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European Journal of Immunology Apr 2022Properdin, the only known positive regulator of the complement system, stabilizes the C3 convertase, thereby increasing its half-life. In contrast to most other...
Properdin, the only known positive regulator of the complement system, stabilizes the C3 convertase, thereby increasing its half-life. In contrast to most other complement factors, properdin is mainly produced extrahepatically by myeloid cells. Recent data suggest a role for properdin as a pattern recognition molecule. Here, we confirmed previous findings of properdin binding to different necrotic cells including Jurkat T cells. Binding can occur independent of C3, as demonstrated by HAP-1 C3 KO cells, excluding a role for endogenous C3. In view of the cellular source of properdin, interaction with myeloid cells was examined. Properdin bound to the surface of viable monocyte-derived pro- and anti-inflammatory macrophages, but not to DCs. Binding was demonstrated for purified properdin as well as fractionated P2, P3, and P4 properdin oligomers. Binding contributed to local complement activation as determined by C3 and C5b-9 deposition on the cell surfaces and seems a prerequisite for alternative pathway activation. Interaction of properdin with cell surfaces could be inhibited with the tick protein Salp20 and by different polysaccharides, depending on sulfation and chain length. These data identify properdin as a factor interacting with different cell surfaces, being either dead or alive, contributing to the local stimulation of complement activation.
Topics: Complement Activation; Complement C3-C5 Convertases; Complement Membrane Attack Complex; Complement Pathway, Alternative; Humans; Necrosis; Properdin
PubMed: 35092629
DOI: 10.1002/eji.202149259 -
Protein & Cell Jul 2012The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors,... (Review)
Review
The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.
Topics: Animals; Complement Activation; Complement System Proteins; HLA Antigens; Humans; Immunity, Innate; Immunologic Deficiency Syndromes; Lectins; Multigene Family; Receptors, Complement
PubMed: 22773339
DOI: 10.1007/s13238-012-2924-6 -
Journal of Innate Immunity 2014
Topics: Animals; Apoptosis; Complement Factor H; Complement System Proteins; Humans; Immunity, Humoral; Immunity, Innate; Macular Degeneration; Neutrophils; Phagocytosis; Polymorphism, Genetic; Properdin
PubMed: 24853386
DOI: 10.1159/000363198 -
Frontiers in Immunology 2023Hepatic ischemia/reperfusion injury (IRI) often causes serious complications in liver surgeries, including transplantation. Complement activation seems to be involved in...
Hepatic ischemia/reperfusion injury (IRI) often causes serious complications in liver surgeries, including transplantation. Complement activation seems to be involved in hepatic IRI; however, no complement-targeted intervention has been clinically applied. We investigated the therapeutic potential of Properdin-targeted complement regulation in hepatic IRI. Male wild-type mice (B10D2/nSn) were exposed to 90-minute partial hepatic IRI to the left and median lobes with either monoclonal anti-Properdin-antibody (Ab) or control-immunoglobulin (IgG) administration. Since the complement system is closely involved in liver regeneration, the influence of anti-Properdin-Ab on liver regeneration was also evaluated in a mouse model of 70% partial hepatectomy. Anti-Properdin-Ab significantly reduced serum transaminases and histopathological damages at 2 and 6 hours after reperfusion (0.001, respectively). These improvements at 2 hours was accompanied by significant reductions in CD41+ platelet aggregation ( =0.010) and ssDNA+ cells (0.001), indicating significant amelioration in hepatic microcirculation and apoptosis, respectively. Characteristically, F4/80+ cells representing macrophages, mainly Kupffer cells, were maintained by anti-Properdin-Ab (0.001). Western blot showed decreased phosphorylation of only Erk1/2 among MAPKs ( =0.004). After 6 hours of reperfusion, anti-Properdin-Ab significantly attenuated the release of HMGB-1, which provokes the release of proinflammatory cytokines/chemokines ( =0.002). Infiltration of CD11b+ and Ly6-G+ cells, representing infiltrating macrophages and neutrophils, respectively, were significantly alleviated by anti-Properdin-Ab (both 0.001). Notably, anti-Properdin-Ab did not affect remnant liver weight and BrdU+ cells at 48 hours after 70% partial hepatectomy ( =0.13 and 0.31, respectively). In conclusion, Properdin inhibition significantly ameliorates hepatic IRI without interfering with liver regeneration.
Topics: Male; Animals; Mice; Properdin; Liver Regeneration; Liver; Reperfusion Injury; Ischemia
PubMed: 37662914
DOI: 10.3389/fimmu.2023.1174243 -
ELife Jan 2021Properdin stabilizes convertases formed upon activation of the complement cascade within the immune system. The biological activity of properdin depends on the...
