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Blandin, Stéphanie A., Eric Marois, and Elena A. Levashina. "Antimalarial Responses in Anopheles gambiae: From a Complement-like Protein to a Complement-like Pathway." Cell Host & Microbe 3, no. 6 (June 2008): 364–74. http://dx.doi.org/10.1016/j.chom.2008.05.007.
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Delvaeye, Mieke, Astrid DeVriese, Michael Moons, Naomi Esmon, Charles Esmon, and Edward M. Conway. "Regulation of Complement Activation by Thrombomodulin." Blood 114, no. 22 (November 20, 2009): 5127. http://dx.doi.org/10.1182/blood.v114.22.5127.5127.
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Abstract Abstract 5127 Thrombomodulin (TM) is an integral membrane glycoprotein, ubiquitously expressed by vascular endothelial cells. Its epidermal growth factor (EGF)-like repeats amplify thrombin-mediated generation of activated protein C and activated thrombin activatable fibrinolysis inhibitor, thereby suppressing coagulation, inflammation and fibrinolysis, and inactivating the anaphylatoxins, C3a and C5a. TM also has direct anti-inflammatory properties, interfering with leukocyte adhesion, and preventing complement activation via its lectin-like domain. We recently established that TM is a physiologically important negative regulator of the alternative pathway (AP) of complement activation, defects of which increase the risk of the thrombotic microangiopathy, atypical hemolytic uremic syndrome. In this report, we assessed the role of TM in the other complement activation pathways. In serum, TM interferes with classical pathway (CP) mediated erythrocyte cell lysis, and protects against CP-induced cell death. TM co-precipitates with C4b, and enhances its inactivation and cleavage to C4c and C4d by complement factor I in the presence of the cofactor C4b binding protein. TM also interferes with the coagulation complement pathway by interfering with thrombin cleavage and activation of C5 to C5a. Overall, TM negatively regulates complement via the major recognized pathways. The findings implicate defects in TM in a wide range of diseases in which complement plays a role, and underlines the potential of TM as a therapeutic target. Disclosures No relevant conflicts of interest to declare.
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Zhang, Kang, Jingyan Zhang, Lei Wang, Qiang Liang, Yuhui Niu, Linlin Gu, Yanming We, and Jianxi Li. "Integrative Transcriptomics and Proteomics Analysis Reveals Immune Response Process in Bovine Viral Diarrhea Virus-1-Infected Peripheral Blood Mononuclear Cells." Veterinary Sciences 10, no. 10 (September 28, 2023): 596. http://dx.doi.org/10.3390/vetsci10100596.
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Bovine viral diarrhea virus (BVDV) causes bovine viral diarrhea-mucosal disease, inflicting substantial economic losses upon the global cattle industry. Peripheral blood mononuclear cells (PBMCs) are the central hub for immune responses during host-virus infection and have been recognized as crucial targets for BVDV infection. In order to elucidate the dynamics of host-BVDV-1 interaction, this study harnessed RNA-seq and iTRAQ methods to acquire an extensive dataset of transcriptomics and proteomics data from samples of BVDV-1-infected PBMCs at the 12-h post-infection mark. When compared to mock-infected PBMCs, we identified 344 differentially expressed genes (DEGs: a total of 234 genes with downregulated expression and 110 genes with upregulated expression) and 446 differentially expressed proteins (DEPs: a total of 224 proteins with downregulated expression and 222 proteins with upregulated expression). Selected DEGs and DEPs were validated through quantitative reverse transcriptase-polymerase chain reaction and parallel reaction monitoring. Gene ontology annotation and KEGG enrichment analysis underscored the significant enrichment of DEGs and DEPs in various immunity-related signaling pathways, including antigen processing and presentation, complement and coagulation cascades, cytokine-cytokine receptor interaction, and the NOD-like receptor signaling pathway, among others. Further analysis unveiled that those DEGs and DEPs with downregulated expression were predominantly associated with pathways such as complement and coagulation cascades, the interleukin-17 signaling pathway, cytokine-cytokine receptor interaction, the PI3K-Akt signaling pathway, the tumor necrosis factor signaling pathway, and the NOD-like receptor signaling pathway. Conversely, upregulated DEGs and DEPs were chiefly linked to metabolic pathways, oxidative phosphorylation, complement and coagulation cascades, and the RIG-I-like receptor signaling pathway. These altered genes and proteins shed light on the intense host-virus conflict within the immune realm. Our transcriptomics and proteomics data constitute a significant foundation for delving further into the interaction mechanism between BVDV and its host.
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Kim, Sook Young, Sang Eun Lee, Man Sup Kwak, and Jeon-Soo Shin. "Regulatory Role of HMGB1 on complement activation via the classical pathway (169.3)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 169.3. http://dx.doi.org/10.4049/jimmunol.188.supp.169.3.
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Abstract Serum complement proteins play an important role in resistance to infection. The complement system is strongly activated in sepsis and the complement-activated products of anaphylatoxins have biological activities leading to inflammation. The nuclear protein, high mobility group box 1 protein (HMGB1) is released by inflammatory stimuli and plays a key role as a pro-inflammatory cytokine-like molecule. To investigate whether HMGB1 can induce complement activation, we have looked at the relationship between HMGB1 and complement system in this study. We first demonstrated the involvement of HMGB1 in binding to C1q for classical pathway activation. We observed the activation of complement cascade components such as C4b, C3b, C3c, and the membrane attack complex after C1q activation by HMGB1 in a dose-dependent manner. Moreover, complement activation could be observed in serum from mice after the intravenous injection of HMGB1. We then investigated the involvement of the A and B domain of HMGB1 during complement activation. HMGB1 B box, a well-known pro-inflammatory domain, was able to activate the complement system like wild type HMGB1, while HMGB1 A box showed no activation. The possible role of HMGB1 A box as an inhibitory domain in complement activation is now under investigation. In conclusion, the classical pathway of complement activation could be activated by the interaction of HMGB1 and C1q, showing the novel role of HMGB1 in the pathogenesis of HMGB1-induced shock.
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De Marco Verissimo, Carolina, Heather L. Jewhurst, József Dobó, Péter Gál, John P. Dalton, and Krystyna Cwiklinski. "Fasciola hepatica is refractory to complement killing by preventing attachment of mannose binding lectin (MBL) and inhibiting MBL-associated serine proteases (MASPs) with serpins." PLOS Pathogens 18, no. 1 (January 10, 2022): e1010226. http://dx.doi.org/10.1371/journal.ppat.1010226.
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The complement system is a first-line innate host immune defence against invading pathogens. It is activated via three pathways, termed Classical, Lectin and Alternative, which are mediated by antibodies, carbohydrate arrays or microbial liposaccharides, respectively. The three complement pathways converge in the formation of C3-convertase followed by the assembly of a lethal pore-like structure, the membrane attack complex (MAC), on the pathogen surface. We found that the infectious stage of the helminth parasite Fasciola hepatica, the newly excysted juvenile (NEJ), is resistant to the damaging effects of complement. Despite being coated with mannosylated proteins, the main initiator of the Lectin pathway, the mannose binding lectin (MBL), does not bind to the surface of live NEJ. In addition, we found that recombinantly expressed serine protease inhibitors secreted by NEJ (rFhSrp1 and rFhSrp2) selectively prevent activation of the complement via the Lectin pathway. Our experiments demonstrate that rFhSrp1 and rFhSrp2 inhibit native and recombinant MBL-associated serine proteases (MASPs), impairing the primary step that mediates C3b and C4b deposition on the NEJ surface. Indeed, immunofluorescence studies show that MBL, C3b, C4b or MAC are not deposited on the surface of NEJ incubated in normal human serum. Taken together, our findings uncover new means by which a helminth parasite prevents the activation of the Lectin complement pathway to become refractory to killing via this host response, in spite of presenting an assortment of glycans on their surface.
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Irmscher, Sarah, Nadia Döring, Luke D. Halder, Emeraldo A. H. Jo, Isabell Kopka, Christine Dunker, Ilse D. Jacobsen, et al. "Kallikrein Cleaves C3 and Activates Complement." Journal of Innate Immunity 10, no. 2 (December 14, 2017): 94–105. http://dx.doi.org/10.1159/000484257.
