3,465 results on '"Complement receptor"'
Search Results
152. Complement activation links inflammation to dental tissue regeneration
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Madison Bergmann, Gilles Richard, Imad About, Thomas Giraud, Charlotte Jeanneau, Institut des Sciences du Mouvement Etienne Jules Marey (ISM), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Argumentation, Décision, Raisonnement, Incertitude et Apprentissage (IRIT-ADRIA), Institut de recherche en informatique de Toulouse (IRIT), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), Aix-Marseille University and CNRS, Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1), and Université Fédérale Toulouse Midi-Pyrénées
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pulp inflammation ,[SDV]Life Sciences [q-bio] ,Complement ,Inflammation ,Complement receptor ,Biology ,03 medical and health sciences ,[SPI]Engineering Sciences [physics] ,0302 clinical medicine ,Immune system ,stomatognathic system ,medicine ,Humans ,[INFO]Computer Science [cs] ,Complement Activation ,General Dentistry ,Dental Pulp ,ComputingMilieux_MISCELLANEOUS ,dental tissue regeneration ,Stem Cells ,Regeneration (biology) ,Mesenchymal stem cell ,Cell Differentiation ,030206 dentistry ,Fibroblasts ,Complement system ,Cell biology ,stomatognathic diseases ,Complement links inflammation to regeneration Pulp biology ,030220 oncology & carcinogenesis ,Pulp (tooth) ,Stem cell ,medicine.symptom ,stem cell recruitment ,nerve sprouting - Abstract
International audience; Objectives: Complement is an efficient plasma immune surveillance system. It initiates inflammation by inducing vascular modifications and attracting immune cells expressing Complement receptors. Investigating Complement receptors in non-immune cells pointed out Complement implication in the regeneration of tissue such as liver, skin or bone. This review will shed the light on its Complement implication in the initial steps of dental tissue regeneration. Materials and methods: Review of literature was conducted on Complement local expression and implication in oral tissue regeneration in vivo and in vitro. Results: Recent data reported expression of Complement receptors and soluble proteins in dental tissues. Cultured pulp fibroblasts secrete all Complement components. Complement C3b and MAC have been shown to control bacteria growth in the dental pulp while C3a and C5a are involved in the initial steps of pulp regeneration. Indeed, C3a induces pulp stem cell/fibroblast proliferation, and fibroblast recruitment, while C5a induces neurite growth, guides stem cell recruitment and odontoblastic differentiation. Similarly, cultured periodontal ligament cells produce C5a which induces bone marrow mesenchymal stem cell recruitment. Conclusions: Overall, this review highlights that local Complement synthesis in dental tissues plays a major role, not only in eliminating bacteria, but also in the initial steps of dental tissue regeneration, thus, providing a link between dental tissue inflammation and regeneration. Clinical relevance: Complement provides an explanation for understanding why inflammation preceeds regeneration. This may also provide a biological rational for understanding the reported success conservative management of mature permanent teeth with carious pulp exposure.
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- 2020
153. Influence of FcγRIIIb polymorphism on its ability to cooperate with FcγRIIa and CR3 in mediating the oxidative burst of human neutrophils.
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Urbaczek, Ana Carolina, Toller-Kawahisa, Juliana Escher, Fonseca, Luiz Marcos, Costa, Paulo Inácio, Faria, Carolina Maria Quinello Gomes, Azzolini, Ana Elisa Caleiro Seixas, Lucisano-Valim, Yara Maria, and Marzocchi-Machado, Cleni Mara
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MEMBRANE proteins , *GENETIC polymorphisms , *NEUTROPHILS , *ACTIVE oxygen in the body , *CELL receptors , *IMMUNE complexes , *CHEMILUMINESCENCE assay - Abstract
Considering that human neutrophil FcγRIIa and FcγRIIIb receptors interact synergistically with CR3 in triggering neutrophil functional responses, allelic polymorphisms in these receptors might influence such interactions. We assessed whether FcγRIIIb polymorphisms affect FcγR/CR cooperation in mediating the neutrophil oxidative burst (OB), in particular the FcγRIIIb/CR3 cooperation that occurs via lectin-saccharide-like interactions. The OB of human neutrophil antigen (HNA)-1a-, HNA-1b-, and HNA-1a/-1b-neutrophils stimulated with immune complexes, opsonized or not with serum complement, was measured by the luminol-enhanced chemiluminescence assay. Compared with HNA-1a-neutrophils, HNA-1b-neutrophils exhibited reduced FcγR-stimulated OB, but increased FcγR/CR-stimulated OB. It suggests that (i) FcγR and CR cooperate more effectively in HNA-1b-neutrophils, and (ii) the HNA-1b allotype influences the FcγRIIIb cooperation with FcγRIIa, but not with CR3. HNA-1a- and HNA-1b-neutrophils exhibited similar OB responses elicited via CR3 alone or via FcγR/CR-independent pathways. In addition, the level of FcγRIIIb, FcγRIIa, and CR3 expression did not differ significantly among the neutrophil groups studied. Together, these results demonstrate that the HNA-1b allotype influences the functional cooperation between FcγRIIIb and FcγRIIa, and suggest that the difference in the glycosylation pattern between HNA-1a and HNA-1b does not affect the FcγRIIIb cooperation with CR3. [ABSTRACT FROM AUTHOR]
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- 2014
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154. Murine complement receptor 1 is required for germinal center B cell maintenance but not initiation.
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Donius, Luke R., Weis, Janis J., and Weis, John H.
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COMPLEMENT receptors , *GERMINAL centers , *B cells , *IMMUNOGLOBULINS , *PLASMA cells , *DENDRITIC cells - Abstract
Abstract: Germinal centers are the anatomic sites for the generation of high affinity immunoglobulin expressing plasma cells and memory B cells. The germinal center B cells that are precursors of these cells circulate between the light zone B cell population that interact with antigen laden follicular dendritic cells (FDC) and the proliferative dark zone B cell population. Antigen retention by follicular dendritic cells is dependent on Fc receptors and complement receptors, and complement receptor 1 (Cr1) is the predominant complement receptor expressed by FDC. The newly created Cr1KO mouse was used to test the effect of Cr1-deficiency on the kinetics of the germinal center reaction and the generation of IgM and switched memory B cell formation. Immunization of Cr1KO mice with a T cell-dependent antigen resulted in the normal initial expansion of B cells with a germinal center phenotype however these cells were preferentially lost in the Cr1KO animal over time (days). Bone marrow chimera animals documented the surprising finding that the loss of germinal center B cell maintenance was linked to the expression of Cr1 on B cells, not the FDC. Cr1-deficiency further resulted in antigen-specific IgM titer and IgM memory B cell reductions, but not antigen-specific IgG after 35–37 days. Investigations of nitrophenyl (NP)-specific IgG demonstrated that Cr1 is not necessary for affinity maturation during the response to particulate antigen. These data, along with those generated in our initial description of the Cr1KO animal describe unique functions of Cr1 on the surface of both B cells and FDC. [Copyright &y& Elsevier]
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- 2014
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155. Deficiency of complement receptors CR2/CR1 in Cr2-/- mice reduces the extent of secondary brain damage after closed head injury.
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Neher, Miriam D., Rich, Megan C., Keene, Chesleigh N., Weckbach, Sebastian, Bolden, Ashley L., Losacco, Justin T., Patane, Jenée, Flierl, Michael A., Kulik, Liudmila, Holers, V. Michael, and Stahel, Philip F.
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BRAIN damage , *BRAIN injuries , *INFLAMMATION , *NEUROLOGY , *IMMUNOGLOBULIN M - Abstract
Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury. [ABSTRACT FROM AUTHOR]
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- 2014
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156. Effects of TRIM59 on RAW264.7 macrophage gene expression and function
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Mengyan Tang, Dong Li, Xun Zhu, Liping Liu, Dongmei Yan, Zhenhua Zhu, Wenxin Zhang, and Zheng Jin
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Phagocytosis ,Immunology ,Antigen presentation ,Apoptosis ,Complement receptor ,CD16 ,Tripartite Motif Proteins ,Mice ,Antigens, CD ,Gene expression ,Immunology and Allergy ,Macrophage ,Animals ,RNA, Small Interfering ,Cell Proliferation ,biology ,Chemistry ,Cell Cycle ,Intracellular Signaling Peptides and Proteins ,Hematology ,Cell biology ,RAW 264.7 Cells ,Integrin alpha M ,Tumor progression ,biology.protein ,Cytokines ,Transcriptome - Abstract
Macrophages have a variety of functions, such as secreting cytokines, phagocytosis, et al. Tripartite motif containing 59 (TRIM59) protein is highly expressed in tumor cells. It can regulate proliferation of tumor cells and promote tumor progression. Recent studies shown that the expression of TRIM59 was different in macrophages when stimulated by different stimuli, however, the effects of TRIM59 on macrophage gene expression profiles and functions are still unknown. In our study, we constructed RAW264.7 macrophages with high and low expression of TRIM59, and used next generation sequencing to explore the effects of TRIM59 on macrophage gene expression profiles. Results showed that TRIM59 affected an abundant number of genes, and may affect phagocytosis and cell cycles. We also examined the expression of surface molecules, secretion of cytokines, phagocytosis, proliferation, and apoptosis of macrophages, and confirmed that TRIM59 increased the expression of FcγRs CD16/32, CD64 and the secretion of TNF-α and IL-10, promoted phagocytosis and proliferation of RAW264.7 cells, inhibited the expression of complement receptor CD11b and antigen presentation related receptors (MHCII, CD80), but TRIM59 had no significant effect on apoptosis. Our study explored the effect of TRIM59 on the gene expression and function of macrophages comprehensively.
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- 2020
157. Novel lipid combination for delivery of plasmid DNA to immune cells in the spleen
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Seigo Kimura, Yaser Hosny Ali Elewa, Ikramy A. Khalil, and Hideyoshi Harashima
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Pharmaceutical Science ,Spleen ,02 engineering and technology ,Complement receptor ,Gene delivery ,Transfection ,03 medical and health sciences ,Immune system ,Gene expression ,medicine ,Cytotoxic T cell ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,DNA ,021001 nanoscience & nanotechnology ,Lipids ,Cell biology ,medicine.anatomical_structure ,biology.protein ,Nanoparticles ,Antibody ,0210 nano-technology ,Plasmids - Abstract
This study reports on the development of a novel lipid combination that permits the efficient and highly selective delivery of plasmid DNA (pDNA) to immune cells in the spleen. Using DODAP, an ionizable lipid that was previously thought to be inefficient for gene delivery, we show for the first time, that this ignored lipid can be successfully used for efficient and targeted gene delivery in vivo, but only when combined with DOPE, a specific helper lipid. Using certain DODAP and DOPE ratios resulted in the formation of lipid nanoparticles (LNPs) with a ~ 1000-fold higher gene expression, and this expression was specific for the spleen, making it the most spleen-selective system for transfection using pDNA. The developed DODAP/DOPE-LNPs target immune cells in the spleen via receptors for complement C3 and this pathway is critical for efficient gene expression. We hypothesize that the high spleen transfection activity of DODAP/DOPE-LNPs is caused by the promotion of gene expression associated with B cell activation via complement receptors. LNPs encapsulating tumor-antigen encoding pDNA showed both prophylactic and therapeutic anti-tumor effects. The optimized LNPs resulted in the production of different cytokines and antigen-specific antibodies as well as exerting antigen-specific cytotoxic effects. This study revives the use of DODAP in gene delivery and highlights the importance of using appropriate lipid combinations for delivering genes to specific cells.
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- 2020
158. A novel mouse model expressing human forms for complement receptors CR1 and CR2
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Dina Fathalla, Harriet M. Jackson, Kate E. Foley, Tim Stearns, Gareth R. Howell, Rita O'Rourke, and B. Paul Morgan
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Male ,0301 basic medicine ,lcsh:QH426-470 ,Cell ,Lupus ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Endogeny ,Complement receptor ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Genetic variation ,Genetics ,medicine ,Animals ,Humans ,Allele ,Promoter Regions, Genetic ,Gene ,Alleles ,Genetics (clinical) ,Complement regulators ,Hematopoietic cells ,Systemic lupus erythematosus ,Homozygote ,Immune cells ,medicine.disease ,Complement system ,Mice, Inbred C57BL ,Complement cascade ,Disease Models, Animal ,lcsh:Genetics ,medicine.anatomical_structure ,030104 developmental biology ,Immune cell infiltration ,Receptors, Complement 3b ,Female ,Receptors, Complement 3d ,Transcriptome ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Research Article - Abstract
Background The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer’s disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2. Genetic variation in CR1 and CR2 have been implicated in modifying disease states but the mechanisms are not known. Results To decipher the roles of human CR1 and CR2 in health and disease, we engineered C57BL/6J (B6) mice to replace endogenous murine Cr2 with human complement receptors, CR1 and CR2 (B6.CR2CR1). CR1 has an array of allotypes in human populations and using traditional recombination methods (Flp-frt and Cre-loxP) two of the most common alleles (referred to here as CR1long and CR1short) can be replicated within this mouse model, along with a CR1 knockout allele (CR1KO). Transcriptional profiling of spleens and brains identified genes and pathways differentially expressed between mice homozygous for either CR1long, CR1short or CR1KO. Gene set enrichment analysis predicts hematopoietic cell number and cell infiltration are modulated by CR1long, but not CR1short or CR1KO. Conclusion The B6.CR2CR1 mouse model provides a novel tool for determining the relationship between human-relevant CR1 alleles and disease.