Properdin stabilizes convertases formed upon activation of the complement cascade within the immune system. The biological activity of properdin depends on the oligomerization state, but whether properdin oligomers are rigid and how their structure links to function remains unknown. We show by combining electron microscopy and solution scattering, that properdin oligomers adopt extended rigid and well-defined conformations which are well approximated by single models of apparent n-fold rotational symmetry with dimensions of 230-360 Å. Properdin monomers are pretzel-shaped molecules with limited flexibility. In solution, properdin dimers are curved molecules, whereas trimers and tetramers are close to being planar molecules. Structural analysis indicates that simultaneous binding through all binding sites to surface-linked convertases is unlikely for properdin trimer and tetramers. We show that multivalency alone is insufficient for full activity in a cell lysis assay. Hence, the observed rigid extended oligomer structure is an integral component of properdin function.
Topics: Binding Sites; HEK293 Cells; Humans; Molecular Conformation; Properdin
PubMed: 33480354
DOI: 10.7554/eLife.63356 -
International Journal of Molecular... Oct 2022Complement pathway proteins are reported to be increased in polycystic ovary syndrome (PCOS) and may be affected by obesity and insulin resistance. To investigate this,...
Complement pathway proteins are reported to be increased in polycystic ovary syndrome (PCOS) and may be affected by obesity and insulin resistance. To investigate this, a proteomic analysis of the complement system was undertaken, including inhibitory proteins. In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls). SOMALogic proteomic analysis was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5). The alternative pathway of the complement system was primarily overexpressed in PCOS, with increased C3 (p < 0.05), properdin and factor B (p < 0.01). In addition, inhibition of this pathway was also seen in PCOS, with an increase in CFHR5, factor H and factor I (p < 0.01). Downstream complement factors iC3b and C3d, associated with an enhanced B cell response, and C5a, associated with an inflammatory cytokine release, were increased (p < 0.01). Hyperandrogenemia correlated positively with properdin and iC3b, whilst insulin resistance (HOMA-IR) correlated with iC3b and factor H (p < 0.05) in PCOS. BMI correlated positively with C3d, factor B, factor D, factor I, CFHR5 and C5a (p < 0.05). This comprehensive evaluation of the complement system in PCOS revealed the upregulation of components of the complement system, which appears to be offset by the concurrent upregulation of its inhibitors, with these changes accounted for in part by BMI, hyperandrogenemia and insulin resistance.
Topics: Female; Humans; Properdin; Complement Factor H; Complement Factor B; Mannose-Binding Lectin; CD55 Antigens; Polycystic Ovary Syndrome; Complement Factor D; Insulin Resistance; Cohort Studies; Proteomics; Complement C1q; Complement C3b; Fibrinogen; Cytokines
PubMed: 36293087
DOI: 10.3390/ijms232012232 -
Medicina (Kaunas, Lithuania) Jan 2021The complement system orchestrates a multi-faceted immune response to the invading pathogen, . Macrophages engulf the mycobacterial bacilli through bacterial cell... (Review)
Review
The complement system orchestrates a multi-faceted immune response to the invading pathogen, . Macrophages engulf the mycobacterial bacilli through bacterial cell surface proteins or secrete proteins, which activate the complement pathway. The classical pathway is activated by C1q, which binds to antibody antigen complexes. While the alternative pathway is constitutively active and regulated by properdin, the direct interaction of properdin is capable of complement activation. The lectin-binding pathway is activated in response to bacterial cell surface carbohydrates such as mannose, fucose, and -acetyl--glucosamine. All three pathways contribute to mounting an immune response for the clearance of mycobacteria. However, the bacilli can reside, persist, and evade clearance by the immune system once inside the macrophages using a number of mechanisms. The immune system can compartmentalise the infection into a granulomatous structure, which contains heterogenous sub-populations of . The granuloma consists of many types of immune cells, which aim to clear and contain the infection whilst sacrificing the affected host tissue. The full extent of the involvement of the complement system during infection with is not fully understood. Therefore, we reviewed the available literature on and other mycobacterial literature to understand the contribution of the complement system during infection.
Topics: Complement System Proteins; Humans; Macrophages; Mycobacterium tuberculosis; Phagocytosis; Tuberculosis
PubMed: 33498555
DOI: 10.3390/medicina57020084 -
Frontiers in Immunology 2021The complement system is designed to recognise and eliminate invading pathogens activation of classical, alternative and lectin pathways. Human properdin stabilises the...