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The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein-kinin, the coagulation, and the fibrinolytic systems. Previous work shows that the contact system also activates complement, and that plasma enzymes like kallikrein, plasmin, thrombin, and FXII are involved in the activation process. Here, we show for the first time that kallikrein cleaves the central complement component C3 directly to yield active components C3b and C3a. The cleavage site within C3 is identical to that recognized by the C3 convertase. Also, kallikrein-generated C3b forms C3 convertases, which trigger the C3 amplification loop. Since kallikrein also cleaves factor B to yield Bb and Ba, kallikrein alone can trigger complement activation. Kallikrein-generated C3 convertases are inhibited by factor H; thus, the kallikrein activation pathway merges with the amplification loop of the alternative pathway. Taken together, these data suggest that activation of the contact system locally enhances complement activation on cell surfaces. The human pathogenic microbe Candida albicans activates the contact system in normal human serum. However, C. albicans immediately recruits factor H to the surface, thereby evading the alternative and likely kallikrein-mediated complement pathways.
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Koethe, S. M., K. E. Nelson, and C. G. Becker. "Activation of the classical pathway of complement by tobacco glycoprotein (TGP)." Journal of Immunology 155, no. 2 (July 15, 1995): 826–35. http://dx.doi.org/10.4049/jimmunol.155.2.826.
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Abstract Tobacco glycoprotein (TGP), a polyphenol-rich glycoprotein isolated from tobacco leaves, activates the classical complement pathway through a mechanism that appears to involve direct interaction with C1q. A binding site on C1q for TGP can be localized by competitive inhibition with DNA to a region located in the junction between the collagen-like and globular regions of the molecule. A protein with activity similar to TGP has also been isolated from cigarette smoke condensate (TGP-S); it shares a binding site on C1q with TGP and has similar functional activity, with the exception that complement activation does not proceed to formation of a C3 cleaving enzyme. The ability of TGP and TGP-S to activate complement can be partially duplicated using polyphenols associated with tobacco leaf and smoke, i.e., chlorogenic acid and rutin. These polyphenols also compete with TGP for a binding site on immobilized C1q, suggesting that the polyphenol portion of TGP is critical for activation of complement. These results provide an additional mechanism for complement activation by cigarette products that, in vivo, could result in a localized complement depletion, generation of biologically active complement cleavage products, and initiation of an inflammatory response.
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Lee, Garam, Yonghyan Nam, Manu Shivakumar, Apoorva Joshi, Weixuan Fu, Rebecca Anne Simmons, Paul Wang, Dokyoon Kim, and Sara Elizabeth Pinney. "A Novel Graph Based Semi-Supervised Learning Approach to Identify Pathways Contributing to the Development of Diabetes and Obesity." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A656—A657. http://dx.doi.org/10.1210/jendso/bvab048.1339.
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Abstract Background: Gestational diabetes (GDM) has profound effects on the intrauterine metabolic milieu, induces marked abnormalities in fetal glucose and insulin secretion and is linked to obesity and diabetes in the offspring, but the mechanisms remain largely unknown. Epigenetic modifications in stems cells may be one mechanism by which an in utero exposure can lead to the development of diabetes and obesity later in life. Objective: To identify novel pathways contributing to the development of diabetes and obesity in offspring exposed to GDM in utero by integrating data generated from transcriptome and methylome analysis from second trimester human amniocytes exposed to GDM in utero. Methods: We analyzed RNAseq and genome wide DNA methylation data (ERRBS) generated from second trimester amniocytes obtained from women with GDM (n=14). Amniocytes have stem cells-like characteristics and are derived from the fetus. Expression data of 22,271 genes were retrieved from RNAseq data. CpGs with significant changes in DNA methylation were mapped into 20,028 genes by collapsing methylation probes into promoter and gene regions. To better understand the associations among diverse gene sets or among gene sets and GDM,we first constructed two weighted co-expression networks from RNAseq and DNA methylation data, respectively. Then, two co-expression networks were integrated using a linear combination. With the integrated co-expression network, graph-based label propagation algorithm was employed to prioritize GDM-associated genes. Results: From the differential expression analysis between GDM and control, the top 20 query genes, including 11 genes and 9 methylated genes, were selected for label propagation. Finally, the top 100 genes were picked up for the pathway enrichment testusing an over-representation analysis approach. Significantly enriched pathways included: Interferon Signaling, N-glycan Antennae Elongation, Sphingolipid Pathway and Metabolism, Classical Complement Pathway, Complement and Coagulation Cascades, Tryptophan Metabolism, Peroxisomal Protein Import, Unsaturated Fatty Acid Metabolism, Complement Activation, Human Innate Immune Response, Ceramide Metabolism, Fertilization Pathway, Keratan Sulfate Biosynthesis Pathway, Transport to the Golgi and Modification Pathway (FDR q<0.05 for all pathways). Conclusion: Using a novel bioinformatic approach to synthesize transcriptome and methylome data derived from human amniocytes exposed to GDM in utero, we identified potential pathways involved in programming of diabetes and obesity in offspring including pathways involving the immune response, complex lipid metabolism, the complement pathway, and protein transport and processing. Further investigation of these pathways may yield new mechanisms contributing to diabetes and obesity.
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Györffy, Balázs A., Judit Kun, György Török, Éva Bulyáki, Zsolt Borhegyi, Péter Gulyássy, Viktor Kis, et al. "Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning." Proceedings of the National Academy of Sciences 115, no. 24 (May 29, 2018): 6303–8. http://dx.doi.org/10.1073/pnas.1722613115.
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C1q, a member of the immune complement cascade, is implicated in the selective pruning of synapses by microglial phagocytosis. C1q-mediated synapse elimination has been shown to occur during brain development, while increased activation and complement-dependent synapse loss is observed in neurodegenerative diseases. However, the molecular mechanisms underlying C1q-controlled synaptic pruning are mostly unknown. This study addresses distortions in the synaptic proteome leading to C1q-tagged synapses. Our data demonstrated the preferential localization of C1q to the presynapse. Proteomic investigation and pathway analysis of C1q-tagged synaptosomes revealed the presence of apoptotic-like processes in C1q-tagged synapses, which was confirmed experimentally with apoptosis markers. Moreover, the induction of synaptic apoptotic-like mechanisms in a model of sensory deprivation-induced synaptic depression led to elevated C1q levels. Our results unveiled that C1q label-based synaptic pruning is triggered by and directly linked to apoptotic-like processes in the synaptic compartment.
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Staels, F., W. Meersseman, P. Stordeur, K. Willekens, S. Van Loo, A. Corveleyn, I. Meyts, G. Meyfroidt, and R. Schrijvers. "Terminal Complement Pathway Deficiency in an Adult Patient with Meningococcal Sepsis." Case Reports in Immunology 2022 (May 23, 2022): 1–6. http://dx.doi.org/10.1155/2022/9057000.
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The complement system is an essential part of our innate immune system. Three enzymatic activation pathways are described, all converging into a common terminal pathway which causes lysis of the target cell. Late complement deficiencies (LCDs) are typically diagnosed in children or adolescents with invasive meningococcal disease (IMD). However, IMD can also be a first manifestation in adulthood and should prompt for the evaluation of the LCD. We report the case of a young adult with IMD who was found to have a LCD, caused by a compound heterozygous mutation in C6. His vaccination status was optimized and prophylactic antibiotic treatment was initiated. By means of this case, we would like to raise awareness of underlying LCD in (young) adults presenting with IMD by N. meningitidis. Screening for complement deficiencies after IMD, followed by genetic testing, can be lifesaving and allows for genetic counselling. In addition, we discuss the diagnosis and treatment of LCD.
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Fontana, Pâmela Dias, Lorena Bavia, Fernanda Bovo, Ariádine Reder C. de Souza, Marcos Lúcio Corazza, and Iara Jose Messias-Reason. "Supercritical Extracts from Arctium lappa as a Potential Inhibitor for the Activation of Complement System." Planta Medica International Open 6, no. 02 (November 2019): e63-e69. http://dx.doi.org/10.1055/a-1025-0085.