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- 2020
159. The Role of Complement in the Mechanism of Action of Therapeutic Anti-Cancer mAbs
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Ronald P. Taylor and Josée Golay
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Antibody-dependent cell-mediated cytotoxicity ,lcsh:Immunologic diseases. Allergy ,Chemistry ,therapeutic monoclonal antibodies (mAbs) ,antibody dependent cellular cytotoxicity ,Immunology ,phagocytosis ,Complement receptor ,CD59 ,Review ,Acquired immune system ,Cell biology ,Complement system ,Classical complement pathway ,Immune system ,complement receptors ,Drug Discovery ,Immunology and Allergy ,complement ,Cytotoxicity ,lcsh:RC581-607 - Abstract
Unconjugated anti-cancer IgG1 monoclonal antibodies (mAbs) activate antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages, and these activities are thought to be important mechanisms of action for many of these mAbs in vivo. Several mAbs also activate the classical complement pathway and promote complement-dependent cytotoxicity (CDC), although with very different levels of efficacy, depending on the mAb, the target antigen, and the tumor type. Recent studies have unraveled the various structural factors that define why some IgG1 mAbs are strong mediators of CDC, whereas others are not. The role of complement activation and membrane inhibitors expressed by tumor cells, most notably CD55 and CD59, has also been quite extensively studied, but how much these affect the resistance of tumors in vivo to IgG1 therapeutic mAbs still remains incompletely understood. Recent studies have demonstrated that complement activation has multiple effects beyond target cell lysis, affecting both innate and adaptive immunity mediated by soluble complement fragments, such as C3a and C5a, and by stimulating complement receptors expressed by immune cells, including NK cells, neutrophils, macrophages, T cells, and dendritic cells. Complement activation can enhance ADCC and ADCP and may contribute to the vaccine effect of mAbs. These different aspects of complement are also briefly reviewed in the specific context of FDA-approved therapeutic anti-cancer IgG1 mAbs.
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- 2020
160. Computational analysis of complement inhibitor compstatin using molecular dynamics
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Lydia E. Kavraki, Dinler A. Antunes, and Didier Devaurs
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Coronavirus disease 2019 (COVID-19) ,Pneumonia, Viral ,Complement receptor ,Computational biology ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,Antiviral Agents ,Peptides, Cyclic ,Catalysis ,Inorganic Chemistry ,Complement inhibitor ,Molecular dynamics ,Structure-Activity Relationship ,0103 physical sciences ,Structure–activity relationship ,Humans ,Computational analysis ,Physical and Theoretical Chemistry ,Pandemics ,Complement component 3 ,010304 chemical physics ,Chemistry ,Organic Chemistry ,COVID-19 ,Hydrogen Bonding ,Complement C3 ,0104 chemical sciences ,Complement system ,Computer Science Applications ,Computational Theory and Mathematics ,Coronavirus Infections - Abstract
The complement system plays a major role in human immunity, but its abnormal activation can have severe pathological impacts. By mimicking a natural mechanism of complement regulation, the small peptide compstatin has proven to be a very promising complement inhibitor. Over the years, several compstatin analogs have been created, with improved inhibitory potency. A recent analog is being developed as a candidate drug against several pathological conditions, including COVID-19. However, the reasons behind its higher potency and increased binding affinity to complement proteins are not fully clear. This computational study highlights the mechanistic properties of several compstatin analogs, thus complementing previous experimental studies. We perform molecular dynamics simulations involving six analogs alone in solution and two complexes with compstatin bound to complement component 3. These simulations reveal that all the analogs we consider, except the original compstatin, naturally adopt a pre-bound conformation in solution. Interestingly, this set of analogs adopting a pre-bound conformation includes analogs that were not known to benefit from this behavior. We also show that the most recent compstatin analog (among those we consider) forms a stronger hydrogen bond network with its complement receptor than an earlier analog.
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- 2020
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161. Moieties of Complement iC3b Recognized by the I-domain of Integrin αXβ2
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Jeongsuk Choi, Sang-Uk Nham, and Dolgorsuren Buyannemekh
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I-domain ,Stereochemistry ,αMβ2 ,Integrin ,binding sites ,protein-protein interactions ,Integrin alphaXbeta2 ,Complement receptor ,Complement factor I ,Protein–protein interaction ,law.invention ,iC3b ,03 medical and health sciences ,αXβ2 ,0302 clinical medicine ,law ,parasitic diseases ,Humans ,complement ,Amino Acid Sequence ,Binding site ,Molecular Biology ,Opsonin ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Cell Biology ,General Medicine ,Protein Structure, Tertiary ,Complement C3b ,biology.protein ,Recombinant DNA ,integrins ,030217 neurology & neurosurgery ,Protein Binding ,Research Article - Abstract
Complement fragment iC3b serves as a major opsonin for facilitating phagocytosis via its interaction with complement receptors CR3 and CR4, also known by their leukocyte integrin family names, αMβ2 and αXβ2, respectively. Although there is general agreement that iC3b binds to the αM and αX I-domains of the respective β2-integrins, much less is known regarding the regions of iC3b contributing to the αX I-domain binding. In this study, using recombinant αX I-domain, as well as recombinant fragments of iC3b as candidate binding partners, we have identified two distinct binding moieties of iC3b for the αX I-domain. They are the C3 convertase-generated N-terminal segment of the C3b α'- chain (α'NT) and the factor I cleavage-generated N-terminal segment in the CUBf region of α-chain. Additionally, we have found that the CUBf segment is a novel binding moiety of iC3b for the αM I-domain. The CUBf segment shows about a 2-fold higher binding activity than the α'NT for αX I-domain. We also have shown the involvement of crucial acidic residues on the iC3b side of the interface and basic residues on the I-domain side.
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- 2020
162. Recent advance of spleen tyrosine kinase in diseases and drugs
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Su Zhang, Zhongcheng Liu, Yanfen Zhang, and Yuxin Shao
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0301 basic medicine ,Immunology ,Integrin ,Syk ,chemical and pharmacologic phenomena ,Environmental pollution ,Complement receptor ,environment and public health ,Autoimmune Diseases ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell surface receptor ,hemic and lymphatic diseases ,Neoplasms ,Immunology and Allergy ,Animals ,Humans ,Syk Kinase ,Lymphocytes ,Receptor ,Pharmacology ,biology ,hemic and immune systems ,Immunity, Innate ,Rats ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,Tyrosine kinase ,Signal Transduction - Abstract
Spleen tyrosine kinase (Syk) is a non-receptor protein tyrosine kinase, also known as p72Syk. It is important for downstream signaling from cell surface receptors, such as Fc receptors, complement receptors and integrin. Syk plays the critical role in triggering immune and allergic reactions, the signaling pathway of Syk has become the research focus on drugs for allergic disease and human malignancies. This review summarized the characteristics of Syk, its mechanism in related reactions, and mainly discussed the signal transduction pathway mediated by Syk. With the development of industry and the aggravation of environmental pollution, the incidence of allergic diseases is increasing, it has become a global priority disease. In this process, Syk participates in IgE/FceRI signaling pathway plays a critical role in triggering allergic reactions. This review described the characteristics and the interaction mechanism of Syk and its binding proteins in disease, and summarized the research status of targeted Syk inhibitors.
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- 2020
163. C3 Opsonization of Anthrax Bacterium and Peptidoglycan Supports Recognition and Activation of Neutrophils
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K. Mark Coggeshall, Ravi S. Keshari, Florea Lupu, Jackie Cochran, and Narcis I. Popescu
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0301 basic medicine ,Microbiology (medical) ,Population ,Complement receptor ,peptidoglycan ,Microbiology ,Article ,03 medical and health sciences ,0302 clinical medicine ,neutrophils ,Virology ,complement ,education ,C3 ,Opsonin ,lcsh:QH301-705.5 ,Bacillus anthracis ,Complement component 5 ,education.field_of_study ,biology ,Chemistry ,fungi ,Degranulation ,anthrax ,biology.organism_classification ,Antibody opsonization ,030104 developmental biology ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Neutrophil degranulation - Abstract
Neutrophils are the most abundant innate cell population and a key immune player against invading pathogens. Neutrophils can kill both bacterium and spores of Bacillus anthracis, the causative anthrax pathogen. Unlike interactions with professional phagocytes, the molecular recognition of anthrax by neutrophils is largely unknown. In this study, we investigated the role of complement C3 deposition on anthrax particles for neutrophil recognition of bacterium and/or its cell wall peptidoglycan, an abundant pathogen-associated molecular pattern that supports anthrax sepsis. C3 opsonization and recognition by complement receptors accounted for 70&ndash, 80% of the affinity interactions between neutrophils and anthrax particles at subphysiologic temperatures. In contrast, C3 supported up to 50% of the anthrax particle ingestion under thermophysiologic conditions. Opsonin-dependent low affinity interactions and, to a lower extent, opsonin-independent mechanisms, provide alternative entry routes. Similarly, C3 supported 58% of peptidoglycan-induced degranulation and, to a lower extent, 23% of bacterium-induced degranulation. Interestingly, an opsonin independent mechanism mediated by complement C5, likely through C5a anaphylatoxin, primes azurophilic granules in response to anthrax particles. Overall, we show that C3 deposition supports anthrax recognition by neutrophils but is dispensable for pathogen ingestion and neutrophil degranulation, highlighting immune recognition redundancies that minimize the risk of pathogen evasion.
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- 2020
164. Differential interactions of serum and bronchoalveolar lavage complement proteins with conidia of airborne fungal pathogen Aspergillus fumigatus
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J. Iñaki Guijarro, Rajashri Shende, Jean-Pierre Gangneux, Taruna Madan, Prajna Lalitha, Sarah Dellière, Irene Daniel, Jagadeesh Bayry, Dharmalingam Kuppamuthu, Jeya Maheshwari Jayapal, Vishukumar Aimanianda, Sarah Sze Wah Wong, Hélène Guegan, Institut Pasteur [Paris], Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Aravind Medical Research Foundation (AMRF), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Aravind Eye Hospital [Madurai, India], Savitribai Phule Pune University [India], Indian Council of Medical Research [New Dehli] (ICMR), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Plateforme technologique de RMN biologique - Biological NMR Technological Platform, 5403-1, Indo-French Centre for the Promotion of Advanced Research, Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), ANR-16-CE11-0020,FUNHYDRO,Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus(2016), and Jonchère, Laurent
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Serum ,beta-Glucans ,polysaccharides ,Integrin alphaXbeta2 ,Complement receptor ,Mannans ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,humoral immunity ,host-pathogen interactions ,Complement Activation ,Mannan-binding lectin ,0303 health sciences ,Immunity, Cellular ,Complement component 2 ,Complement C3 ,Opsonin Proteins ,Spores, Fungal ,macrophages ,Antibody opsonization ,Infectious Diseases ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,Lectin pathway ,[SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Bronchoalveolar Lavage Fluid ,Protein Binding ,Immunology ,Primary Cell Culture ,Macrophage-1 Antigen ,Biology ,Microbiology ,03 medical and health sciences ,proteomics ,Phagocytosis ,Aspergillosis ,Humans ,Opsonin ,complement system ,030304 developmental biology ,Cellular Microbiology: Pathogen-Host Cell Molecular Interactions ,Host Microbial Interactions ,Aspergillus fumigatus ,Galactose ,Fungal Polysaccharides ,cytokines ,Complement system ,Immunity, Humoral ,complement receptors ,Alternative complement pathway ,cell wall ,Parasitology ,Aspergillus fumigatus conidia ,Reactive Oxygen Species ,030215 immunology - Abstract
Even though both cellular and humoral immunities contribute to host defense, the role played by humoral immunity against the airborne opportunistic fungal pathogen Aspergillus fumigatus has been underexplored. In this study, we aimed at deciphering the role of the complement system, the major humoral immune component, against A. fumigatus. Mass spectrometry analysis of the proteins extracted from A. fumigatus conidial (asexual spores and infective propagules) surfaces opsonized with human serum indicated that C3 is the major complement protein involved. Flow cytometry and immunolabeling assays further confirmed C3b (activated C3) deposition on the conidial surfaces. Assays using cell wall components of conidia indicated that the hydrophobin RodAp, β-(1,3)-glucan (BG) and galactomannan (GM) could efficiently activate C3. Using complement component-depleted sera, we showed that while RodAp activates C3 by the alternative pathway, BG and GM partially follow the classical and lectin pathways, respectively. Opsonization facilitated conidial aggregation and phagocytosis, and complement receptor (CR3 and CR4) blockage on phagocytes significantly inhibited phagocytosis, indicating that the complement system exerts a protective role against conidia by opsonizing them and facilitating their phagocytosis mainly through complement receptors. Conidial opsonization with human bronchoalveolar lavage fluid (BALF) confirmed C3 to be the major complement protein interacting with conidia. Nevertheless, complement C2 and mannose-binding lectin (MBL), the classical and lectin pathway components, respectively, were not identified, indicating that BALF activates the alternative pathway on the conidial surface. Moreover, the cytokine profiles were different upon stimulation of phagocytes with serum- and BALF-opsonized conidia, highlighting the importance of studying interaction of conidia with complement proteins in their biological niche.
