk of dementia. In a cohort of Alzheimer's disease cases [n = 1439, mean age 68 years (standard deviation = 8.2)] and screened controls [n = 508, mean age 82 years (standard deviation = 6.8)], we measured plasma concentrations of the 40 and 42 amino acid-long amyloid-β (Aβ) fragments (Aβ40 and Aβ42, respectively), tau phosphorylated at amino acid 181 (P-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) using state-of-the-art Single molecule array (Simoa) technology. We tested the relationships between the biomarkers and Alzheimer's disease genetic risk, age at onset and disease duration. We also conducted a genome-wide association study for association of disease risk genes with these biomarkers. The prediction accuracy of Alzheimer's disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached area under receiver operating characteristic curve (AUC) = 0.81, with the most significant contributors being ε4, Aβ40 or Aβ42, GFAP and NfL. All biomarkers were significantly associated with age in cases and controls (P < 4.3 × 10-5). Concentrations of the Aβ-related biomarkers in plasma were significantly lower in cases compared with controls, whereas other biomarker levels were significantly higher in cases. In the case-control genome-wide analyses, APOE-ε4 was associated with all biomarkers (P = 0.011-4.78 × 10-8), except NfL. No novel genome-wide significant single nucleotide polymorphisms were found in the case-control design; however, in a case-only analysis, we found two independent genome-wide significant associations between the Aβ42/Aβ40 ratio and WWOX and COPG2 genes. Disease prediction modelling by the combination of all biomarkers indicates that the variance attributed to P-tau181 is mostly captured by APOE-ε4, whereas Aβ40, Aβ42, GFAP and NfL biomarkers explain additional variation over and above APOE. We identified novel plausible genome wide-significant genes associated with Aβ42/Aβ40 ratio in a sample which is 50 times smaller than current genome-wide association studies in Alzheimer's disease.
    MeSH term(s) Humans ; Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis ; Alzheimer Disease/genetics ; Genome-Wide Association Study ; Amyloid beta-Peptides ; Biomarkers ; Amino Acids/genetics ; Apolipoproteins E/genetics ; tau Proteins/genetics ; Peptide Fragments
    Chemical Substances Amyloid beta-Peptides ; Biomarkers ; Amino Acids ; Apolipoproteins E ; tau Proteins ; Peptide Fragments
    Language English
    Publishing date 2022-04-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awac128
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  7. Article ; Online: Dendritic spine loss in epileptogenic Type II focal cortical dysplasia: Role of enhanced classical complement pathway activation.

    Rossini, Laura / De Santis, Dalia / Cecchini, Erica / Cagnoli, Cinzia / Maderna, Emanuela / Cartelli, Daniele / Morgan, Bryan Paul / Torvell, Megan / Spreafico, Roberto / di Giacomo, Roberta / Tassi, Laura / de Curtis, Marco / Garbelli, Rita

    Brain pathology (Zurich, Switzerland)

    2022  Volume 33, Issue 3, Page(s) e13141

    Abstract: Dendritic spines are the postsynaptic sites for most excitatory glutamatergic synapses. We previously demonstrated a severe spine loss and synaptic reorganization in human neocortices presenting Type II focal cortical dysplasia (FCD), a developmental ... ...

    Abstract Dendritic spines are the postsynaptic sites for most excitatory glutamatergic synapses. We previously demonstrated a severe spine loss and synaptic reorganization in human neocortices presenting Type II focal cortical dysplasia (FCD), a developmental malformation and frequent cause of drug-resistant focal epilepsy. We extend the findings, investigating the potential role of complement components C1q and C3 in synaptic pruning imbalance. Data from Type II FCD were compared with those obtained in focal epilepsies with different etiologies. Neocortical tissues were collected from 20 subjects, mainly adults with a mean age at surgery of 31 years, admitted to epilepsy surgery with a neuropathological diagnosis of: cryptogenic, temporal lobe epilepsy with hippocampal sclerosis, and Type IIa/b FCD. Dendritic spine density quantitation, evaluated in a previous paper using Golgi impregnation, was available in a subgroup. Immunohistochemistry, in situ hybridization, electron microscopy, and organotypic cultures were utilized to study complement/microglial activation patterns. FCD Type II samples presenting dendritic spine loss were characterized by an activation of the classical complement pathway and microglial reactivity. In the same samples, a close relationship between microglial cells and dendritic segments/synapses was found. These features were consistently observed in Type IIb FCD and in 1 of 3 Type IIa cases. In other patient groups and in perilesional areas outside the dysplasia, not presenting spine loss, these features were not observed. In vitro treatment with complement proteins of organotypic slices of cortical tissue with no sign of FCD induced a reduction in dendritic spine density. These data suggest that dysregulation of the complement system plays a role in microglia-mediated spine loss. This mechanism, known to be involved in the removal of redundant synapses during development, is likely reactivated in Type II FCD, particularly in Type IIb; local treatment with anticomplement drugs could in principle modify the course of disease in these patients.
    MeSH term(s) Adult ; Humans ; Dendritic Spines/pathology ; Complement Pathway, Classical ; Focal Cortical Dysplasia ; Malformations of Cortical Development/pathology ; Epilepsy/pathology ; Drug Resistant Epilepsy/pathology
    Language English
    Publishing date 2022-12-23
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1051484-3
    ISSN 1750-3639 ; 1015-6305
    ISSN (online) 1750-3639
    ISSN 1015-6305
    DOI 10.1111/bpa.13141
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  8. Article ; Online: Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

    Baillie, Kirsten / Davies, Helen E / Keat, Samuel B K / Ladell, Kristin / Miners, Kelly L / Jones, Samantha A / Mellou, Ermioni / Toonen, Erik J M / Price, David A / Morgan, Bryan Paul / Zelek, Wioleta M

    medRxiv

    Abstract: Background: Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless ... ...