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Abstract Arctium lappa is a perennial species of the Asteraceae family originally from Europe and Asia. Considered a weed species in the southern region of Brazil, it is popularly used as a natural anti-inflammatory. The complement system is an important component of the innate immune response. However, its exacerbated activation can lead to harmful conditions like autoimmune and inflammatory disorders. Plants that inhibit the activation of complement can be a promising tool in the treatment of inflammatory diseases. Here, we evaluated the effect of A. lappa leaves extracts on the activation of the classical and alternative pathways of complement system. Two extracts were obtained under supercritical conditions using scCO2 with ethanol as cosolvent, at 313.15K, 15 MPa (E1) and 25 MPa (E2). Classical and alternative activation were evaluated using complement fixation test. Different concentrations of A. lappa extracts E1 and E2 showed an inhibitory effect on both complement pathways, and heparin was used as control. The IC50 of E1, E2, and heparin were 28.26, 20.12 and 92.54 µg/mL for classical and 26.12, 27.70, 27.78 µg/mL for the alternative pathway. Results demonstrate that A. lappa is a promising complementary treatment for diseases associated with complement activation.
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Blackwell, J. M., R. A. Ezekowitz, M. B. Roberts, J. Y. Channon, R. B. Sim, and S. Gordon. "Macrophage complement and lectin-like receptors bind Leishmania in the absence of serum." Journal of Experimental Medicine 162, no. 1 (July 1, 1985): 324–31. http://dx.doi.org/10.1084/jem.162.1.324.
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We have examined the relative roles of the macrophage (M phi) plasma membrane receptor for the cleaved third complement component (iC3b, CR3) and of the mannosyl/fucosyl receptor (MFR) in binding and ingestion of Leishmania donovani. In the absence of exogenous complement, the binding and ingestion of promastigotes, which are good activators of the alternative complement pathway, were inhibited by the anti-CR3 monoclonal antibody M1/70, by the Fab portion of an anti-C3 antibody, or by the nucleophile, sodium salicyl hydroxamate, an inhibitor of C3 fixation. This provides strong evidence that M phi-derived, cleaved C3 (iC3b) present on the promastigote surface mediates binding to CR3. Equivalent inhibition of promastigote binding and ingestion was also observed using the soluble inhibitors of MFR activity, mannan or ribonuclease B. No additive effect for blocking the two M phi receptors simultaneously was observed. For amastigotes, which are poor activators of the alternative pathway, a lesser but nevertheless equivalent effect was observed for the three soluble inhibitors of CR3-mediated binding vs. the two soluble inhibitors of MFR-mediated binding. Modulation experiments in which either CR3 or MFR had been rendered inaccessible demonstrated that both receptors must be present on the segment of M phi membrane to which the parasite binds. The combined function of these two distinct M phi receptors may provide a general mechanism for recognition and ingestion of other pathogenic protozoa known to activate the alternative pathway.
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Suankratay, Chusana, Xiao-Hui Zhang, Yonghong Zhang, Thomas F. Lint, and Henry Gewurz. "Requirement for the Alternative Pathway as Well as C4 and C2 in Complement-Dependent Hemolysis Via the Lectin Pathway." Journal of Immunology 160, no. 6 (March 15, 1998): 3006–13. http://dx.doi.org/10.4049/jimmunol.160.6.3006.
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Abstract Mannan-binding lectin (MBL) is a C1q-like molecule opsonic for several micro-organisms. MBL can activate C4, C2, and later acting complement components in the presence of serine proteases similar to but distinct from C1r and C1s via the lectin pathway of complement activation. We report here that mannan-coated MBL-sensitized erythrocytes are lysed via the lectin pathway in human serum-Mg-EGTA. The surprising occurrence of MBL-initiated lysis in the absence of calcium contrasts with the calcium requirement for C1q-initiated activation of C4 and C2. C2 is required, and lysis is significantly enhanced when indicator cells presensitized with C4 and then coated with mannan (EAC4-M) are used. The alternative pathway also is required, since lysis is lost when either factor D or factor B is removed and is restored upon reconstitution with the purified protein. Even though MBL is a C-type lectin, it is retained on mannan-coated erythrocytes in the absence of calcium. This contrasts with the absence of calcium-independent retention on mannan immobilized on polystyrene plates or beads, and helps explain the MBL-initiated hemolysis in Mg-EGTA. These investigations show that the alternative pathway as well as C4 and C2 of the classical pathway are required for complement-dependent hemolysis via the lectin pathway and provide a method for assay of lectin pathway-mediated complement activity in human serum that should be useful in unraveling the molecular interactions of this pathway.
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Jodele, Sonata, Mario Medvedovic, Nathan Luebbering, Jenny Chen, Christopher E. Dandoy, Benjamin L. Laskin, and Stella M. Davies. "Interferon-complement loop in transplant-associated thrombotic microangiopathy." Blood Advances 4, no. 6 (March 24, 2020): 1166–77. http://dx.doi.org/10.1182/bloodadvances.2020001515.
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Abstract Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.
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Zhao, Xiang, Yuan Zhang, Tianxiang Gao, and Na Song. "Spleen Transcriptome Profiling Reveals Divergent Immune Responses to LPS and Poly (I:C) Challenge in the Yellow Drum (Nibea albiflora)." International Journal of Molecular Sciences 24, no. 9 (April 23, 2023): 7735. http://dx.doi.org/10.3390/ijms24097735.
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The yellow drum (Nibea albiflora) is a marine teleost fish with strong disease resistance, yet the understanding of its immune response and key functional genes is fragmented. Here, RNA-Seq was used to investigate the regulation pathways and genes involved in the immune response to infection with lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (poly (I:C)) on the spleen of the yellow drum. There were fewer differentially expressed genes (DEGs) in the LPS-infected treatment group at either 6 or 48 h. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEGs were mainly significantly enriched in c5-branching dibasic acid metabolic and complement and coagulation cascades pathways. The yellow drum responded more strongly to poly (I:C) infection, with 185 and 521 DEGs obtained under 6 and 48 h treatments, respectively. These DEGs were significantly enriched in the Toll-like receptor signaling pathway, RIG-I-like receptor signaling pathway, Jak-STAT signaling pathway, NOD-like signaling pathway, and cytokine–cytokine receptor interaction. The key functional genes in these pathways played important roles in the immune response and maintenance of immune system homeostasis in the yellow drum. Weighted gene co-expression network analysis (WGCNA) revealed several important hub genes. Although the functions of some genes have not been confirmed, our study still provides significant information for further investigation of the immune system of the yellow drum.
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Falguni, Mehnaz Mustari, Junela Cecile Hunat, Kathryn Elizabeth Nunez, Vy Ngo, and Erin M. Harberts. "TLR4-Independent Mechanisms of Complement Activation During Endotoxemia." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 160.28. http://dx.doi.org/10.4049/jimmunol.210.supp.160.28.
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Abstract Almost two million American adults are diagnosed with sepsis annually of which 350,000 succumb to the infection. Toll-like-receptor 4 (TLR4) canonically recognizes lipopolysaccharide (LPS), an outer membrane structure of Gram-negative bacteria. This recognition leads to pro-inflammatory cytokine release and propagation of other immune compartments. Complement is an acellular innate immune recognition system and has three general categories for activation: classical, lectin and alternative pathway. Previous research has found that complement proteins are dysregulated independent of TLR4 in serum during murine endotoxemia. This study investigates mechanisms of complement activation by describing location of complement gene upregulation and protein distribution in WT and TLR4−/− mice. mRNA was extracted from murine organ samples collected 0, 6, 12, and 18 hours post-induction of endotoxemia. RT-qPCR is then performed to measure expression fold changes of complement genes F5, F13a1, C1qb, Cfd, Masp1, and Mbl1. Genes involved in the lectin pathway were observed to be upregulated at the 6-hour timepoint and then downregulated throughout the progression of disease. C3 is a complement protein that is cleaved to create C3a, an anaphylatoxin, contributing to activation of acute phase inflammatory responses. Levels of C3a are analyzed using Western blots from WT and TLR4−/− mice as a marker of activation. The effects of LPS chemical structure on the efficiency of C3 cleavage is also analyzed. Identification of TLR4-independent pathways will allow for more targeted immune therapies for adverse outcomes related to sepsis. Supported by National Institute of Health and Towson University Bridges to Doctorate Program NIH (1T32GM146694-01), Fisher College of Science and Math at Towson University, and an FY2022 grant from the Towson University Faculty Development and Research Committee (FDRC) awarded to Erin Harberts titled “Septic Shock: Defining Alternative Pathways of Activation”.