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- 2020
165. Candidiasis and Mechanisms of Antifungal Resistance
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Bettina C Fries, Sutthichai Sae-Tia, and Somanon Bhattacharya
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0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,030106 microbiology ,Complement receptor ,Drug resistance ,Review ,5-Flucytosine resistance ,ergosterol biosynthesis ,echinochandin resistance ,Biochemistry ,Microbiology ,Organ transplantation ,03 medical and health sciences ,azole resistance ,polyene resistance ,Medicine ,Pharmacology (medical) ,Microbiome ,General Pharmacology, Toxicology and Pharmaceutics ,Pathogen ,business.industry ,lcsh:RM1-950 ,antifungal resistance ,candidiasis ,Corpus albicans ,030104 developmental biology ,Infectious Diseases ,lcsh:Therapeutics. Pharmacology ,Nucleic acid biosynthesis ,efflux pump ,Efflux ,business - Abstract
Candidiasis can be present as a cutaneous, mucosal or deep-seated organ infection, which is caused by more than 20 types of Candida sp., with C. albicans being the most common. These are pathogenic yeast and are usually present in the normal microbiome. High-risk individuals are patients of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), organ transplant, and diabetes. During infection, pathogens can adhere to complement receptors and various extracellular matrix proteins in the oral and vaginal cavity. Oral and vaginal Candidiasis results from the overgrowth of Candida sp. in the hosts, causing penetration of the oral and vaginal tissues. Symptoms include white patches in the mouth, tongue, throat, and itchiness or burning of genitalia. Diagnosis involves visual examination, microscopic analysis, or culturing. These infections are treated with a variety of antifungals that target different biosynthetic pathways of the pathogen. For example, echinochandins target cell wall biosynthesis, while allylamines, azoles, and morpholines target ergosterol biosynthesis, and 5-Flucytosine (5FC) targets nucleic acid biosynthesis. Azoles are commonly used in therapeutics, however, because of its fungistatic nature, Candida sp. evolve azole resistance. Besides azoles, Candida sp. also acquire resistance to polyenes, echinochandins, and 5FC. This review discusses, in detail, the drug resistance mechanisms adapted by Candida sp.
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- 2020
166. Activated Human Memory B Lymphocytes Use CR4 (CD11c/CD18) for Adhesion, Migration, and Proliferation
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Zsuzsa Nagy-Baló, Richárd Kiss, Alina Menge, Csaba Bödör, Zsuzsa Bajtay, and Anna Erdei
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,proliferation ,Palatine Tonsil ,Immunology ,CR4 (CD11c/CD18) ,CD11c ,Receptors, Antigen, B-Cell ,Blood Donors ,Complement receptor ,Lymphocyte Activation ,migration ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,medicine ,Cell Adhesion ,Immunology and Allergy ,Humans ,Memory B cell ,B cell ,Cells, Cultured ,Cell Proliferation ,Original Research ,B-Lymphocytes ,biology ,Chemistry ,breakpoint cluster region ,TLR9 ,hemic and immune systems ,Molecular biology ,β2 integrin ,CD11c Antigen ,adhesion ,030104 developmental biology ,medicine.anatomical_structure ,Integrin alpha M ,Immunoglobulin class switching ,CD18 Antigens ,Toll-Like Receptor 9 ,biology.protein ,human memory B cells ,lcsh:RC581-607 ,Immunologic Memory ,030215 immunology - Abstract
Complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) of myeloid cells are known for long to participate in actin linked functions like phagocytosis, adhesion, and migration. The expression and role of these two β2-integrins however, in human B lymphocytes have only scarcely been studied so far, although it has been shown recently that CD11c+ B cells are mainly memory cells. In our systematic study we investigated B cells isolated from tonsils and peripheral blood of healthy donors. We found, that while only 5% of resting tonsillar B cells expressed CD11c, their number increased up to 26% after 3 days of BCR stimulation. Lower, but still remarkable percentage of B lymphocytes were positive for CD11c after stimulation via TLR9 alone or via TLR9 and BCR simultaneously. At the same time, we detected no significant expression of CD11b on resting or activated tonsillar B cells. Blood B lymphocytes showed a similar expression pattern of both β2-integrins. We demonstrated that CD11c molecules appearing on the surface of B cells are newly synthesized, reaching the number of 9,500 per activated B cell. We found that CR4 expressing B cells belong to the memory pool and the increase of CD11c expression on tonsillar B cells upon BCR mediated activation occurs parallel with class switching. Analysis of the function of CD11c revealed, that this β2-integrin contributes to the adhesion and migration of activated B lymphocytes. We also demonstrated that the CR4 mediated adhesion promotes the proliferation of the BCR activated cells. Our studies are the first to demonstrate that CD11c expressed on BCR-activated human B cells are not only passive markers but functional drivers of memory B cell responses.
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- 2020
167. Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity
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Prachi Namjoshi, Timothy J. Sellati, Sarah J. Rosa, Edmund J. Gosselin, Lauren E Shoudy, Donald Steiner, Sudeep Kumar, Kristen M Holland-Tummillo, Karsten R. O. Hazlett, and Anju Singh
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0301 basic medicine ,Microbiology (medical) ,Gram-negative bacteria ,lcsh:Medicine ,Heterologous ,vaccine-targeting ,Complement receptor ,medicine.disease_cause ,Article ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,complement ,Molecular Biology ,Escherichia coli ,Francisella tularensis ,plug & play ,General Immunology and Microbiology ,biology ,lcsh:R ,autotransporter ,biology.organism_classification ,gram-negative ,tularemia ,030104 developmental biology ,Infectious Diseases ,plug & ,Bacterial antigen ,play ,Bacteria ,030215 immunology - Abstract
The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as proof-of-concept with isolated proteins and/or inactivated bacteria. We have engineered a plasmid-based, complement receptor-targeting platform that is readily applicable to live forms of multiple gram-negative bacteria, including, but not limited to, Escherichia coli, Klebsiella pneumoniae, and Francisella tularensis. Using F. tularensis as a model, we find that targeted bacteria show increased binding and uptake by macrophages, which coincides with increased p38 and p65 phosphorylation. Mice vaccinated with targeted bacteria produce higher titers of specific antibody that recognizes a greater diversity of bacterial antigens. Following challenge with homologous or heterologous isolates, these mice exhibited less weight loss and/or accelerated weight recovery as compared to counterparts vaccinated with non-targeted immunogens. Collectively, these findings provide proof-of-concept for plasmid-based, complement receptor-targeting of live gram-negative bacteria.
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- 2020
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168. Combined Anti-Cancer Strategies Based on Anti-Checkpoint Inhibitor Antibodies
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Alain E. Andrea and Josée Golay
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lcsh:Immunologic diseases. Allergy ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,therapeutic antibodies ,Complement receptor ,Review ,Monoclonal antibody ,immune checkpoint inhibitors ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Drug Discovery ,Blocking antibody ,medicine ,Immunology and Allergy ,cancer ,Tumor microenvironment ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,microenvironment ,030220 oncology & carcinogenesis ,Cancer research ,business ,lcsh:RC581-607 ,030215 immunology - Abstract
Therapeutic monoclonal antibodies for the treatment of cancer came of age in 1997, with the approval of anti-CD20 Rituximab. Since then, a wide variety of antibodies have been developed with many different formats and mechanisms of action. Among these, antibodies blocking immune checkpoint inhibitors (ICI) have revolutionized the field, based on the novelty of their concept and their demonstrated efficacy in several types of cancer otherwise lacking effective immunotherapy approaches. ICI are expressed by tumor, stromal or immune cells infiltrating the tumor microenvironment, and negatively regulate anti-tumor immunity. Antibodies against the first discovered ICI, CTLA-4, PD-1 and PD-L1, have shown significant activity in phase III studies against melanoma and other solid cancers, alone or in combination with chemotherapy or radiotherapy. However, not all cancers and not all patients respond to these drugs. Therefore, novel antibodies targeting additional ICI are currently being developed. In addition, CTLA-4, PD-1 and PD-L1 blocking antibodies are being combined with each other or with other antibodies targeting novel ICI, immunostimulatory molecules, tumor antigens, angiogenic factors, complement receptors, or with T cell engaging bispecific antibodies (BsAb), with the aim of obtaining synergistic effects with minimal toxicity. In this review, we summarize the biological aspects behind such combinations and review some of the most important clinical data on ICI-specific antibodies.
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- 2020
169. Complement Receptor Targeted Liposomes Encapsulating the Liver X Receptor Agonist GW3965 Accumulate in and Stabilize Atherosclerotic Plaques
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Benne, Naomi, Martins Cardoso, Renata, Boyle, Aimee L., Kros, Alexander, Jiskoot, Wim, Kuiper, Johan, Bouwstra, Joke, Van Eck, Miranda, Slütter, Bram, Immunologie, Dep Farmaceutische wetenschappen, Immunologie, and Dep Farmaceutische wetenschappen
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Agonist ,liposomes ,Benzylamines ,medicine.drug_class ,Biomedical Engineering ,Pharmaceutical Science ,02 engineering and technology ,Complement receptor ,Pharmacology ,Lyp-1 ,010402 general chemistry ,01 natural sciences ,Benzoates ,Biomaterials ,Mice ,medicine ,Macrophage ,Animals ,Liver X receptor ,Receptor ,Foam cells ,Liver X Receptors ,Liposome ,Chemistry ,Reverse cholesterol transport ,021001 nanoscience & nanotechnology ,Atherosclerosis ,Plaque, Atherosclerotic ,foam cells ,0104 chemical sciences ,Receptors, Complement ,LDL receptor ,Liposomes ,lipids (amino acids, peptides, and proteins) ,atherosclerosis ,0210 nano-technology ,liver X receptor - Abstract
Atherosclerosis is characterized by the retention of lipids in foam cells in the arterial intima. The liver X receptor (LXR) agonist GW3965 is a promising therapeutic compound, since it induces reverse cholesterol transport in foam cells. However, hepatic LXR activation increases plasma and liver lipid levels, inhibiting its clinical development. Herein, a formulation that specifically enhances GW3965 deposition in the atherosclerotic lesion is aimed to be developed. GW3965 is encapsulated in liposomes functionalized with the cyclic peptide Lyp-1 (CGNKRTRGC), which binds the p32 receptor expressed on foam cells. These liposomes show preferential uptake by foam cells in vitro and higher accumulation in atherosclerotic plaques in mice compared to non-targeted liposomes as determined by in vivo imaging. Flow cytometry analysis of plaques reveals increased retention of Lyp-1 liposomes in atherosclerotic plaque macrophages compared to controls (p < 0.05). Long term treatment of established plaques in LDLR -/- mice with GW3965-containing Lyp-1 liposomes significantly reduces plaque macrophage content by 50% (p < 0.01). Importantly, GW3965-containing Lyp-1 liposomes do not increase plasma or hepatic lipid content. Thus, GW3965-containing Lyp-1 liposomes successfully target the atherosclerotic macrophages allowing plaque stabilization without commonly observed side effects of LXR agonists.