The complement system is designed to recognise and eliminate invading pathogens activation of classical, alternative and lectin pathways. Human properdin stabilises the alternative pathway C3 convertase, resulting in an amplification loop that leads to the formation of C5 convertase, thereby acting as a positive regulator of the alternative pathway. It has been noted that human properdin on its own can operate as a pattern recognition receptor and exert immune functions outside its involvement in complement activation. Properdin can bind directly to microbial targets DNA, sulfatides and glycosaminoglycans, apoptotic cells, nanoparticles, and well-known viral virulence factors. This study was aimed at investigating the complement-independent role of properdin against Influenza A virus infection. As one of the first immune cells to arrive at the site of IAV infection, we show here that IAV challenged neutrophils released properdin in a time-dependent manner. Properdin was found to directly interact with haemagglutinin, neuraminidase and matrix 1 protein Influenza A virus proteins in ELISA and western blot. Furthermore, modelling studies revealed that properdin could bind HA and NA of the H1N1 subtype with higher affinity compared to that of H3N2 due to the presence of an HA cleavage site in H1N1. In an infection assay using A549 cells, properdin suppressed viral replication in pH1N1 subtype while promoting replication of H3N2 subtype, as revealed by qPCR analysis of M1 transcripts. Properdin treatment triggered an anti-inflammatory response in H1N1-challenged A549 cells and a pro-inflammatory response in H3N2-infected cells, as evident from differential mRNA expression of TNF-α, NF-κB, IFN-α, IFN-β, IL-6, IL-12 and RANTES. Properdin treatment also reduced luciferase reporter activity in MDCK cells transduced with H1N1 pseudotyped lentiviral particles; however, it was increased in the case of pseudotyped H3N2 particles. Collectively, we conclude that infiltrating neutrophils at the site of IAV infection can release properdin, which then acts as an entry inhibitor for pandemic H1N1 subtype while suppressing viral replication and inducing an anti-inflammatory response. H3N2 subtype can escape this immune restriction due to altered haemagglutinin and neuraminindase, leading to enhanced viral entry, replication and pro-inflammatory response. Thus, depending on the subtype, properdin can either limit or aggravate IAV infection in the host.
Topics: Animals; Dogs; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza, Human; Madin Darby Canine Kidney Cells; Neutrophils; Properdin
PubMed: 34956182
DOI: 10.3389/fimmu.2021.747654 -
Journal of Innate Immunity 2014Neutrophils and complement are key members of innate immunity. The alternative pathway (AP) of complement consists of C3, factor B, factor D and properdin, which...
Neutrophils and complement are key members of innate immunity. The alternative pathway (AP) of complement consists of C3, factor B, factor D and properdin, which amplifies AP activation. AP has been implicated in many neutrophil-mediated diseases, such as anti-neutrophil cytoplasmic antibody-associated vasculitis. The exact mechanism by which the AP and neutrophils interact remains largely unstudied. We investigated the ability of the AP to interact with neutrophil components which can be exposed and released upon activation. Our studies focused on neutrophil enzymes, including myeloperoxidase (MPO), proteinase 3 (PR3), azurocidin, elastase, lysozyme and cathepsin G. All enzymes except for azurocidin were able to bind properdin. However, only MPO could induce C3 activation. MPO mediated AP complement activation in the presence of MgEGTA compared to the EDTA control. This activation resulted in C3 deposition and required properdin to occur. Furthermore, we could show that MPO binds properdin directly, which then serves as a focus for AP activation. In summary, properdin can directly interact with neutrophil components. MPO demonstrates the ability to activate the AP which is dependent on properdin. Finally, MPO is capable of inducing properdin-initiated C3 and C5b-9 deposition in vitro.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antimicrobial Cationic Peptides; Blood Proteins; Carrier Proteins; Cathepsin G; Complement C3; Complement Membrane Attack Complex; Complement Pathway, Alternative; Humans; Immunity, Innate; Muramidase; Myeloblastin; Neutrophils; Pancreatic Elastase; Peroxidase; Properdin; Protein Binding
PubMed: 24355864
DOI: 10.1159/000356980 -
Nature Communications Jan 2022Activation of the serum-resident complement system begins a cascade that leads to activation of membrane-resident complement receptors on immune cells, thus coordinating...
Activation of the serum-resident complement system begins a cascade that leads to activation of membrane-resident complement receptors on immune cells, thus coordinating serum and cellular immune responses. Whilst many molecules act to control inappropriate activation, Properdin is the only known positive regulator of the human complement system. By stabilising the alternative pathway C3 convertase it promotes complement self-amplification and persistent activation boosting the magnitude of the serum complement response by all triggers. In this work, we identify a family of tick-derived alternative pathway complement inhibitors, hereafter termed CirpA. Functional and structural characterisation reveals that members of the CirpA family directly bind to properdin, inhibiting its ability to promote complement activation, and leading to potent inhibition of the complement response in a species specific manner. We provide a full functional and structural characterisation of a properdin inhibitor, opening avenues for future therapeutic approaches.
Topics: Amino Acid Sequence; Animals; Arthropod Proteins; Complement Activation; Complement C3; Complement Inactivating Agents; Complement Pathway, Alternative; Humans; Kinetics; Properdin; Rhipicephalus; Sequence Alignment
PubMed: 35031611
DOI: 10.1038/s41467-021-27920-2