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Horváth, Orsolya, Zoltán Prohászka, Krisztián Kállay, Csaba Kassa, Anita Stréhn, Katalin Csordás, János Sinkó, and Gergely Kriván. "Változások az őssejt-transzplantációhoz társult thromboticus microangiopathia diagnosztikus kritériumrendszerében." Orvosi Hetilap 158, no. 27 (July 2017): 1043–50. http://dx.doi.org/10.1556/650.2017.30786.
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Abstract: Hematopoietic stem cell transplantation associated thrombotic microangiopathy is a multifactorial complication, and has variable incidence in study populations due to different diagnostic criteria. The diversity of activity parameters, like elevated laktát-dehidrogenáz, hematological parameters and kidney function are not specific variables after stem cell transplantation. Dysregulation of the classical and alternative pathway can play an important role in the pathomechanism of thrombotic microangiopathy, but the understanding of the role of complement activation under transplantation conditions requires further investigation. Monitoring of complement parameters, including terminal complement pathway activation complex during transplantation may help physicians to improve diagnostic strategy, to evaluate therapeutical options and to predict and follow up efficacy of complement blockade methods and supportive therapy. This review focuses on the development of diagnostic criteria and therapeutical options in thrombotic microangiopathy, and presents some preliminary findings while using different diagnostic criteria in pediatric patients. Orv Hetil. 2017; 158(27): 1043–1050.
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Bradt, Bonnie M., William P. Kolb, and Neil R. Cooper. "Complement-dependent Proinflammatory Properties of the Alzheimer's Disease β-Peptide." Journal of Experimental Medicine 188, no. 3 (August 3, 1998): 431–38. http://dx.doi.org/10.1084/jem.188.3.431.
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Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the β-amyloid peptide (Aβ), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Aβ deposits in NP. We report that Aβ peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Aβ with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.
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Xu, Yuanyuan, Christina Ligoudistianou, and John E. Volanakis. "A novel human complement-related protein, C1r-like protease (C1r-LP) activates the early components of the classical complement pathway." Molecular Immunology 44, no. 1-3 (January 2007): 260–61. http://dx.doi.org/10.1016/j.molimm.2006.07.267.
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Krenev, Ilia A., Pavel V. Panteleev, Ekaterina S. Umnyakova, Nikolay P. Gorbunov, Valeria A. Kostevich, Sergey V. Balandin, Tatiana V. Ovchinnikova, Galina M. Aleshina, and Mikhail N. Berlov. "In Vitro Modulation of Complement Activation by Therapeutically Prospective Analogues of the Marine Polychaeta Arenicin Peptides." Marine Drugs 20, no. 10 (September 28, 2022): 612. http://dx.doi.org/10.3390/md20100612.
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The widespread resistance to antibiotics in pathogenic bacteria makes the development of a new generation of antimicrobials an urgent task. The development of new antibiotics must be accompanied by a comprehensive study of all of their biological activities in order to avoid adverse side-effects from their application. Some promising antibiotic prototypes derived from the structures of arenicins, antimicrobial peptides from the lugworm Arenicola marina, have been developed. Previously, we described the ability of natural arenicins -1 and -2 to modulate the human complement system activation in vitro. In this regard, it seems important to evaluate the effect of therapeutically promising arenicin analogues on complement activation. Here, we describe the complement-modulating activity of three such analogues, Ar-1[V8R], ALP1, and AA139. We found that the mode of action of Ar-1[V8R] and ALP1 on the complement was similar to that of natural arenicins, which can both activate and inhibit the complement, depending on the concentration. However, Ar-1[V8R] behaved predominantly as an inhibitor, showing only a moderate increase in C3a production in the alternative pathway model and no enhancement at all of the classical pathway of complement activation. In contrast, the action of ALP1 was characterized by a marked increase in the complement activation through the classical pathway in the concentration range of 2.5–20 μg/mL. At the same time, at higher concentrations (80–160 μg/mL), this peptide exhibited a complement inhibitory effect characteristic of the other arenicins. Peptide AA139, like other arenicins, exhibited an inhibitory effect on complement at a concentration of 160 μg/mL, but was much less pronounced. Overall, our results suggest that the effect on the complement system should be taken into account in the development of antibiotics based on arenicins.
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Armento, Angela, Tiziana L. Schmidt, Inga Sonntag, David A. Merle, Mohamed Ali Jarboui, Ellen Kilger, Simon J. Clark, and Marius Ueffing. "CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway." International Journal of Molecular Sciences 22, no. 16 (August 13, 2021): 8727. http://dx.doi.org/10.3390/ijms22168727.
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Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.
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Yu, Xiaoli, Fenfang Wu, Liyong Chen, Xin Liu, Huaying Wang, Peng Su, Yinglun Han, et al. "Lamprey variable lymphocyte receptors mediate complement-dependent cytotoxicity (172.20)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 172.20. http://dx.doi.org/10.4049/jimmunol.188.supp.172.20.
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Abstract An alternative adaptive immune system is present in the most basal vertebrates, lampreys and hagfish, the only surviving jawless vertebrates. These eel-like fish use leucine-rich-repeat (LRR)-based receptors, called variable lymphocyte receptors (VLRs), for antigen recognition instead of the immunoglobulin (Ig)-based receptors used in jawed vertebrates. We showed that in Japanese lamprey (Lampetra japonica), antigen-specific VLRB antibodies interact with C1q-like and C3 proteins to mediate complement-dependent cytotoxicity for bacteria and tumor cells. The immune based lysis involved deposition of VLRB and C1q-like protein complex on the surface of target cells, activation of C3, and ultimate disruption of cell wall integrity. The demonstration of functional interaction between VLRB and complement components in lamprey provides evidence for the emergence of cooperative innate and adaptive immune responses at a pivotal point in vertebrate evolution, before or in parallel with the evolution of Ig-based antibodies and the classical complement activation pathway.
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Ramphul, Urvashi N., Lindsey S. Garver, Alvaro Molina-Cruz, Gaspar E. Canepa, and Carolina Barillas-Mury. "Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells." Proceedings of the National Academy of Sciences 112, no. 5 (December 31, 2014): 1273–80. http://dx.doi.org/10.1073/pnas.1423586112.
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The malaria parasite, Plasmodium, must survive and develop in the mosquito vector to be successfully transmitted to a new host. The Plasmodium falciparum Pfs47 gene is critical for malaria transmission. Parasites that express Pfs47 (NF54 WT) evade mosquito immunity and survive, whereas Pfs47 knockouts (KO) are efficiently eliminated by the complement-like system. Two alternative approaches were used to investigate the mechanism of action of Pfs47 on immune evasion. First, we examined whether Pfs47 affected signal transduction pathways mediating mosquito immune responses, and show that the Jun-N-terminal kinase (JNK) pathway is a key mediator of Anopheles gambiae antiplasmodial responses to P. falciparum infection and that Pfs47 disrupts JNK signaling. Second, we used microarrays to compare the global transcriptional responses of A. gambiae midguts to infection with WT and KO parasites. The presence of Pfs47 results in broad and profound changes in gene expression in response to infection that are already evident 12 h postfeeding, but become most prominent at 26 h postfeeding, the time when ookinetes invade the mosquito midgut. Silencing of 15 differentially expressed candidate genes identified caspase-S2 as a key effector of Plasmodium elimination in parasites lacking Pfs47. We provide experimental evidence that JNK pathway regulates activation of caspases in Plasmodium-invaded midgut cells, and that caspase activation is required to trigger midgut epithelial nitration. Pfs47 alters the cell death pathway of invaded midgut cells by disrupting JNK signaling and prevents the activation of several caspases, resulting in an ineffective nitration response that makes the parasite undetectable by the mosquito complement-like system.
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Korbelik, Mladen. "Complement upregulation in photodynamic therapy-treated tumors: Role of Toll-like receptor pathway and NFκB." Cancer Letters 281, no. 2 (August 2009): 232–38. http://dx.doi.org/10.1016/j.canlet.2009.02.049.
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Fujita, Yoshiko, Saburo Yamaguchi, Akemi Kakino, Shin Iwamoto, Ryo Yoshimoto, and Tatsuya Sawamura. "Lectin-like Oxidized LDL Receptor 1 Is Involved in CRP-Mediated Complement Activation." Clinical Chemistry 57, no. 10 (October 1, 2011): 1398–405. http://dx.doi.org/10.1373/clinchem.2011.168625.