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- 2020
170. Proresolving lipid mediators enhance PMN-mediated bacterial clearance
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Mauro Perretti and Lucy V. Norling
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0301 basic medicine ,Phagocytosis ,Complement receptor ,03 medical and health sciences ,TLR9 ,0302 clinical medicine ,Immunology and Inflammation ,neutrophils ,Proteinase 3 ,Humans ,resolution of inflammation ,Multidisciplinary ,biology ,Chemistry ,Lipid signaling ,Pneumonia ,Biological Sciences ,Cell biology ,Lipoxins ,030104 developmental biology ,Apoptosis ,030220 oncology & carcinogenesis ,Neutrophil elastase ,Toll-Like Receptor 9 ,biology.protein ,aspirin-triggered LXA4 and RvD1 ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Significance Timely resolution of bacterial infections critically depends on phagocytosis of invading pathogens by polymorphonuclear neutrophil granulocytes, followed by neutrophil apoptosis and removal by macrophages. Neutrophils integrate cues from the inflammatory microenvironment. Here we show a Toll-like receptor 9-mediated mechanism, involving regulation of phagocytosis and phagocytosis-induced neutrophil apoptosis, by which bacterial DNA, a pathogen-associated molecular pattern, and the danger signal mitochondrial DNA may impair host defense to bacteria and prolong the inflammatory response. We also report that the proresolution aspirin-triggered lipids 15-epi-lipoxin A4 and 17-epi-resolvin D1 restore impaired phagocytosis and enhance bacterial clearance and phagocytosis-induced neutrophil apoptosis, thereby facilitating resolution of acute lung inflammation. These findings imply the lipoxin receptor ALX/FPR2 as a potential therapeutic target for combating bacterial infections., Timely resolution of bacterial infections critically depends on phagocytosis of invading pathogens by polymorphonuclear neutrophil granulocytes (PMNs), followed by PMN apoptosis and efferocytosis. Here we report that bacterial DNA (CpG DNA) and mitochondrial DNA impair phagocytosis and attenuate phagocytosis-induced apoptosis in human PMNs through Toll-like receptor 9 (TLR9)-mediated release of neutrophil elastase and proteinase 3 and subsequent down-regulation of the complement receptor C5aR. Consistently, CpG DNA delays pulmonary clearance of Escherichia coli in mice and suppresses PMN apoptosis, efferocytosis, and generation of proresolving lipid mediators, thereby prolonging lung inflammation evoked by E. coli. Genetic deletion of TLR9 renders mice unresponsive to CpG DNA. We also show that aspirin-triggered 15-epi-lipoxin A4 (15-epi-LXA4) and 17-epi-resolvin D1 (17-epi-RvD1) through the receptor ALX/FPR2 antagonize cues from CpG DNA, preserve C5aR expression, restore impaired phagocytosis, and redirect human PMNs to apoptosis. Treatment of mice with 15-epi-LXA4 or 17-epi-RvD1 at the peak of inflammation accelerates clearance of bacteria, blunts PMN accumulation, and promotes PMN apoptosis and efferocytosis, thereby facilitating resolution of E. coli-evoked lung injury. Collectively, these results uncover a TLR9-mediated endogenous mechanism that impairs PMN phagocytosis and prolongs inflammation, and demonstrate both endogenous and therapeutic potential for 15-epi-LXA4 and 17-epi-RvD1 to restore impaired bacterial clearance and facilitate resolution of acute lung inflammation.
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- 2020
171. Autoantibodies against C5aR1, C3aR1, CXCR3, and CXCR4 are decreased in primary Sjogren's syndrome
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Xiaoyang Yue, Zuguo Liu, Junfeng Zheng, Gabriela Riemekasten, Qiaoniang Huang, Antje Müller, Jiao Luo, Junping Yin, Fengyuan Deng, Frank Petersen, Yan Chen, Harald Heidecke, Xinhua Yu, Juan Chen, and Xing Gao
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0301 basic medicine ,Adult ,Male ,Receptors, CXCR4 ,Receptors, CXCR3 ,Lymphocyte ,Immunology ,Complement receptor ,CHO Cells ,CXCR3 ,Epitope ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Cricetulus ,medicine ,Animals ,Humans ,Lymphocytes ,Receptor ,Molecular Biology ,Receptor, Anaphylatoxin C5a ,Aged ,Autoantibodies ,biology ,business.industry ,Autoantibody ,Middle Aged ,medicine.disease ,Receptors, Complement ,stomatognathic diseases ,030104 developmental biology ,medicine.anatomical_structure ,Sjogren's Syndrome ,Rheumatoid arthritis ,Case-Control Studies ,biology.protein ,Female ,Antibody ,business ,030215 immunology - Abstract
Background Networks formed of numerous autoantibodies (aabs) directed against G-protein coupled receptors (GPCR) have been suggested to play important role in autoimmune disorders. In present study, we aimed to evaluate the association between anti-GPCR antibodies and primary Sjogren’s syndrome (pSS) to determine the potential pathogenic factors. Methods By applying a cell membrane-based ELISA technique, which is capable of detecting aabs against conformational epitopes within GPCR, serum levels of fourteen GPCR were determined in well-characterized patients with pSS (n = 52) and gender-matched healthy controls (n = 54). Comparisons between groups were analyzed by two-tailed Mann-Whitney U test, Bonferroni correction was applied for multiple comparisons. Spearman`s rank correlation coefficients were calculated between variables and visualized by heat map. Results Compared to healthy subjects, sera of patients with pSS showed significantly higher binding to β2AR and ETAR, but lower binding to C5aR1, C3aR1, CXCR3, and CXCR4. Autoantibodies against C5aR1, C3aR1, CXCR3, and CXCR4 were also decreased in patients with rheumatoid arthritis. In pSS patients, levels of anti-CXCR3 and anti-CXCR4 antibodies were negatively correlated with circulating lymphocyte counts. Furthermore, correlation signatures of anti-GPCR antibodies changed dramatically in the patients with pulmonary involvement. Conclusions This study demonstrates an association between pSS and autoantibodies recognizing GPCR, especially those functionally involved in immune cell migration and exocrine glandular secretion.
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- 2020
172. Decreased expression of a phagocytic receptor Siglec-1 on alveolar macrophages in chronic obstructive pulmonary disease
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Mitsuhiro Yamada, Naoya Fujino, Masakazu Ichinose, Rie Tanaka, Yoshinori Okada, Satoshi O. Suzuki, Hirohito Sano, Hisatoshi Sugiura, Atsushi Tanno, and Taizou Hirano
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Male ,0301 basic medicine ,Sialic Acid Binding Ig-like Lectin 1 ,Phagocytosis ,CD36 ,Gene Expression ,Complement receptor ,Alveolar macrophage ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Macrophages, Alveolar ,medicine ,Humans ,Macrophage ,Receptor ,Cells, Cultured ,Aged ,lcsh:RC705-779 ,Phagocytes ,Lung ,Siglec-1 ,biology ,business.industry ,Research ,Chronic obstructive pulmonary disease ,lcsh:Diseases of the respiratory system ,Middle Aged ,respiratory system ,Flow Cytometry ,Respiratory Function Tests ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Integrin alpha M ,Immunology ,biology.protein ,Female ,business - Abstract
Background Alveolar macrophages are professional phagocytes that remove microbial pathogens inhaled into the lung. The phagocytic ability is compromised in chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms underlying this defect in phagocytosis are not clearly defined. Materials and methods Cell suspensions were collected from lung tissues of patients undergoing lung resection. Alveolar macrophages were detected as FSChi/ SSChi/CD45+/CD206+ cells in the isolated cell suspension by flow-cytometry. The cell surface expression of plasma membrane-bound phagocytic receptors (Fcγ receptor I (FcγRI), a complement receptor CD11b, macrophage scavenger receptor-1 (MSR-1), CD36 and Siglec-1) was determined on the alveolar macrophages. Correlations between the expression levels of the phagocytic receptors and disease severity were analysed. Phagocytosis of fluorescence-tagged bacteria by human alveolar macrophages was evaluated. Results The flow-cytometry analyses revealed that FcγRI, CD11b, MSR-1 and Siglec-1, but not CD36, were expressed on human alveolar macrophages. Among these receptors, Siglec-1 expression was significantly decreased on alveolar macrophages in COPD ex-smokers (n = 11), compared to control never-smokers (n = 11) or control ex-smokers (n = 9). The Siglec-1 expression on alveolar macrophages was significantly correlated with lung function (forced expiratory volume in 1 s) and with the severity of emphysema. Treatment of human alveolar macrophages with an anti-Siglec1 blocking antibody decreased phagocytosis of non-typeable Haemophilus influenzae (NTHi). Conclusion Our findings demonstrated reduced expression of Siglec-1 on alveolar macrophages in COPD, which is involved in engulfment of NTHi.
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- 2020
173. Vitamin D upregulates the macrophage complement receptor immunoglobulin in innate immunity to microbial pathogens
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Andrew J McPhee, Usma Munawara, Sarah Harvey, Annabelle G. Small, Trishni Putty, Khalida Perveen, Antonio Ferrante, Alex Quach, Jaspreet Kaur, and Charles S. T. Hii
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0301 basic medicine ,QH301-705.5 ,Phagocytosis ,Calcium and vitamin D ,Medicine (miscellaneous) ,Immunoglobulins ,Complement receptor ,General Biochemistry, Genetics and Molecular Biology ,vitamin D deficiency ,Article ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Calcitriol ,medicine ,Macrophage ,Biology (General) ,Toll-like receptor ,Phagocytes ,Innate immune system ,biology ,Chemistry ,Macrophages ,Antimicrobial responses ,medicine.disease ,Immunity, Innate ,Up-Regulation ,030104 developmental biology ,biology.protein ,Receptors, Complement 3b ,Antibody ,General Agricultural and Biological Sciences ,Infection ,030215 immunology - Abstract
Vitamin D deficiency remains a global concern. This ‘sunshine’ vitamin is converted through a multistep process to active 1,25-dihydroxyvitamin D3 (1,25D), the final step of which can occur in macrophages. Here we demonstrate a role for vitamin D in innate immunity. The expression of the complement receptor immunoglobulin (CRIg), which plays an important role in innate immunity, is upregulated by 1,25D in human macrophages. Monocytes cultured in 1,25D differentiated into macrophages displaying increased CRIg mRNA, protein and cell surface expression but not in classical complement receptors, CR3 and CR4. This was associated with increases in phagocytosis of complement opsonised Staphylococcus aureus and Candida albicans. Treating macrophages with 1,25D for 24 h also increases CRIg expression. While treating macrophages with 25-hydroxyvitamin D3 does not increase CRIg expression, added together with the toll like receptor 2 agonist, triacylated lipopeptide, Pam3CSK4, which promotes the conversion of 25-hydroxyvitamin D3 to 1,25D, leads to an increase in CRIg expression and increases in CYP27B1 mRNA. These findings suggest that macrophages harbour a vitamin D-primed innate defence mechanism, involving CRIg., Annabelle Small et al. report a new role for vitamin D in innate immunity. They find that the vitamin D metabolite 1,25D increases phagocytosis and expression of complement receptor immunoglobulin (CRIg) by macrophages and that treatment of macrophages with a toll like receptor 2 agonist promotes conversion of 25-hydroxyvitamin D3 to 1,25D.
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- 2020
174. Utilization of complement receptors in immune cell-microbe interaction
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Anna Erdei, Zsuzsa Bajtay, Szilvia Lukácsi, Zsuzsa Nagy-Baló, Kristof Kovacs, Kristof Kliment, Bernadett Mácsik-Valent, Műszaki Fizikai és Anyagtudományi Intézet, Biológia Doktori Iskola, Immunológiai Tanszék, and MTA-ELTE Immunológiai Kutatócsoport
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Biophysics ,chemical and pharmacologic phenomena ,Complement receptor ,Biology ,Infections ,Biochemistry ,03 medical and health sciences ,Classical complement pathway ,Structural Biology ,Genetics ,Animals ,Humans ,Complement Pathway, Classical ,Molecular Biology ,Opsonin ,030304 developmental biology ,0303 health sciences ,Innate immune system ,030302 biochemistry & molecular biology ,Complement Pathway, Mannose-Binding Lectin ,Cell Biology ,Complement System Proteins ,Acquired immune system ,Complement system ,Cell biology ,Receptors, Complement ,Lectin pathway ,Host-Pathogen Interactions ,Complement membrane attack complex - Abstract
The complement system is a major humoral component of immunity and is essential for the fast elimination of pathogens invading the body. In addition to its indispensable role in innate immunity, the complement system is also involved in pathogen clearance during the effector phase of adaptive immunity. The fastest way of killing the invader is lysis by the membrane attack complex, which is formed by the terminal components of the complement cascade. Not all pathogens are lysed however and, if opsonized by a variety of molecules, they undergo phagocytosis and disposal inside immune cells. The most important complement-derived opsonins are C1q, the first component of the classical pathway, MBL, the initiator of the lectin pathway and C3-derived activation fragments, including C3b, iC3b and C3d, which all serve as ligands for their corresponding receptors. In this review, we discuss how complement receptors are utilized by various immune cells to tackle invading microbes, or by pathogens to evade host response.
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- 2020
175. Interaction between genetic factors, Porphyromonas gingivalis and microglia to promote Alzheimer’s disease
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Ingar Olsen and Simarjit Kaur Singhrao
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0301 basic medicine ,Microbiology (medical) ,brain ,microglia ,Complement receptor ,Infectious and parasitic diseases ,RC109-216 ,Microbiology ,03 medical and health sciences ,A900 ,0302 clinical medicine ,Immune system ,immune cells ,medicine ,Genetic predisposition ,Dentistry (miscellaneous) ,Porphyromonas gingivalis ,training ,tolerance ,Microglia ,Clusterin ,biology ,Neurodegeneration ,030206 dentistry ,C500 ,medicine.disease ,biology.organism_classification ,QR1-502 ,hyperactivity ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,inflammation ,Immunology ,biology.protein ,Alzheimer's disease ,p. gingivalis - Abstract
In late-onset Alzheimer disease (AD) pathogenesis, genes, infections and immunity could be significant factors. We have reviewed if the keystone periodontal pathogen Porphyromonas gingivalis may affect genes and microglia (primary immune cells in the brain) to promote AD development. Genes for apolipoprotein, clusterin, CD33, triggering receptor expressed on myeloid cells-2 (TREM-2), tyrosine kinase binding protein (TYR-OBP), and complement receptors can affect microglia. Most of these genes can also be affected by P. gingivalis via its mastering of immune suppression. Besides, P. gingivalis can affect microglia directly in several ways. Taken together, genetic predisposition, P. gingivalis infection and microglia could promote neurodegeneration typical of that reported for AD.