    Abstract Background: Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID. Methods: We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/gender/infection/vaccine-matched patients with long COVID. Findings: Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785. Conclusions: These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID. Funding: This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute.
    Keywords covid19
    Language English
    Publishing date 2023-10-28
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2023.10.26.23297597
    Database COVID19

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  9. Article ; Online: CD93 regulates central nervous system inflammation in two mouse models of autoimmune encephalomyelitis.

    Griffiths, Mark R / Botto, Marina / Morgan, Bryan Paul / Neal, James W / Gasque, Philippe

    Immunology

    2018  Volume 155, Issue 3, Page(s) 346–355

    Abstract: Microglia and non-professional immune cells (endothelial cells, neurons) participate in the recognition and removal of pathogens and tissue debris in the injured central nervous system through major pro-inflammatory processes. However, the mechanisms ... ...

    Abstract Microglia and non-professional immune cells (endothelial cells, neurons) participate in the recognition and removal of pathogens and tissue debris in the injured central nervous system through major pro-inflammatory processes. However, the mechanisms involved in regulating these responses remain ill-characterized. We herein show that CD93, also known as complement C1qRp/AA4 stem cell marker, has an important role in the regulation of inflammatory processes. The role of CD93 was evaluated in two models of neuroinflammation. We used the MOG-experimental autoimmune encephalomyelitis (EAE) model and the antibody-dependent EAE (ADEAE), which were induced in wild-type and CD93 knockout mice. We found that CD93 was highly expressed by neurons, endothelial cells and microglia (ramified >> amoeboid). Astrocytes and oligodendrocytes did not to express CD93. We further observed that CD93-deficient (CD93
    MeSH term(s) Animals ; Encephalomyelitis, Autoimmune, Experimental/genetics ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/pathology ; Gene Expression Regulation/immunology ; Inflammation/genetics ; Inflammation/immunology ; Inflammation/pathology ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/immunology ; Mice ; Mice, Knockout ; Microglia/immunology ; Microglia/pathology ; Organ Specificity/genetics ; Organ Specificity/immunology ; Receptors, Complement/genetics ; Receptors, Complement/immunology ; Spinal Cord/immunology ; Spinal Cord/pathology
    Chemical Substances Membrane Glycoproteins ; Receptors, Complement ; complement 1q receptor
    Language English
    Publishing date 2018-07-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80124-0
    ISSN 1365-2567 ; 0019-2805 ; 0953-4954
    ISSN (online) 1365-2567
    ISSN 0019-2805 ; 0953-4954
    DOI 10.1111/imm.12974
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  10. Article ; Online: Terminal complexes of the complement system: new structural insights and their relevance to function.

    Morgan, Bryan Paul / Walters, David / Serna, Marina / Bubeck, Doryen

    Immunological reviews

    2016  Volume 274, Issue 1, Page(s) 141–151

    Abstract: Complement is a key component of innate immunity in health and a powerful driver of inflammation and tissue injury in disease. The biological and pathological effects of complement activation are mediated by activation products. These come in two flavors: ...

    Abstract Complement is a key component of innate immunity in health and a powerful driver of inflammation and tissue injury in disease. The biological and pathological effects of complement activation are mediated by activation products. These come in two flavors: (i) proteolytic fragments of complement proteins (C3, C4, C5) generated during activation that bind specific receptors on target cells to mediate effects; (ii) the multimolecular membrane attack complex generated from the five terminal complement proteins that directly binds to and penetrates target cell membranes. Several recent publications have described structural insights that have changed perceptions of the nature of this membrane attack complex. This review will describe these recent advances in understanding of the structure of the membrane attack complex and its by-product the fluid-phase terminal complement complex and relate these new structural insights to functional consequences and cell responses to complement membrane attack.
    MeSH term(s) Animals ; Cell Membrane/metabolism ; Complement Activation ; Complement Membrane Attack Complex/metabolism ; Complement System Proteins/immunology ; Humans ; Immunity, Innate ; Protein Conformation ; Structure-Activity Relationship
    Chemical Substances Complement Membrane Attack Complex ; Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2016-10-25
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 391796-4
    ISSN 1600-065X ; 0105-2896
    ISSN (online) 1600-065X
    ISSN 0105-2896
    DOI 10.1111/imr.12461
    Database MEDical Literature Analysis and Retrieval System OnLINE

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