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BACKGROUND C-reactive protein (CRP) is purported to be a risk factor that acts independently of LDL cholesterol in predicting all-cause mortality in patients with ischemic heart disease. Lectin-like oxidized LDL receptor 1 (LOX-1) impairs endothelial function and exacerbates myocardial injury. We recently demonstrated that CRP increased vascular permeability through direct binding to LOX-1. Here we examined, using a hypertensive rat model, whether LOX-1 is involved in CRP-induced complement activation. METHODS AND RESULTS In the cultured LOX-1–expressing cell line hLOX-1-CHO, CRP increased complement activation, but did not do so in native CHO cells. Depleting C1q from serum abolished CRP-induced complement activation. Incubation of CRP with serum on immobilized recombinant LOX-1 similarly showed that CRP activated C1q-requiring classical complement pathway in a LOX-1–dependent manner. Interestingly, the interaction between CRP and LOX-1 was dependent on Ca2+ ion and competed with phosphocholine, suggesting that LOX-1 bound to the B-face of CRP with a phosphocholine-binding domain. This was in contrast to Fcγ receptors, to which CRP bound in A-face with complement-binding domain. In vivo, intradermal injection of CRP to hypertensive SHRSP rats induced complement activation detected by C3d deposition and leukocyte infiltration around the injected area. Anti–LOX-1 antibody reduced the extent of complement activation and leukocyte infiltration. CONCLUSIONS LOX-1 appears to be involved in CRP-induced complement activation, and thus may serve to locate the site of CRP-induced complement activation and inflammation.
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Timmann, C., M. Leippe, and R. D. Horstmann. "Two major serum components antigenically related to complement factor H are different glycosylation forms of a single protein with no factor H-like complement regulatory functions." Journal of Immunology 146, no. 4 (February 15, 1991): 1265–70. http://dx.doi.org/10.4049/jimmunol.146.4.1265.
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Abstract Factor H is a 150-kDa serum glycoprotein with key regulatory functions in the alternative pathway of complement activation. Two glycoproteins with a molecular mass of approximately 42 and 37 kDa that react with an antiserum against factor H were purified from human plasma. The two glycoproteins have identical N-terminal amino acid sequences but differ in glycosylation. Sequence comparisons indicated that they both correspond to a 1.4-kb mRNA recently cloned from human liver cDNA. The serum concentration of the two glycoproteins together was estimated to be approximately 40 mg/liter. They were found not to exert factor H-like regulatory functions in the alternative pathway. Thus, the 42-kDa glycoprotein described here appears to be distinct from the previously characterized factor H-related protein of similar size, suggesting that human serum contains two factor-H related molecules which both have a molecular mass of 41 to 43 kDa but which differ largely in structure.
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Sharo, Catherine, Tianhua Zhai, and Zuyi Huang. "Investigation of Potential Drug Targets Involved in Inflammation Contributing to Alzheimer’s Disease Progression." Pharmaceuticals 17, no. 1 (January 20, 2024): 137. http://dx.doi.org/10.3390/ph17010137.
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Alzheimer’s disease has become a major public health issue. While extensive research has been conducted in the last few decades, few drugs have been approved by the FDA to treat Alzheimer’s disease. There is still an urgent need for understanding the disease pathogenesis, as well as identifying new drug targets for further drug discovery. Alzheimer’s disease is known to arise from a build-up of amyloid beta (Aβ) plaques as well as tangles of tau proteins. Along similar lines to Alzheimer’s disease, inflammation in the brain is known to stem from the degeneration of tissue and build-up of insoluble materials. A minireview was conducted in this work assessing the genes, proteins, reactions, and pathways that link brain inflammation and Alzheimer’s disease. Existing tools in Systems Biology were implemented to build protein interaction networks, mainly for the classical complement pathway and G protein-coupled receptors (GPCRs), to rank the protein targets according to their interactions. The top 10 protein targets were mainly from the classical complement pathway. With the consideration of existing clinical trials and crystal structures, proteins C5AR1 and GARBG1 were identified as the best targets for further drug discovery, through computational approaches like ligand–protein docking techniques.
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Beucher, M., and K. A. Norris. "Sequence Diversity of the Trypanosoma cruzi Complement Regulatory Protein Family." Infection and Immunity 76, no. 2 (December 10, 2007): 750–58. http://dx.doi.org/10.1128/iai.01104-07.
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ABSTRACT As a central component of innate immunity, complement activation is a critical mechanism of containment and clearance of microbial pathogens in advance of the development of acquired immunity. Several pathogens restrict complement activation through the acquisition of host proteins that regulate complement activation or through the production of their own complement regulatory molecules (M. K. Liszewski, M. K. Leung, R. Hauhart, R. M. Buller, P. Bertram, X. Wang, A. M. Rosengard, G. J. Kotwal, and J. P. Atkinson, J. Immunol. 176:3725-3734, 2006; J. Lubinski, L. Wang, D. Mastellos, A. Sahu, J. D. Lambris, and H. M. Friedman, J. Exp. Med. 190:1637-1646, 1999). The infectious stage of the protozoan parasite Trypanosoma cruzi produces a surface-anchored complement regulatory protein (CRP) that functions to inhibit alternative and classical pathway complement activation (K. A. Norris, B. Bradt, N. R. Cooper, and M. So, J. Immunol. 147:2240-2247, 1991). This study addresses the genomic complexity of the T. cruzi CRP and its relationship to the T. cruzi supergene family comprising active trans-sialidase (TS) and TS-like proteins. The TS superfamily consists of several functionally distinct subfamilies that share a characteristic sialidase domain at their amino termini. These TS families include active TS, adhesions, CRPs, and proteins of unknown functions (G. A. Cross and G. B. Takle, Annu. Rev. Microbiol. 47:385-411, 1993). A sequence comparison search of GenBank using BLASTP revealed several full-length paralogs of CRP. These proteins share significant homology at their amino termini and a strong spatial conservation of cysteine residues. Alternative pathway complement regulation was confirmed for CRP paralogs with 58% (low) and 83% (high) identity to AAB49414. CRPs are functionally similar to the microbial and mammalian proteins that regulate complement activation. Sequence alignment of mammalian complement control proteins to CRP showed that these sequences are distinct, supporting a convergent evolutionary pathway. Finally, we show that a clonal line of T. cruzi expresses multiple unique copies of CRP that are differentially recognized by patient sera.
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Feng, Yuebiao, Lu Chen, Li Gao, Li Dong, Han Wen, Xiumei Song, Fang Luo, Gong Cheng, and Jingwen Wang. "Rapamycin inhibits pathogen transmission in mosquitoes by promoting immune activation." PLOS Pathogens 17, no. 2 (February 24, 2021): e1009353. http://dx.doi.org/10.1371/journal.ppat.1009353.
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Repeated blood meals provide essential nutrients for mosquito egg development and routes for pathogen transmission. The target of rapamycin, the TOR pathway, is essential for vitellogenesis. However, its influence on pathogen transmission remains to be elucidated. Here, we show that rapamycin, an inhibitor of the TOR pathway, effectively suppresses Plasmodium berghei infection in Anopheles stephensi. An. stephensi injected with rapamycin or feeding on rapamycin-treated mice showed increased resistance to P. berghei infection. Exposing An. stephensi to a rapamycin-coated surface not only decreased the numbers of both oocysts and sporozoites but also impaired mosquito survival and fecundity. Transcriptome analysis revealed that the inhibitory effect of rapamycin on parasite infection was through the enhanced activation of immune responses, especially the NF-κB transcription factor REL2, a regulator of the immune pathway and complement system. Knockdown of REL2 in rapamycin-treated mosquitoes abrogated the induction of the complement-like proteins TEP1 and SPCLIP1 and abolished rapamycin-mediated refractoriness to Plasmodium infection. Together, these findings demonstrate a key role of the TOR pathway in regulating mosquito immune responses, thereby influencing vector competence.
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van den Berg, Rocco H., Maria C. Faber-Krol, Sandra van Wetering, Pieter S. Hiemstra, and Mohamed R. Daha. "Inhibition of Activation of the Classical Pathway of Complement by Human Neutrophil Defensins." Blood 92, no. 10 (November 15, 1998): 3898–903. http://dx.doi.org/10.1182/blood.v92.10.3898.