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- 2020
176. RIAM-VASP Module Relays Integrin Complement Receptors in Outside-In Signaling Driving Particle Engulfment
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Jose L. Sanchez-Trincado, Raúl Torres-Ruiz, Esther M. Lafuente, María Yáñez-Mó, Sandra Rodriguez-Perales, Carlos Cabañas, Pedro A. Reche, Víctor Toribio, Alvaro Torres-Gomez, Ministerio de Economía y Competitividad (España), Complutense University of Madrid (España), Asociación Española Contra el Cáncer, Unión Europea. Comisión Europea, Ministerio de Economia y Competividad (MINECO), Universidad Complutense de Madrid (UCM), Asociacion Espanola Contra el Cancer (AECC), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Universidad Complutense de Madrid, and UAM. Departamento de Biología Molecular
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Integrins ,β2 integrins ,Complement receptor ,RIAM ,CR4 ,2 integrins ,complement ,Phosphorylation ,Internalization ,Receptor ,lcsh:QH301-705.5 ,media_common ,CR3 ,biology ,Cell adhesion molecule ,Chemistry ,Microfilament Proteins ,phagocytosis ,General Medicine ,VASP ,Biología y Biomedicina / Biología ,Cell biology ,Receptors, Complement ,Gene Knockdown Techniques ,Oftalmología ,Signal transduction ,Signal Transduction ,media_common.quotation_subject ,Phagocytosis ,Integrin ,Complement ,HL-60 Cells ,macromolecular substances ,Outside-in ,Article ,Humans ,Adaptor Proteins, Signal Transducing ,Manganese ,Cell Membrane ,Membrane Proteins ,Complement System Proteins ,Phosphoproteins ,Actins ,Mac-1 ,lcsh:Biology (General) ,biology.protein ,Cell Adhesion Molecules - Abstract
The phagocytic integrins and complement receptors &alpha, M&beta, 2/CR3 and &alpha, X&beta, 2/CR4 are classically associated with the phagocytosis of iC3b-opsonized particles. The activation of this receptor is dependent on signals derived from other receptors (inside-out signaling) with the crucial involvement of the Rap1-RIAM-Talin-1 pathway. Here, we analyze the implication of RIAM and its binding partner VASP in the signaling events occurring downstream of &beta, 2 integrins (outside-in) during complement-mediated phagocytosis. To this end, we used HL-60 promyelocytic cell lines deficient in RIAM or VASP or overexpressing EGFP-tagged VASP to determine VASP dynamics at phagocytic cups. Our results indicate that RIAM-deficient HL-60 cells presented impaired particle internalization and altered integrin downstream signaling during complement-dependent phagocytosis. Similarly, VASP deficiency completely blocked phagocytosis, while VASP overexpression increased the random movement of phagocytic particles at the cell surface, with reduced internalization. Moreover, the recruitment of VASP to particle contact sites, amount of pSer157-VASP and formation of actin-rich phagocytic cups were dependent on RIAM expression. Our results suggested that RIAM worked as a relay for integrin complement receptors in outside-in signaling, coordinating integrin activation and cytoskeletal rearrangements via its interaction with VASP.
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- 2020
177. The Roles and Contributions of the Complement System in the Pathophysiology of Autoimmune Diseases
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Robert B. Sim, Wilhelm J. Schwaeble, and Youssif M. Ali
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Autoimmune disease ,Classical complement pathway ,Lectin pathway ,Immunology ,Alternative complement pathway ,medicine ,Autoantibody ,Complement receptor ,Biology ,medicine.disease ,Complement system ,Transplant rejection - Abstract
Complement destroys invading pathogens and initiates vital defense mechanisms including chemotaxis, phagocytosis, cell adhesion, B cell differentiation and maintenance of immune tolerance. It also facilitates tissue formation and remodeling, homeostasis, and resolution of inflammation via apoptosis and clearance of cellular debris. Defects in complement are associated with immunodeficiencies and autoimmune diseases, while failure to regulate causes tissue damage, anaphylaxis, transplant rejection, and necrosis. More recent research has added to an increasing list of autoimmune pathologies with direct or indirect links to the complement system. This chapter aims to provide an updated summary and points to new possible avenues of therapeutic interventions in the treatment of autoimmune disease.
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- 2020
178. Cholesterol crystals use complement to increase NLRP3 signaling pathways in coronary and carotid atherosclerosis
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Nathalie Niyonzima, Lars Gullestad, Bjørnar Sporsheim, Tom Eirik Mollnes, Geir Øystein Andersen, Xiang Yi Kong, Ida Gregersen, Øystein Sandanger, Sverre Holm, Arne Yndestad, Anne Mari Rokstad, Kirsten Sørensen, Pål Aukrust, Siril Skaret Bakke, Terje Espevik, Tuva B. Dahl, Hilde Lang Orrem, Liv Ryan, Jan Kristian Damås, Bente Halvorsen, Eicke Latz, and Mona Skjelland
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Carotid Artery Diseases ,0301 basic medicine ,Inflammasomes ,lcsh:Medicine ,Complement receptor ,Coronary artery disease ,0302 clinical medicine ,Carotid atherosclerosis ,Complement C1q ,lcsh:R5-920 ,Interleukin ,Inflammasome ,General Medicine ,Plaque, Atherosclerotic ,Liquid Crystals ,Cholesterol ,030220 oncology & carcinogenesis ,Cytokines ,Tumor necrosis factor alpha ,Disease Susceptibility ,Inflammation Mediators ,medicine.symptom ,lcsh:Medicine (General) ,Research Paper ,Signal Transduction ,medicine.drug ,medicine.medical_specialty ,Complement system ,Complement C5a ,Inflammation ,Complement factor I ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Internal medicine ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Humans ,business.industry ,Gene Expression Profiling ,lcsh:R ,Computational Biology ,Complement System Proteins ,Atherosclerosis ,Cholesterol crystals ,NLRP3 inflammasome ,030104 developmental biology ,Endocrinology ,Leukocytes, Mononuclear ,business - Abstract
Background: During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease. Methods: We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling. Findings: Transcripts of interleukin (IL)-1beta(b) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1b protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1b, IL-18 and IL-1a. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components. Interpretation: We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis. © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
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- 2020
179. Complement inhibitor Crry expression in mouse placenta is essential for maintaining normal blood pressure and fetal growth
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Manu Banadakoppa, Kathleen A Pennington, Chandra Yallampalli, and Meena Balakrishnan
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0301 basic medicine ,Embryology ,Physiology ,Placenta ,Maternal Health ,Complement System ,Blood Pressure ,Complement receptor ,Biochemistry ,Vascular Medicine ,Fetal Development ,Complement inhibitor ,Mice ,0302 clinical medicine ,Pre-Eclampsia ,Pregnancy ,Antibiotics ,Immune Physiology ,Medicine and Health Sciences ,RNA, Small Interfering ,Complement Activation ,Multidisciplinary ,Immune System Proteins ,Antimicrobials ,Obstetrics and Gynecology ,Drugs ,Complement C3 ,Animal Models ,Receptors, Complement ,medicine.anatomical_structure ,Experimental Organism Systems ,Doxycycline ,embryonic structures ,Medicine ,Female ,Anatomy ,Research Article ,Science ,Immunology ,Mouse Models ,Biology ,Research and Analysis Methods ,Microbiology ,Preeclampsia ,Andrology ,03 medical and health sciences ,Antimalarials ,Model Organisms ,Downregulation and upregulation ,Microbial Control ,medicine ,Animals ,Blastocyst ,Pharmacology ,Fetus ,Embryos ,Reproductive System ,Biology and Life Sciences ,Proteins ,medicine.disease ,Complement system ,Mice, Inbred C57BL ,Pregnancy Complications ,030104 developmental biology ,Complement Inactivating Agents ,Gene Expression Regulation ,Immune System ,Receptors, Complement 3b ,Animal Studies ,Women's Health ,030215 immunology ,Developmental Biology - Abstract
Many circumstantial evidences from human and animal studies suggest that complement cascade dysregulation may play an important role in pregnancy associated complications including preeclampsia. Deletion of rodent specific complement inhibitor gene, Complement Receptor 1-related Gene/Protein y (Crry) produces embryonic lethal phenotype due to complement activation. It is not clear if decreased expression of Crry during pregnancy produces hypertensive phenotype. We downregulated Crry in placenta by injecting inducible lentivialshRNA vectors into uterine horn of pregnant C57BL/6 mice at the time of blastocyst hatching. Placenta specific downregulation of Crry without significant loss of embryos was achieved upon induction of shRNA using an optimal doxycycline dose at mid gestation. Crry downregulation resulted in placental complement deposition. Late-gestation measurements showed that fetal weights were reduced and blood pressure increased in pregnant mice upon downregulation of Crry suggesting a critical role for Crry in fetal growth and blood pressure regulation.
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- 2020
180. Complement Receptor-Mediated Phagocytosis Induces Proinflammatory Cytokine Production in Murine Macrophages
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Rene E. Harrison, Rebecca Emily-Sue Heineman, Xiao Rui Lisa Li, and Durga Acharya
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lcsh:Immunologic diseases. Allergy ,medicine.medical_treatment ,Phagocytosis ,Immunology ,Fc receptor ,Complement receptor ,macrophage ,Proinflammatory cytokine ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,cytokine ,Immunology and Allergy ,Macrophage ,Animals ,Cytokine Antibody ,complement ,Opsonin ,030304 developmental biology ,Original Research ,0303 health sciences ,biology ,Chemistry ,Calpain ,Macrophages ,NF-kappa B ,phagocytosis ,Cell biology ,Receptors, Complement ,Cytokine ,inflammation ,030220 oncology & carcinogenesis ,biology.protein ,Cytokines ,lcsh:RC581-607 - Abstract
Macrophages are professional phagocytes that are uniquely situated between the innate and adaptive arms of immunity with a high capacity for phagocytosis and proinflammatory cytokine production as well as antigen presentation. Phagocytosis is a critical process to eliminate microbes, apoptotic cells and other foreign particles and is accelerated by host-generated opsonins, such as antibodies and complement. Early phagocytosis studies established the paradigm that FcγR-mediated phagocytosis was more proinflammatory than Complement Receptor (CR)-mediated uptake in macrophages. Using qPCR, cytokine antibody arrays and ELISA, we revisited this research question in primary macrophages. Using qPCR we determined that CR-mediated phagocytosis increases levels of TNF-α, IL-1β, IL-6, and MMP-9, compared to FcγR-mediated phagocytosis and control unstimulated cells. We confirmed these findings at the protein level using cytokine antibody arrays and ELISAs. We next investigated the mechanism behind upregulated cytokine production during CR-mediated phagocytosis. IκBα protein levels were reduced after phagocytosis of both IgG- and C3bi-sRBCs indicating proteolytic degradation and implicating NF-κB activation. Inhibition of NF-κB activation impacted IL-6 production during phagocytosis in macrophages. Due to the roles of calpain in IκBα and integrin degradation, we hypothesized that CR-mediated phagocytosis may utilize calpain for proinflammatory mediator enhancement. Using qPCR and cytokine antibody array analysis, we saw significant reduction of cytokine expression during CR-mediated phagocytosis following the addition of the calpain inhibitor, PD150606, compared to untreated cells. These results suggest that the upregulation of proinflammatory mediators during CR-mediated phagocytosis is potentially dependent upon calpain-mediated activation of NF-κB.
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- 2020
181. Antibody-Dependent Enhancement of Viral Infections
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Ruta Kulkarni
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Immune system ,Viral replication ,Viral entry ,viruses ,Viral Vaccine ,biology.protein ,Antibody-dependent enhancement ,Complement receptor ,Biology ,Antibody ,Virology ,Virus - Abstract
Antiviral antibodies constitute an important component of the host immune response against viral infections and serve to neutralize and reduce infectivity of the virus. However, these antibodies, intended to protect the host, may sometimes prove beneficial to the virus, by facilitating viral entry and replication in the target cell. This phenomenon, known as antibody-dependent enhancement (ADE) of infection, is a result of interaction of virus–antibody immune complexes with Fcγ and/or complement receptors on certain types of host cells and promotes viral entry into the host cells. The internalized immune complexes then modulate host immune response so as to enhance viral replication and aggravate disease severity. The possibility of induction of ADE remains a concern in the development and implementation of viral vaccines and immunotherapeutics.
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- 2020
182. Complement protein levels in plasma astrocyte-derived exosomes are abnormal in conversion from mild cognitive impairment to Alzheimer's disease dementia
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Edward J. Goetzl, Charisse N. Winston, Janice B. Schwartz, Fanny M. Elahi, Robert A. Rissman, and Zetterberg, Henrik
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medicine.medical_specialty ,Aging ,Cognitive loss ,chemical and pharmacologic phenomena ,Complement receptor ,lcsh:Geriatrics ,Neurodegenerative ,Alzheimer's Disease ,lcsh:RC346-429 ,03 medical and health sciences ,Classical complement pathway ,0302 clinical medicine ,Neuroinflammation ,Clinical Research ,Internal medicine ,Acquired Cognitive Impairment ,Genetics ,Medicine ,Dementia ,Neurodegeneration ,lcsh:Neurology. Diseases of the nervous system ,030304 developmental biology ,Complement regulators ,0303 health sciences ,biology ,business.industry ,CD46 ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Blood-Based Biomarkers ,medicine.disease ,Complement system ,Brain Disorders ,lcsh:RC952-954.6 ,Psychiatry and Mental health ,Endocrinology ,Neurological ,Alternative complement pathway ,biology.protein ,Factor D ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Introduction Levels of complement proteins (CPs) in plasma astrocyte-derived exosomes (ADEs) that are abnormal in Alzheimer's disease (AD) have not been assessed in mild cognitive impairment (MCI). Methods Participants (n = 20 per group) had either MCI converting to dementia within 3 years (MCIC), MCI remaining stable over 3 years (MCIS), Alzheimer's disease, or were controls. CPs of ADEs isolated from plasmas by anti-human glutamine aspartate transporter antibody absorption were quantified by ELISAs. Results ADE levels of C1q and C4b of the classical pathway, factor D and fragment Bb of the alternative pathway, and C5b, C3b, and C5b-C9 of both pathways were significantly higher in patients with MCIC than those with MCIS. ADE levels of inhibitory CPs decay-accelerating factor, CD46, CD59, and type 1 complement receptor were significantly lower in patients with MCIC than those with MCIS. Discussion ADE CPs are components of neurotoxic neuroinflammation that may be predictive biomarkers of MCI conversion to Alzheimer's disease.
- Published
- 2019
183. When rubber meets the road: how innate features of adaptive immune cells play critical roles in transplant alloimmunity
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Anna B. Morris and Mandy L. Ford
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Transplantation ,Alloimmunity ,Complement receptor ,030230 surgery ,Biology ,Adaptive Immunity ,Acquired immune system ,Article ,Immunity, Innate ,B-1 cell ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,Immunology and Allergy ,Humans ,Transplantation, Homologous ,030211 gastroenterology & hepatology ,Signal transduction ,Neuroscience ,Signal Transduction - Abstract
Purpose of review Studies on adaptive cells have largely focused on features that are specific to adaptive immunity. However, adaptive cells utilize innate cell features to modulate their responses, and this area of T and B-cell biology is understudied. This review will highlight recent work done to understand how innate features of adaptive immune cells modulate alloimmunity. Recent findings Over the past year, research has shown that T-cell-expressed danger-associated molecular patterns, Toll-like receptors, complement receptors, and Fc receptors regulate T-cell alloimmunity in a cell-intrinsic manner. Further, IL-17 and p40 of IL-12 have been implicated in the migration of T cells into allografts. Lastly, innate B cells, specifically B1 cells, have been shown to produce clinically relevant autoantibody associated with poor graft outcome. Summary These data provide evidence that innate features are utilized by adaptive immune cells to control adaptive alloimmunity.
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- 2019
184. Human Dendritic Cells Express the Complement Receptor Immunoglobulin Which Regulates T Cell Responses
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Annabelle G. Small, Charles S. T. Hii, Trishni Putty, Antonio Ferrante, Alex Quach, Catherine A. Abbott, Khalida Perveen, Usma Munawara, and Nick N. Gorgani
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,T cell ,T-Lymphocytes ,Cell ,Immunology ,T cells ,dexamethasone ,Complement receptor ,Biology ,Immunophenotyping ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Humans ,Receptor ,Original Research ,Immunity, Cellular ,immunosuppression ,complement receptor immunoglobulin (CRIg) ,Dendritic cell ,Dendritic Cells ,Acquired immune system ,cytokines ,Coculture Techniques ,Cell biology ,Receptors, Complement ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,biology.protein ,Antibody ,lcsh:RC581-607 ,Biomarkers ,030215 immunology - Abstract
The B7 family-related protein V-set and Ig containing 4 (VSIG4), also known as Z39Ig and Complement Immunoglobulin Receptor (CRIg), is the most recent of the complement receptors to be identified, with substantially distinct properties from the classical complement receptors. The receptor displays both phagocytosis–promoting and anti-inflammatory properties. The receptor has been reported to be exclusively expressed in macrophages. We now present evidence, that CRIg is also expressed in human monocyte-derived dendritic cells (MDDC), including cell surface expression, implicating its role in the adaptive immunity. Three CRIg transcripts were detected and by Western blotting analysis both the known Long (L) and Short (S) forms were prominent but we also identified another form running between these two. Cytokines regulated the expression of CRIg on dendritic cells, leading to its up- or down regulation. Furthermore, the steroid dexamethasone markedly upregulated CRIg expression, and in co-culture experiments, the dexamethasone conditioned dendritic cells caused significant inhibition of the phytohemagglutinin-induced and alloantigen-induced T cell proliferation responses. In the alloantigen-induced response the production of IFNγ, TNF-α, IL-13, IL-4, and TGF-β1, were also significantly reduced in cultures with dexamethasone-treated DCs. Under these conditions dexamethasone conditioned DCs did not increase the percentage of regulatory T cells (Treg). Interestingly, this suppression could be overcome by the addition of an anti-CRIg monoclonal antibody to the cultures. Thus, CRIg expression may be a control point in dendritic cell function through which drugs and inflammatory mediators may exert their tolerogenic- or immunogenic-promoting effects on dendritic cells.
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- 2019
185. Different Calcium and Src Family Kinase Signaling in Mac-1 Dependent Phagocytosis and Extracellular Vesicle Generation
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Attila Mócsai, Erzsébet Ligeti, Viktória Szeifert, Balázs Bartos, Ákos M. Lőrincz, and Dávid Szombath
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,Phagocytosis ,Immunology ,Macrophage-1 Antigen ,Complement receptor ,complement receptor ,03 medical and health sciences ,Mice ,0302 clinical medicine ,neutrophils ,LYN ,antibacterial effect ,Immunology and Allergy ,Animals ,Humans ,Src family kinase ,Calcium Signaling ,Receptor ,Opsonin ,Original Research ,calcium ,Chemistry ,phagocytosis ,Extracellular vesicle ,Cell biology ,030104 developmental biology ,src-Family Kinases ,Signal transduction ,extracellular vesicles ,signaling ,lcsh:RC581-607 ,030215 immunology - Abstract
Encountering opsonized particles by neutrophils results in phagocytosis of the particle and generation of extracellular vesicles with antibacterial property (aEV). The aim of the present study is to compare the involvement of different receptors and receptor-proximal signaling pathways in these two parallel processes. Investigating human neutrophils from peripheral blood, we show that complement receptors are decisive for both processes whereas immunoglobulin binding Fc receptors (FcR) only participate moderately in phagocytosis and pattern recognition receptors induce mild EV production but only minimal phagocytosis. Studying bone marrow derived neutrophils of genetically modified animals we verify that the involved complement receptor is CR3, also known as the β2 integrin Mac-1. We show that genetic deletion of the adaptor molecules FcRγ chain or DAP12 does not influence either process, suggesting potential redundant function. Combined absence of the Src family kinases Hck, Fgr, and Lyn drastically impairs phagocytosis but does not influence aEV production. In contrast, deletion of PLCγ2 has no influence on phagocytosis, but reduces aEV formation. In accord with the essential role of PLCγ2, aEV biogenesis both from murine and from human neutrophils is dependent on presence of extracellular calcium. Absence of external calcium prevented the generation of antibacterial EVs, whereas the spontaneous EV formation was not influenced. We thus show that phagocytosis and biogenesis of antibacterial EVs are independent processes and proceed on different signaling pathways although the same receptor plays the critical role in both. Our data reveal the possibility in neutrophilic granulocytes to modulate aEV production without disturbing the phagocytic process.
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- 2019
186. Targeting the Immune Complex–Bound Complement C3d Ligand as a Novel Therapy for Lupus
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V. Michael Holers, Liudmila Kulik, Jennifer Laskowski, Rachel A. Woolaver, Brandon Renner, Taras Lyubchenko, Zhiying You, Lian Zhang, and Joshua M. Thurman
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Mice, Inbred MRL lpr ,Complement receptor 1 ,Immunology ,Epitopes, T-Lymphocyte ,chemical and pharmacologic phenomena ,Autoimmunity ,Complement receptor ,Antigen-Antibody Complex ,medicine.disease_cause ,Ligands ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,immune system diseases ,medicine ,Immunology and Allergy ,Animals ,Humans ,Lupus Erythematosus, Systemic ,skin and connective tissue diseases ,B cell ,Autoantibodies ,Mice, Knockout ,Lupus erythematosus ,Systemic lupus erythematosus ,biology ,Chemistry ,Antibodies, Monoclonal ,medicine.disease ,Immune complex ,Disease Models, Animal ,medicine.anatomical_structure ,Complement C3d ,Immunoglobulin G ,Cytokines ,Female ,biology.gene ,Inflammation Mediators ,Biomarkers ,030215 immunology ,Protein Binding - Abstract
Humoral autoimmunity is central to the development of systemic lupus erythematosus (SLE). Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling. C3d and CR2 also mediate immune complex binding to follicular dendritic cells. As the development of SLE involves subversion of normal B cell tolerance checkpoints, one might expect that CR2 ligation by C3d-bound immune complexes would promote development of SLE. However, prior studies in murine models of SLE using gene-targeted Cr2−/− mice, which lack both CR2 and complement receptor 1 (CR1), have demonstrated contradictory results. As a new approach, we developed a highly specific mouse anti-mouse C3d mAb that blocks its interaction with CR2. With this novel tool, we show that disruption of the critical C3d–CR2 ligand-receptor binding step alone substantially ameliorates autoimmunity and renal disease in the MRL/lpr model of SLE.
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- 2019
187. Emerging recognition of the complement system in hepatic ischemia/reperfusion injury, liver regeneration and recovery (Review)
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Guandou Yuan, Zhigao Hu, Yi Zhou, Songqing He, and Cheng-Jie Lin
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0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Complement receptor ,Review ,Pharmacology ,liver ,ischemia/reperfusion injury ,03 medical and health sciences ,Complement inhibitor ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,medicine ,complement ,business.industry ,complement inhibitor ,General Medicine ,medicine.disease ,Liver regeneration ,Complement system ,Transplantation ,030104 developmental biology ,030220 oncology & carcinogenesis ,regeneration ,Hepatectomy ,Complement membrane attack complex ,business ,Reperfusion injury - Abstract
Hepatic ischemia/reperfusion injury (IRI) is a result of the ischemic cascade and may occur in the settings of liver trauma, resection and transplantation. Components of the complement system have been indicated to be mediators of hepatic IRI and regulators of liver regeneration. As such, their potential to mediate both beneficial and harmful effects render them key targets for therapy. In the present study, the mechanisms of complement mediating hepatic IRI were discussed with a focus on the different functions of complement in hepatic injury and liver recovery, and an explanation for this apparent paradox is provided, i.e. that the complement products C3a and C5a have an important role in liver damage; however, C3a and C5a are also necessary for liver regeneration. Furthermore, situated at the end of the complement activation cascade, the membrane attack complex is crucial in hepatic IRI and inhibiting the complex with a site-targeted murine complement inhibitor, complement receptor 2-CD59, may improve liver regeneration after partial hepatectomy, even when hepatectomy is combined with ischemia and reperfusion.
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- 2019
188. IMMU-35. COMPLEMENT SYSTEM AND GLIOBLASTOMA: AN INTRICATE RELATIONSHIP
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Veerakumar Balasubramaniyan, Sabbir Khan, Sandeep Mittal, Shayak Sengupta, Kristin Alfaro-Munoz, John DeGroot, and Kain McGee
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Cancer Research ,Tumor microenvironment ,Immunology ,Complement receptor ,Biology ,medicine.disease ,Complement system ,Oncology ,Macrophage-1 antigen ,Glioma ,Cell separation ,medicine ,Anaphylatoxin ,Neurology (clinical) ,Neuroscience ,Glioblastoma - Abstract
The complement system is a vital part of the innate immune system which plays a critical role in immune surveillance and inflammatory processes. Malignant and host cells express various complement inhibitory proteins on their surface to protect against complement mediated cytotoxicity. Imbalanced complement activation triggers inflammation and alters the tumor microenvironment. Complement activation has been shown to induce proliferation and migration of breast, ovarian and lung cancer cells. At this time, the expression and functional role of the complement cascade in glioblastoma (GBM) remain elusive. Here, we investigated the role of complement proteins and their receptor expression in human primary glioma stem-like cells (GSCs) and human GBM tissues. Western blot data demonstrated a high level of expression of central complement components and their receptors in GSCs. RT-PCR data further confirmed the high expression of complement genes which was similar or higher to normal human astrocytes (HA), a cell with high baseline expression levels of complement genes. Flow cytometry analysis revealed that almost 95% of GSCs expressed the anaphylatoxin complement receptors C3aR and C5aR on their cell surfaces which was consistent with our immunohistochemistry analysis of freshly resected GBM tissues. Furthermore, anaphylatoxin C5a exposure increased the proliferation of a subgroup of GSCs while reduced in another subset. Interestingly, C5a exposure was found to increase the expression of various pro-inflammatory markers in GSCs with reduced proliferation. Fluorescence-activated cell sorting (FACS) analysis of freshly isolated human GBM tissue revealed predominant expression of C5aR on cancer cells (CD11b-/CD45- cells) rather than on immune cells. RT-PCR analysis also demonstrated high expression levels of complement genes with concomitant decrease in complement inhibitory genes in human GBM tissue. Evaluation of the differential role of the complement system in GSCs along with their role in in vivo glioma models is ongoing.