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Abstract Defensins are small, cationic antimicrobial peptides that are present in the azurophilic granules of neutrophils. Earlier studies have shown that defensins may influence complement activation by specific interaction with activated C1, C1q, and C1-inhibitor. In the present study, we show that the defensin human neutrophil peptide-1 (HNP-1) is able to inhibit activation of the classical complement pathway by inhibition of C1q hemolytic activity. The binding site for HNP-1 on C1q is most likely located on the collagen-like stalks, as a clear, dose-dependent binding of HNP-1 to either intact C1q or to the collagen-like stalks of C1q was demonstrated using enzyme-linked immunosorbent assay (ELISA). Besides binding of HNP-1 to C1q, also a limited binding to C1 and to a mixture of C1r and C1s was observed, whereas no binding to C1-inhibitor was found. Because binding of HNP-1 to C1-inhibitor has been suggested in earlier studies, we also assessed the binding of HNP-1 to mixtures of C1-inhibitor with either C1r/ C1s or C1. No binding was found. Using a competition ELISA, it was found that HNP-1, but not protamine, inhibited binding of biotin-labeled HNP-1 to C1q in a dose-dependent fashion. In the fluid phase, preincubation of HNP-1 with C1q resulted in complex formation of HNP-1 and C1q and generation of stable complexes. In conclusion, HNP-1 is able to bind to C1q in the fluid phase and inhibits the classical complement pathway. This mechanism may be involved in the control of an inflammatory response in vivo.
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van den Berg, Rocco H., Maria C. Faber-Krol, Sandra van Wetering, Pieter S. Hiemstra, and Mohamed R. Daha. "Inhibition of Activation of the Classical Pathway of Complement by Human Neutrophil Defensins." Blood 92, no. 10 (November 15, 1998): 3898–903. http://dx.doi.org/10.1182/blood.v92.10.3898.422k03_3898_3903.
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Defensins are small, cationic antimicrobial peptides that are present in the azurophilic granules of neutrophils. Earlier studies have shown that defensins may influence complement activation by specific interaction with activated C1, C1q, and C1-inhibitor. In the present study, we show that the defensin human neutrophil peptide-1 (HNP-1) is able to inhibit activation of the classical complement pathway by inhibition of C1q hemolytic activity. The binding site for HNP-1 on C1q is most likely located on the collagen-like stalks, as a clear, dose-dependent binding of HNP-1 to either intact C1q or to the collagen-like stalks of C1q was demonstrated using enzyme-linked immunosorbent assay (ELISA). Besides binding of HNP-1 to C1q, also a limited binding to C1 and to a mixture of C1r and C1s was observed, whereas no binding to C1-inhibitor was found. Because binding of HNP-1 to C1-inhibitor has been suggested in earlier studies, we also assessed the binding of HNP-1 to mixtures of C1-inhibitor with either C1r/ C1s or C1. No binding was found. Using a competition ELISA, it was found that HNP-1, but not protamine, inhibited binding of biotin-labeled HNP-1 to C1q in a dose-dependent fashion. In the fluid phase, preincubation of HNP-1 with C1q resulted in complex formation of HNP-1 and C1q and generation of stable complexes. In conclusion, HNP-1 is able to bind to C1q in the fluid phase and inhibits the classical complement pathway. This mechanism may be involved in the control of an inflammatory response in vivo.
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Khandelwal, Sanjay, Lubica Rauova, Ayiesha Barnes, Ann Rux, Serge Yarovoi, Sooho S. Myoung, Alexandra Johnson, et al. "Complement Regulates the Procoagulant Effects of HIT Immune Complexes." Blood 136, Supplement 1 (November 5, 2020): 11–12. http://dx.doi.org/10.1182/blood-2020-138631.
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Heparin induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by ultra-large immune complexes (ULICs) containing IgG antibodies bound to multivalent complexes of platelet factor 4 (PF4) and heparin (H). HIT ULICs activate cellular FcγIIA receptors that initiate diverse cellular effector functions including neutrophil degranulation and monocyte expression of tissue factor (TF). Previous studies have shown that HIT ULICs also potently activate complement through the classical pathway (Cines et al., 1980). Whether complement activation contributes to FcγRIIA-dependent prothrombotic pathways has not been addressed in detail. In studies that follow, we describe: 1) robust complement activation by HIT ULICs in plasma and whole blood (WB), 2) cell-surface deposition of complement and IgG triggered by HIT ULICs, 3) complement-dependent neutrophil degranulation and monocyte TF expression, 4) efficacy of proximal, but not terminal, pathway inhibition in regulating monocyte TF expression, and 5) deposition of complement in thrombi formed in "HIT mice" that generate ULICs containing KKO, a HIT-like monoclonal antibody (Arepally et al., 2000). Consistent with prior studies showing involvement of the classical pathway in HIT (Cines et al., 1980), we observed that binding of C1q induced marked enlargement of HIT ULICs in buffer assessed by dynamic light scattering as well as in plasma using confocal microscopy (data not shown). To assess complement activation by HIT ULICs, we incubated WB and plasma with PF4 (25 µg/mL) ± heparin (1 U/mL) in the presence of KKO (or isotype, "ISO"; 50 µg/mL) or HIT IgG (or control IgG, "CON"; 500 µg/mL) and measured C3c with a capture immunoassay as previously described (Khandelwal et al., 2018). KKO (Figure 1A) or HIT ULICs (n=3; HIT1-3, Figure 1B), showed robust generation of C3c in the presence of PF4/heparin, but not antigens alone or with control IgG (ISO/CON). Complement activation by HIT ULICs leads to downstream generation of C5a and formation of sC5b-9 (data not shown). Pre-incubation of plasma or WB with a variety of classical pathway inhibitors, including a C1r inhibitor derived from Borrelia burgdorferi (BBK 32), C1 esterase inhibitor (Berinert, CSL Behring) and anti-C1q antibody (α-C1q Ab; Annexon Biosciences) inhibited C3c generation by KKO ULICs (p <0.001), whereas inhibitors of the alternative pathway (anti-properdin antibody) or C5 inhibitor (α-C5 Ab; Eculizumab, Alexion Pharmaceuticals) did not (data not shown). Incubation of WB with KKO or HIT ULICs, but not ISO or CON IgG, markedly increased deposition of C3 and IgG on neutrophils, monocytes and B cells (data not shown) and lead to cell activation assessed by neutrophil degranulation (MMP9 release) and monocyte TF expression (data not shown). To examine the contribution of complement activation in monocyte TF expression, WB was pre-incubated with α-C1q, α-C5 or IV.3 (a monoclonal antibody to FcγRIIA) or isotype controls prior to addition of HIT ULICs. As shown in Figure 2, the classical pathway inhibitor, α-C1q Ab markedly diminished TF expression (about 70% reduction; p<0.001 vPF4/H/ KKO), as did IV.3 (about 85% reduction; p<0.001 vPF4/H/ KKO) but not α-C5 Ab or ISO antibodies, demonstrating: 1) FcγRIIA independent mechanism of monocyte TF expression and 2) a requirement for proximal rather than terminal complement pathway components in the induction of monocyte TF. We next asked if complement activation facilitates binding of ULICs and promotes subsequent ULIC engagement of FcγRIIA. To examine complement dependent binding of HIT ULICs, we incubated WB with α-C1q Ab prior to addition of KKO ULICs and measured ULIC binding to monocytes and TF expression. As shown in Figure 3, classical pathway inhibition markedly reduced cell-surface IgG (Figure 3A) and monocyte TF expression (Figure 3B). The effects of complement inhibition could not be overcome with increasing amounts of KKO IgG (2-4 fold excess). We observed significant co-localization of complement with KKO ULICs in a cremaster-laser injury model in "HIT mice" and in in situ thrombi formed in uninjured vessels (data not shown). Together, these studies demonstrate an independent role for complement activation in regulating the binding and procoagulant effects of HIT ULICs and identify new non-anticoagulant therapeutic targets that could improve clinical outcomes in this otherwise potentially devastating thrombotic disorder. Disclosures Arepally: Novartis: Consultancy; Alexion: Other; Annexon Biosciences: Consultancy, Other; Veralox Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biokit: Consultancy, Patents & Royalties; Apotex: Consultancy, Research Funding.