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- 2019
189. Oxidative Stress Increases Endogenous Complement-Dependent Inflammatory and Angiogenic Responses in Retinal Pigment Epithelial Cells Independently of Exogenous Complement Sources
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Nicole Schäfer, Konstanze Kühn, Diana Pauly, Maria Reichenthaler, Ricardo Brandwijk, Joachim Wegener, Volker Enzmann, Florian Urban, Erik J. M. Toonen, and Timon-Orest Trakkides
- Subjects
0301 basic medicine ,Physiology ,ddc:540 ,Clinical Biochemistry ,610 Medizin ,Inflammation ,610 Medicine & health ,Complement receptor ,retinal pigment epithelial cells ,medicine.disease_cause ,Biochemistry ,olaparib ,Article ,oxidative stress ,complement system ,inflammasome ,foxp3 ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Molecular Biology ,ddc:610 ,Retinal pigment epithelium ,biology ,Chemistry ,Cell Biology ,Cell biology ,Complement system ,030104 developmental biology ,medicine.anatomical_structure ,Integrin alpha M ,540 Chemie ,030220 oncology & carcinogenesis ,Factor H ,biology.protein ,Properdin ,sense organs ,medicine.symptom ,Oxidative stress - Abstract
Oxidative stress-induced damage of the retinal pigment epithelium (RPE) and chronic inflammation have been suggested as major contributors to a range of retinal diseases. Here, we examined the effects of oxidative stress on endogenous complement components and proinflammatory and angiogenic responses in RPE cells. ARPE-19 cells exposed for 1&ndash, 48 h to H2O2 had reduced cell&ndash, cell contact and increased markers for epithelial&ndash, mesenchymal transition but showed insignificant cell death. Stressed ARPE-19 cells increased the expression of complement receptors CR3 (subunit CD11b) and C5aR1. CD11b was colocalized with cell-derived complement protein C3, which was present in its activated form in ARPE-19 cells. C3, as well as its regulators complement factor H (CFH) and properdin, accumulated in the ARPE-19 cells after oxidative stress independently of external complement sources. This cell-associated complement accumulation was accompanied by increased nlrp3 and foxp3 expression and the subsequently enhanced secretion of proinflammatory and proangiogenic factors. The complement-associated ARPE-19 reaction to oxidative stress, which was independent of exogenous complement sources, was further augmented by the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. Our results indicate that ARPE-19 cell-derived complement proteins and receptors are involved in ARPE-19 cell homeostasis following oxidative stress and should be considered as targets for treatment development for retinal degeneration.
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- 2019
190. Immune repertoire in the transcriptome of Littorina littorea reveals new trends in lophotrochozoan proto-complement evolution
- Author
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Alexander M. Gorbushin
- Subjects
0301 basic medicine ,Annelida ,Lineage (evolution) ,Gastropoda ,Immunology ,Lophotrochozoa ,Trematode Infections ,Complement receptor ,Complement factor B ,Host-Parasite Interactions ,03 medical and health sciences ,Phagocytosis ,Animals ,Humans ,Complement Activation ,Phylogeny ,Inflammation ,Phylogenetic tree ,biology ,Gene Expression Profiling ,biology.organism_classification ,Biological Evolution ,Invertebrates ,Immunity, Innate ,Receptors, Complement ,Complement system ,030104 developmental biology ,Cephalopoda ,Evolutionary biology ,Complement C3b ,Protostome ,Trematoda ,Transcriptome ,Ecdysozoa ,Complement Factor B ,Developmental Biology - Abstract
The evolution of complement system in invertebrates is poorly investigated. While the repertoire of complement genes in several Ecdysozoa lineages is found substantially different from that of Deuterostomia, the composition and function of the complement in the second protostome lineage, Lophotrochozoa, remains unclear. Here we report the general description of new transcriptomic data on the common periwinkle, Littorina littorea, and trace the evolutionary trajectories of the ancestral proto-complement repertoire. The repertoire is defined as immune cascade providing the minimum set of C3-associated molecules required for C3b amplification, opsonization of the targets and their phagocytosis: thioester protein (TEP) C3, serine protease C2/factor B (Bf) and complement receptors (CR). The reference transcriptome of L. littorea was built from the dual-species RNA-seq experiment with the periwinkle and its tissue digenean parasite Himasthla elongata. Five TEPs, including the ortholog of the C3, are found expressed in the in the mollusk's inflamed tissues. The homolog of the complement receptors CR1/CR2 is also expressed, however the ortholog of Bf is not. The extensive phylogenetic analysis showed that the C3 ortholog and the complement receptors are retained in all key lophotrochozoan taxa: Mollusca, Annelida and Brachiopoda. However, the Bf ortholog was lost at least three times independently in different lineages: i) Cephalopoda, ii) a common ancestor of all Gastropoda and iii) one of the Annelida lineage, Clitellata. Both C3 and Bf molecules were retained in bivalve species, brachiopods and annelid worms from the Polychaeta lineage. Hypothetically, the function of the lost Bf in these animals can be compensated by Factor L (Lf) – the serine protease first found in L. littorea and homologous to both, the Bf and the arthropod factor C (Cf). The contrast differences in proto-complement repertoire between the sister mollusk’ taxa, Bivalvia and Gastropoda (the conserved and modified sets, respectively), can underlie differences in their susceptibility to digenean infection.
- Published
- 2018
191. Formyl-Peptide Receptor Activation Enhances Phagocytosis of Community-Acquired Methicillin-Resistant Staphylococcus aureus
- Author
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Christian Beck, Andreas Peschel, Elisabeth Weiß, Dorothee Kretschmer, and Katja Schlatterer
- Subjects
Methicillin-Resistant Staphylococcus aureus ,0301 basic medicine ,Neutrophils ,Phagocytosis ,Fc receptor ,Macrophage-1 Antigen ,Blood Donors ,Complement receptor ,medicine.disease_cause ,Microbiology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,Receptors, Lipoxin ,Receptor ,Opsonin ,Cells, Cultured ,Formyl peptide receptor ,biology ,Chemistry ,Interleukin-8 ,Receptors, IgG ,Pattern recognition receptor ,Staphylococcal Infections ,Receptors, Formyl Peptide ,Community-Acquired Infections ,030104 developmental biology ,Infectious Diseases ,Staphylococcus aureus ,Receptors, Pattern Recognition ,Receptors, Complement 3b ,biology.protein ,030215 immunology - Abstract
BackgroundFormyl-peptide receptors (FPRs) are important pattern recognition receptors that sense specific bacterial peptides. Formyl-peptide receptors are highly expressed on neutrophils and monocytes, and their activation promotes the migration of phagocytes to sites of infection. It is currently unknown whether FPRs may also influence subsequent processes such as bacterial phagocytosis and killing. Staphylococcus aureus, especially highly pathogenic community-acquired methicillin-resistant S aureus strains, release high amounts of FPR2 ligands, the phenol-soluble modulins.MethodsWe demonstrate that FPR activation leads to upregulation of complement receptors 1 and 3 as well as FCγ receptor I on neutrophils and, consequently, increased opsonic phagocytosis of S aureus and other pathogens.ResultsIncreased phagocytosis promotes killing of S aureus and interleukin-8 release by neutrophils.ConclusionsWe show here for the first time that FPRs govern opsonic phagocytosis. Manipulation of FPR2 activation could open new therapeutic opportunities against bacterial pathogens.
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- 2019
192. Pathogen clearance and immune adherence 'revisited': Immuno-regulatory roles for CRIg
- Author
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Admar Verschoor and Menno van Lookeren Campagne
- Subjects
0301 basic medicine ,Agglutination ,Kupffer Cells ,Immunology ,Complement receptor ,Biology ,Immunomodulation ,03 medical and health sciences ,Immune system ,Animals ,Humans ,Immunology and Allergy ,Opsonin ,Innate immune system ,Pathogen-Associated Molecular Pattern Molecules ,Immune adherence ,Bacterial Infections ,Complement C3 ,Opsonin Proteins ,Acquired immune system ,Receptors, Complement ,Cell biology ,Antibody opsonization ,030104 developmental biology ,Receptors, Pattern Recognition ,Host-Pathogen Interactions ,Immunoglobulin superfamily - Abstract
Rapid elimination of microbes from the bloodstream, along with the ability to mount an adaptive immune response, are essential for optimal host-defense. Kupffer cells are strategically positioned in the liver sinusoids and efficiently capture circulating microbes from the hepatic artery and portal vein, thus preventing bacterial dissemination. In vivo and in vitro studies have probed how complement receptor of the immunoglobulin superfamily (CRIg), also referred to as Z39Ig and V-set and Ig domain-containing 4 (VSIG4), acts as a critical player in pathogen recognition and clearance. While recent data suggested that CRIg may bind bacterial cell wall components directly, the single transmembrane receptor is best known for its interaction with complement C3 opsonization products on the microbial surface. On Kupffer cells, CRIg must capture opsonized microbes against the shear forces of the blood flow. In vivo work reveals how immune adherence (IA), a process in which blood platelets or erythrocytes associate with circulating bacteria, plays a critical role in regulating pathogen capture by CRIg under flow conditions. In addition to its typical innate immune functions, CRIg was shown to directly and indirectly influence adaptive immune responses. Here, we review our current understanding of the diverse roles of CRIg in pathogen elimination, anti-microbial immunity and autoimmunity. In particular, we will explore how, through selective capturing by CRIg, an important balance is achieved between the immunological and clearance functions of liver and spleen.
- Published
- 2018
193. Clinical and immunological effects of adsorptive myeloid lineage leukocyte apheresis in patients with immune disorders
- Author
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Takuro Kanekura
- Subjects
Myeloid ,030232 urology & nephrology ,Dermatology ,Complement receptor ,Granulocyte ,Skin Diseases ,Monocytes ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Psoriatic arthritis ,0302 clinical medicine ,Immune system ,medicine ,Humans ,Leukapheresis ,business.industry ,Monocyte ,General Medicine ,medicine.disease ,Treatment Outcome ,medicine.anatomical_structure ,Immune System Diseases ,Rheumatoid arthritis ,Immunology ,Myeloid-derived Suppressor Cell ,Adsorption ,business ,Granulocytes - Abstract
Adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn® is an extracorporeal treatment, which uses cellulose acetate (CA) beads as adsorptive leukocytapheresis carriers designed to remove elevated and potentially activated myeloid lineage leukocytes. Reports on the clinical efficacy of GMA in patients with skin lesions have appeared in the published work. Dermatological diseases, which are known to respond to GMA, include pyoderma gangrenosum, skin lesions of Behcet's disease, rheumatoid arthritis, pustular psoriasis, psoriatic arthritis, adult-onset Still's disease, Sweet's syndrome, cutaneous allergic vasculitis and systemic lupus erythematosus rashes. In association with clinical studies, efforts to understand the mechanisms of GMA have made significant progress. GMA selectively depletes elevated myeloid lineage leukocytes through binding between blood immunoglobulin G or complement iC3b, which form on the surface of CA beads and the Fcγ receptors or complement receptors expressed on the myeloid lineage cells. However, GMA has immunomodulatory effects including down-modulation of inflammatory cytokine profile, changes in leukocyte surface receptors and induction of regulatory T cells. These actions render GMA a unique non-pharmacological treatment option for patients with chronic dermatoid conditions, which are difficult to treat with pharmacological preparations.