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Moors, M. A., T. L. Stull, K. J. Blank, H. R. Buckley, and D. M. Mosser. "A role for complement receptor-like molecules in iron acquisition by Candida albicans." Journal of Experimental Medicine 175, no. 6 (June 1, 1992): 1643–51. http://dx.doi.org/10.1084/jem.175.6.1643.
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Candida albicans, an opportunistic fungal pathogen of humans, is dependent upon iron for growth. Consequently, human serum inhibits C. albicans growth due to the presence of high affinity iron-binding proteins that sequester serum iron, making it unavailable for use by the organism. We report that in the inhibitory environment of human serum, the growth of C. albicans can be restored by the addition of exogenous hemoglobin or heme, but not by protoporphyrin IX, the heme precursor that does not contain iron. We further report that C. albicans can utilize cell surface proteins that are homologues of the mammalian complement receptors (CR) to rosette complement-coated red blood cells (RBC) and obtain RBC-derived iron for growth. The ability of Candida to acquire RBC-derived iron under these conditions is dependent upon Candida-RBC rosetting mediated by CR-like molecules. Unopsonized RBC do not support Candida growth in serum, and restoration of Candida growth in serum by complement-opsonized RBC is inhibited by monoclonal antibodies to the human CR type 3 (CR3). In addition, activation of the human alternative pathway of complement by Candida leads to "bystander" deposition of C3 fragments on the surface of autologous, unopsonized RBC, generating the ligands necessary for Candida-RBC rosetting. These results suggest that C. albicans has evolved a unique strategy for acquiring iron from the host, which exploits the host complement system, and which may contribute to the pathogenic potential of the organism.
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Fouët, Guillaume, Isabelle Bally, Anne Chouquet, Jean-Baptiste Reiser, Nicole M. Thielens, Christine Gaboriaud, and Véronique Rossi. "Molecular Basis of Complement C1q Collagen-Like Region Interaction with the Immunoglobulin-Like Receptor LAIR-1." International Journal of Molecular Sciences 22, no. 10 (May 12, 2021): 5125. http://dx.doi.org/10.3390/ijms22105125.
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The immune system homeostasis relies on a tight equilibrium of interconnected stimulatory and inhibitory signals. Disruption of this balance is characteristic of autoimmune diseases such as systemic lupus erythematosus (SLE). Aside from activating the classical complement pathway and enhancing pathogens and apoptotic cells phagocytosis, C1q has been recently shown to play an important role in immune modulation and tolerance by interacting with several inhibitory and stimulatory immune receptors. Due to its functional organization into collagen-like (CLR) and globular (GR) regions and its multimeric nature, C1q is able to interact simultaneously with several of these receptors and locally congregate pro- and anti-inflammatory signals, thus modulating the immune response. Leukocyte associated immunoglobulin-like (Ig-like) receptor 1 (LAIR-1), a ubiquitous collagen receptor expressed in many immune cell types, has been reported to interact with the CLR of C1q. In this study, we provide new insights into the molecular and structural determinants underlying C1q/LAIR-1 interaction. Recombinant LAIR-1 extracellular Ig-like domain was produced and tested for its interaction with C1q. A molecular dissection of C1q combined with competition assays reveals that LAIR-1 interacts with C1q’s CLR through a binding site close but different from the one of its associated C1r2s2 proteases tetramer. On the other side, we identified LAIR-1 residues involved in C1q interaction by site-directed mutational analysis. All together, these results lead to propose a possible model for C1q interaction with LAIR-1 and will contribute to the fundamental understanding of C1q-mediated immune tolerance.
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Yuan, Hongyu, Rong Chen, Yanjie Liu, Mansoor Tariq, Yaping Sun, and Chun Xia. "Crystallization and preliminary crystallographic studies of the complement 1qA globular domain from zebrafish,Dare-C1qAgD." Acta Crystallographica Section F Structural Biology Communications 70, no. 7 (June 18, 2014): 911–14. http://dx.doi.org/10.1107/s2053230x14010747.
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Complement 1q (C1q) is the first component of the complement system which can initiate the classical complement pathway. In human, C1q is composed of 18 polypeptide chains: six C1qA chains, six C1qB chains and six C1qC chains. Each chain has a signal peptide and is comprised of a collagen-like region and a C-terminal C1q globular domain (C1qgD), which is organized as a heterotrimer. C1qgD can recognize antigen–antibody complexes containing IgG and IgM or can bind directly to the C-reactive protein. Although the classical complement pathway is found from fish to mammals, only the human C1qgD structure has been determined. Compared with that of mammals, fish C1q exhibits similar immune functions and genome arrangement. In order to illustrate the structure of C1qgD in fish, zebrafish (Danio rerio) C1qA globular domain (Dare-C1qAgD) was expressed, purified and crystallized. X-ray diffraction data were collected from a crystal to a resolution of 2.05 Å; the crystal belonged to the orthorhombic space groupP212121, with unit-cell parametersa= 50.347,b= 85.059,c= 95.560 Å. It contained three molecules in the asymmetric unit. The Matthews coefficient valueVMwas 2.31 Å3 Da−1, with a calculated solvent content of 46.7%. The data will help to give insight into the structural basis of C1qA in fish species.
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Lim, Jongwon, and Suhee Hong. "Transcriptome Analysis in the Head Kidney of Rainbow Trout (Oncorhynchus mykiss) Immunized with a Combined Vaccine of Formalin-Inactivated Aeromonas salmonicida and Vibrio anguillarum." Vaccines 9, no. 11 (October 22, 2021): 1234. http://dx.doi.org/10.3390/vaccines9111234.
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This study aimed to identify the molecular mechanisms regulated by a combined vaccine against Aeromonas salmonicida and Vibrio anguillarum (O1 serotype). These bacteria cause furunculosis and vibriosis, respectively, and are associated with a high mortality in rainbow trout in Korea. The vaccine upregulated gene expression of TCRα, T-bet, sIgM, and mIgM, markers of an activated adaptive immune response. On days 1, 3, and 5, transcriptome analysis revealed 862 (430 up- and 432 downregulated), 492 (204 up- and 288 downregulated), and 741 (270 up- and 471 downregulated) differentially expressed genes (DEGs), respectively. Gene ontology (GO) enrichment analysis identified 377 (108 MF, 132 CC, 137 BP), 302 (60 MF, 180 CC, 62 BP), and 314 (115 MF, 129 CC, 70 BP) GOs at days 1, 3, and 5, respectively. Kyoto Encyclopedia of Genetic and Genomic enrichment analysis identified eight immune system-related pathways like cytokine-cytokine receptor interaction, NF-kappaB signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, cytosolic DNA sensing pathway, cell adhesion molecule, complement and coagulation cascade, and antigen processing and presentation. In the analysis of the protein–protein interaction of immune-related DEGs, a total of 59, 21, and 21 interactional relationships were identified at days 1, 3, and 5, respectively, with TNF having the highest centrality at all three time points.
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Chang, Jae C. "Acute Respiratory Distress Syndrome as an Organ Phenotype of Vascular Microthrombotic Disease: Based on Hemostatic Theory and Endothelial Molecular Pathogenesis." Clinical and Applied Thrombosis/Hemostasis 25 (January 1, 2019): 107602961988743. http://dx.doi.org/10.1177/1076029619887437.