- Published
- 2018
194. Expression of complement receptor 3 (CR3) and regulatory protein CD46 on dendritic cells of antiretroviral naïve and treated HIV-1 infected individuals: Correlation with immune activation status
- Author
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Madhav Mohata, Anjali Hazarika, Omkar Chaudhary, Nitesh Mishra, Sanjeev Sinha, Bimal Kumar Das, Heena Aggarwal, and Kalpana Luthra
- Subjects
Adult ,Male ,0301 basic medicine ,Anti-HIV Agents ,Immunology ,Macrophage-1 Antigen ,HIV Infections ,Complement receptor ,Biology ,Membrane Cofactor Protein ,03 medical and health sciences ,0302 clinical medicine ,Viral envelope ,Viral entry ,Humans ,Molecular Biology ,Opsonin ,Host cell membrane ,CD46 ,Dendritic Cells ,Complement system ,Antibody opsonization ,030104 developmental biology ,HIV-1 ,Female ,030215 immunology - Abstract
During infection and budding, human immunodeficiency virus-1 (HIV-1) acquires regulators of Complement Activation (RCAs) along with the host cell membrane on the viral envelope. Activation of host complement system results in opsonization of virus by complement fragments, however the virus evades complement mediated lysis (CoML) by virtue of the RCAs on the viral envelope. The RCAs on HIV-1 envelope process complement protein C3 into various fragments that promote viral entry and infection of cells through different complement receptors. Complement opsonized HIV-1 has been shown in vitro to infect dendritic cells (DCs) in a CR3 dependent manner, although the role of CR3 and CD46 in natural HIV-1 infection is not clear. Surface expression of CR3 and CD46 on DC subsets of 30 antiretroviral naïve, 31 treated (cART) HIV-1 infected individuals and 30 seronegative controls was measured by flow cytometry and plasma levels of cytokines and complement activity (C3c levels) were quantitated by sandwich ELISA. Significantly lower surface expression of CR3 and CD46 was observed on DC subsets in naïve and treated HIV-1 infected individuals compared to controls. Significantly higher complement activation and plasma levels of IL-4, IL-8, IL-10 and IFN-γ were observed in treatment naïve HIV-1 infected individuals than controls. Significantly lower plasma levels of IL-4, IL-6, IL-8 and IL-10 were observed in treated vs. naïve HIV-1 infected individuals. Our findings suggest that alterations in expression of CR3 and CD46 on DCs along with complement activity could be factors that influence viral persistence and HIV-1 disease progression and need to be further evaluated.
- Published
- 2018
195. Backbone 1H, 13C, and 15N assignments of the extracellular region of human Fcγ receptor IIIb
- Author
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Rina Yogo, Koichi Kato, and Saeko Yanaka
- Subjects
0301 basic medicine ,biology ,Chemistry ,Phagocytosis ,Degranulation ,Complement receptor ,Biochemistry ,Immunoglobulin G ,03 medical and health sciences ,030104 developmental biology ,Immune system ,Structural Biology ,biology.protein ,Extracellular ,Receptor ,Opsonin - Abstract
Fcγ receptor (FcγR) promotes various immune responses through interactions with the Fc portion of immunoglobulin G (IgG). FcγRIIIb is a glycosylphosphatidylinositol-linked protein expressed on neutrophils and triggers degranulation and opsonic phagocytosis. The extracellular region of FcγR is composed of two Ig-fold domains and can be cleaved as a soluble form (sFcγRIIIb), which is also reactive with complement receptor type 3. Although structure and Fc interaction of sFcγRIIIb have been characterized by X-ray crystallography, little has been known about its structure in solution. We herein report the backbone NMR assignments of human sFcγRIIIb to gain basic understanding of functional IgG-FcγRIII interactions of immunological and biopharmaceutical interest regarding the structural investigation.
- Published
- 2018
196. Role of complement anaphylatoxin receptors in a mouse model of acute burn-induced pain
- Author
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Irina Vetter, Jennifer R. Deuis, Richard J. Lewis, Michael M. Morgan, and Trent M. Woodruff
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Immunology ,Pain ,Inflammation ,Complement receptor ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Anaphylatoxin ,Receptor ,Receptor, Anaphylatoxin C5a ,Molecular Biology ,Mice, Knockout ,Anaphylatoxin receptors ,business.industry ,Receptors, Complement ,Complement system ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Hyperalgesia ,Acute Disease ,Neuropathic pain ,Female ,medicine.symptom ,Burns ,business ,030217 neurology & neurosurgery - Abstract
The complement system is an essential component of the innate immune response. The anaphylatoxins C3a and C5a are key drivers of the complement system, acting through the receptors C3aR, C5aR1 and C5aR2 to regulate inflammation. While a role for C5a activation of C5aR1 in inflammatory and neuropathic pain has been established, the role of the complement system in burn-induced pain has not been investigated. To address this gap, we assessed the role of complement receptors C3aR, C5aR1 and C5aR2 in a mouse model of acute burn-induced pain. Superficial burn injury was induced in C57BL/6 mice by firm application of left hind paw plantar surface to a hot plate set at 52.5 °C for 25 s. Development of burn-induced mechanical allodynia, thermal allodynia, weight bearing changes and edema was assessed in C3aR-/-, C5aR1-/- and C5aR2-/- mice and compared to their wild type controls over three days. Burn-induced mechanical allodynia, thermal allodynia and weight bearing changes developed normally C3aR-/-, C5aR1-/- and C5aR2-/- mice. However, burn-induced edema was significantly reduced in C5aR2-/- male mice, but not C5aR2-/- female mice. These results suggest that the complement system has a limited role in the development of acute burn-induced pain.
- Published
- 2018
197. C5aR activation in the absence of C5a: A new disease mechanism of autoimmune hemolytic anemia in mice
- Author
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Bernhard Brüne, Mareen Ziegelmann, Georgios Sogkas, Reinhold E. Schmidt, Shahzad N. Syed, and Eduard Rau
- Subjects
0301 basic medicine ,Erythrocytes ,Kupffer Cells ,Immunology ,Autoimmunity ,Complement C5a ,Complement receptor ,Disease ,Biology ,Mice ,03 medical and health sciences ,Phagocytosis ,Downregulation and upregulation ,medicine ,Animals ,Immunology and Allergy ,Receptor, Anaphylatoxin C5a ,Mice, Knockout ,C5a ANAPHYLATOXIN RECEPTOR ,Mechanism (biology) ,Receptors, IgG ,medicine.disease ,Erythrophagocytosis ,Mice, Inbred C57BL ,030104 developmental biology ,New disease ,Anemia, Hemolytic, Autoimmune ,Autoimmune hemolytic anemia - Abstract
IgG Fc receptors (FcγRs) and the C5a anaphylatoxin receptor (C5aR) were identified as key regulators of type II autoimmune injury in mice. However, and with respect to C5aR, the relative importance of C5a for IgG autoantibody-induced cellular destruction remained unclear. Using an experimental model of autoimmune hemolytic anemia (AIHA), we here report marked differences in the development of AIHA between mice lacking C5aR and C5-deficient (Hc0 ) strain, indicating a limited role of C5 in this type of C5aR-regulated disease. Ex-vivo-analyses of liver homogenates from anemic Hc0 mice demonstrate C5a-independent C5aR activation, upregulation of FcγR expression and amplification of erythrophagocytosis by macrophages. As assessed by pharmacological inhibition studies, targeting of C5aR, but not of C5, is effective in treating experimental AIHA. Collectively, these results define a previously unrecognized disease mechanism of C5aR activation in AIHA that does not necessarily involve C5 and C5a.
- Published
- 2018
198. Chemical Approaches to Modulating Complement-Mediated Diseases
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Weijun Xu, David P. Fairlie, Abishek Iyer, and Robert Reid
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0301 basic medicine ,Cell ,Inflammation ,Complement receptor ,Disease ,Biology ,Autoimmune Diseases ,03 medical and health sciences ,Classical complement pathway ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Complement Activation ,Complement System Proteins ,3. Good health ,Complement system ,Complement Inactivating Agents ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,biology.protein ,Molecular Medicine ,medicine.symptom ,Antibody ,030215 immunology - Abstract
Numerous diseases are driven by chronic inflammation, placing major burdens on our health systems. Controlling inflammation is an important preventative and therapeutic goal. Over 40 "Complement" proteins are produced in blood or on cell surfaces through activation of the Complement protein network mainly by infection or injury. These proteins complement immune cells and antibodies to identify, tag, destroy, and eliminate pathogens and infected or damaged cells and repair tissues. If the inflammatory stimulus is not removed by localized acute immune responses, Complement activation may be prolonged or misdirected to healthy cells, and chronic inflammation can lead to inflammatory or autoimmune diseases. The formation, structures, and interplay between Complement proteins are complex, and this has limited our detailed understanding of their roles and importance in physiology and disease. With the availability of new structures for Complement proteins, new knowledge of how they function, and new modulators of Complement-driven signaling, there are also new opportunities to intervene in Complement-mediated disease. Small molecule and peptide-based drug leads, identified as clues for Complement-directed therapeutic development, are assembled here together with the available evidence for their efficacy in cellular and animal models of human inflammatory disease and in some human clinical conditions.
- Published
- 2017
199. Rare Inherited Defects of the Complement System in Purpura Fulminans
- Author
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Walter H. Dzik, Betty Rouaisnel, Agnes Toth-Petroczy, Michael Bouzinier, Justine H. Ryu, Olga Pozdnyakova, Bryce E. Pasko, Richard L. Maas, Valentina Nardi, Joel B. Krier, Julie-Aurore Losman, Pavan K. Bendapudi, Lindsay Tomczak, James Hudspeth, Elizabeth L. Fieg, Onuralp Soylemez, Alissa Robbins, Sanjay Ram, and Meaghan Colling
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Complement receptor ,medicine.disease ,Biochemistry ,Thrombosis ,Sepsis ,Internal medicine ,Cohort ,Coagulopathy ,medicine ,Complication ,business ,Exome sequencing ,Purpura fulminans - Abstract
Background: Purpura fulminans (PF) is a rare but devastating complication of sepsis in which patients experience overwhelming systemic thrombosis leading to end organ damage, distal limb ischemia, and death. Survivors are often left with lifelong disfigurement and/or disability due to severe acral tissue injury and the need for amputation of necrotic extremities. Given that most patients who develop PF have no known underlying medical conditions and are much younger than those typically afflicted with sepsis, we sought to investigate whether genetic determinants predispose individuals to developing PF. Methods: We performed whole exome sequencing on the Boston PF Cohort (N=40). We used pathway-based collapsing analysis (PBCA) combined with mutational burden testing to evaluate for enrichment of rare coding variants in the complement system using as a comparator unselected patients with sepsis from the NHLBI ARDSnet iSPAAR cohort (N=87). Several novel variants in integrin complement receptors were identified and subsequently cloned and functionally characterized. Results: Patients in the Boston PF Cohort were relatively young at the time of presentation, with a median (IQR) age of 37.5 (20.3-58.8) years. Patients were afflicted with gram negative organisms 45% of the time, while 27.5% were infected with gram positive organisms. In another 27.5%, no pathogen was identified. PF patients had strikingly abnormal markers of severe sepsis and coagulopathy, including the following median (IQR) values: lactate 7.1 (5.3-11.8) mmol/L, platelet count 28,000 (15,000-48,500) per μl, aPTT 68.0 (48.3-142.5) seconds, INR 2.8 (1.9-4.0), and protein C activity 26.0% (13.5-38.5). No patient had a known congenital immune defect. Whole exome sequencing (mean read depth 80X) identified 30 unique heterozygous complement system variants in 26/40 (65%) patients with PF (Figure 1A-B). Variants in this pathway were highly enriched in PF patients compared to the control cohort (P Conclusions: Our data suggest that rare inherited defects in the complement system predispose individuals to the maladaptive thrombo-inflammatory response to infection that characterizes PF. By advancing our understanding of the molecular pathogenesis of PF, this work could provide important insights into the broader problem of coagulopathy in sepsis. Furthermore, targeted gene discovery approaches based on PBCA may serve as a model for future genomic studies of rare hemostatic diseases. Disclosures No relevant conflicts of interest to declare.
- Published
- 2020
200. Phagocytic receptors on macrophages distinguish between different Sporothrix schenckii morphotypes
- Author
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Guzman-Beltran, Silvia, Perez-Torres, Armando, Coronel-Cruz, Cristina, and Torres-Guerrero, Haydee
- Subjects
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SPOROTRICHOSIS , *PHAGOCYTES , *MACROPHAGES , *PATHOGENIC microorganisms , *MYCOSES , *IMMUNE response , *PHAGOCYTOSIS , *CONIDIA , *N-acetylglucosamine , *REACTIVE oxygen species - Abstract
Abstract: Sporothrix schenckii is a human pathogen that causes sporotrichosis, a cutaneous subacute or chronic mycosis. Little is known about the innate immune response and the receptors involved in host recognition and phagocytosis of S. schenckii. Here, we demonstrate that optimal phagocytosis of conidia and yeast is dependent on preimmune human serum opsonisation. THP-1 macrophages efficiently ingested opsonised conidia. Competition with d-mannose, methyl α-d-mannopyranoside, d-fucose, and N-acetyl glucosamine blocked this process, suggesting the involvement of the mannose receptor in binding and phagocytosis of opsonised conidia. Release of TNF-α was not stimulated by opsonised or non-opsonised conidia, although reactive oxygen species (ROS) were produced, resulting in the killing of conidia by THP-1 macrophages. Heat inactivation of the serum did not affect conidia internalization, which was markedly decreased for yeast cells, suggesting the role of complement components in yeast uptake. Conversely, release of TNF-α and production of ROS were induced by opsonised and non-opsonised yeast. These data demonstrate that THP-1 macrophages respond to opsonised conidia and yeast through different phagocytic receptors, inducing a differential cellular response. Conidia induces a poor pro-inflammatory response and lower rate of ROS-induced cell death, thereby enhancing the pathogen''s survival. [Copyright &y& Elsevier]
- Published
- 2012
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