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Acute respiratory distress syndrome (ARDS) is a life-threatening noncardiogenic circulatory disorder of the lungs associated with critical illnesses such as sepsis, trauma, and immune and collagen vascular disease. Its mortality rate is marginally improved with the best supportive care. The demise occurs due to progressive pulmonary hypoxia and multi-organ dysfunction syndrome (MODS) with severe inflammation. Complement activation is a part of immune response against pathogen or insult in which membrane attack complex (MAC) is formed and eliminates microbes. If complement regulatory protein such as endothelial CD59 is underexpressed, MAC may also cause pulmonary vascular injury to the innocent bystander endothelial cell of host and provokes endotheliopathy that causes inflammation and pulmonary vascular microthrombosis, leading to ARDS. Its pathogenesis is based on a novel “two-path unifying theory” of hemostasis and “two-activation theory of the endothelium” promoting molecular pathogenesis. Endotheliopathy activates two independent molecular pathways: inflammatory and microthrombotic. The former triggers the release inflammatory cytokines and the latter promotes exocytosis of unusually large von Willebrand factor multimers (ULVWF) and platelet activation. Inflammatory pathway initiates inflammation, but microthrombotic pathway more seriously produces “microthrombi strings” composed of platelet-ULVWF complexes, which become anchored on the injured endothelial cells, and causes disseminated intravascular microthrombosis (DIT). DIT is a hemostatic disease due to lone activation of ULVWF path without activated tissue factor path. It leads to endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which orchestrates consumptive thrombocytopenia, microangiopathic hemolytic anemia, and MODS. Thrombotic thrombocytopenic purpura (TTP)-like syndrome is the hematologic phenotype of EA-VMTD. ARDS is one of organ phenotypes among MODS associated with TTP-like syndrome. The most effective treatment of ARDS can be achieved by counteracting the activated microthrombotic pathway based on two novel hemostatic theories.
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Landis, Clive. "Pharmacologic Strategies for Combating the Inflammatory Response." Journal of ExtraCorporeal Technology 39, no. 4 (December 2007): 291–95. http://dx.doi.org/10.1051/ject/200739291.
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The “systemic inflammatory response” is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance lies with combinatorial—or promiscuous—pharmacotherapy. Combinations of anti-fibrinolytics, anti-coagulants targeted higher up the coagulation cascade, anti-thrombin receptor therapy, improved coated circuits, anti-complement, anti-leukocyte, and antioxidant therapies may blunt sufficient arms of the systemic inflammatory response to be clinically effective. The alternative is a promiscuous drug like aprotinin, which targets plasmin in the fibrinolytic pathway, kallikrein in the coagulation pathway, thrombin receptors on platelets and endothelium, and leukocytes at the extravasation step. Because of the overriding safety concerns relating to the use of anti-fibrinolytics in cardiothoracic surgery, any future combinatorial or promiscuous pharmacotherapy involving anti-fibrinolytics will require solid underpinning with a known mechanism of action and clinical safety data powered to detect well-defined adverse events (stroke, myocardial injury, renal failure requiring dialysis), preferably in isolation and not as a composite endpoint.
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von Lackum, Kate, Jennifer C. Miller, Tomasz Bykowski, Sean P. Riley, Michael E. Woodman, Volker Brade, Peter Kraiczy, Brian Stevenson, and Reinhard Wallich. "Borrelia burgdorferi Regulates Expression of Complement Regulator-Acquiring Surface Protein 1 during the Mammal-Tick Infection Cycle." Infection and Immunity 73, no. 11 (November 2005): 7398–405. http://dx.doi.org/10.1128/iai.73.11.7398-7405.2005.
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ABSTRACT During the natural mammal-tick infection cycle, the Lyme disease spirochete Borrelia burgdorferi comes into contact with components of the alternative complement pathway. B. burgdorferi, like many other human pathogens, has evolved the immune evasion strategy of binding two host-derived fluid-phase regulators of complement, factor H and factor H-like protein 1 (FHL-1). The borrelial complement regulator-acquiring surface protein 1 (CRASP-1) is a surface-exposed lipoprotein that binds both factor H and FHL-1. Analysis of CRASP-1 expression during the mammal-tick infectious cycle indicated that B. burgdorferi expresses this protein during mammalian infection, supporting the hypothesized role for CRASP-1 in immune evasion. However, CRASP-1 synthesis was repressed in bacteria during colonization of vector ticks. Analysis of cultured bacteria indicated that CRASP-1 is differentially expressed in response to changes in pH. Comparisons of CRASP-1 expression patterns with those of other infection-associated B. burgdorferi proteins, including the OspC, OspA, and Erp proteins, indicated that each protein is regulated through a unique mechanism.
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Wang, Hongjie, Ilya Vinnikov, Qianxing Zhou, Thati Madhusudhan, Khurrum Shahzad, Muhammed Kashif, Juliane Wolter, et al. "The Lectin-Like Domain of Thrombomodulin Protects Against Diabetic Nephropathy by Inhibiting Complement Activation." Blood 116, no. 21 (November 19, 2010): 654. http://dx.doi.org/10.1182/blood.v116.21.654.654.
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Abstract Abstract 654 Introduction: Thrombomodulin (TM) is type 1 transmembrane glycoprotein predominately expressed on vascular endothelial cells. TM consists of distinct structural domains, which enable interaction with multiple ligands and thus modulation of coagulation, fibrinolysis, complement activation, inflammation, cell proliferation, and apoptosis. We have previously shown that TM protects against diabetic nephropathy (dNP) through activation of protein C (PC), which inhibits glomerular apoptosis. Recent studies showed that TM mediates cytoprotective effects independent of PC activation through it's lectin-like domain (LLD). The LLD directly interferes with complement activation and protect against arthritis. dNP is associated with an infiltration of inflammatory cells, enhanced cytokine production, and complement activation raising the question whether endothelial TM may protect against DN through a dual mechanism depending on (a) PC activation and (b) complement inhibition through the LLD. Methods: Experimental dNP was evaluated in mice with targeted deletion of the LLD of TM (TMLed/Led mice). Persistent hyperglycemia was induced using streptozotocin in TMLed/Led mice and in control wild type mice (wt). Subgroups of mice were treated with low molecular heparin (LMWH) to inhibit complement activation and coagulation activation, fondaparinux to inhibit coagulation activation, or treated with minocycline to inhibit glomerular apoptosis. After 28 weeks albuminuria was determined and mice were sacrificed to isolated tissues and blood samples for analyses. Results: Albuminuria, histological indices of diabetic nephropathy and glomerular C3 deposition were increased in diabetic wt mice and further increased in diabetic TMLed/Led mice. Only treatment with LMWH, but not with fondaparinux corrected the aggravated DN in TMLed/Led mice, despite equal anticoagulation in both groups. Glomerular complement depositions (immunohistochemistry) were significantly reduced following in vivo LMWH treatment, but no in fondaparinux treated mice. In vitro, endothelial cells expressing a TM mutant lacking the LLD had diminished capacity to bind and inactivate C3b and were thus sensitive to complement mediated cell lyses. Of note, apoptosis (TUNEL) and expression levels of apoptosis regulators (p53, Bax/Blc-2 ratio, Western) did not differ between untreated or LMWH/fondaparinux treated diabetic TMLed/Led mice, indicating that the protective effect of the LLD is independent of apoptosis inhibition. Consistently, inhibition of apoptosis with minocycline failed to normalize albuminuria or prevent histological indices of dNP in diabetic TMLed/Led mice. Likewise, we did not observe difference in HMGB-1 levels within the kidney or in plasma sample, and inhibition of HMGB-1 using sodium Tanshinon II asilate failed to reduce dNP in diabetic TMLed/Led mice. Discussion and Conclusion: We identify a novel pathway through which endothelial TM protects against dNP. TM protects against dNP by inhibiting complement activation through its LLD. This function is independent of the recently identified activated PC dependent inhibition of glomerular apoptosis. Thus, endothelial TM prevents dNP through two independent pathways. These results provide further experimental support for a causative role of endothelial dysfunction for DN. Disclosures: No relevant conflicts of interest to declare.
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Andreo-Vidal, Andrés, Oleksandr Yushchuk, Flavia Marinelli, and Elisa Binda. "Cross-Talking of Pathway-Specific Regulators in Glycopeptide Antibiotics (Teicoplanin and A40926) Production." Antibiotics 12, no. 4 (March 24, 2023): 641. http://dx.doi.org/10.3390/antibiotics12040641.
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Teicoplanin and A40926 (natural precursor of dalbavancin) are clinically relevant glycopeptide antibiotics (GPAs) produced by Actinoplanes teichomyceticus NRRL B-16726 and Nonomuraea gerenzanensis ATCC 39727. Their biosynthetic enzymes are coded within large biosynthetic gene clusters (BGCs), named tei for teicoplanin and dbv for A40926, whose expression is strictly regulated by pathway-specific transcriptional regulators (PSRs), coded by cluster-situated regulatory genes (CSRGs). Herein, we investigated the “cross-talk” between the CSRGs from tei and dbv, through the analysis of GPA production levels in A. teichomyceticus and N. gerenzanensis strains, with knockouts of CSRGs cross-complemented by the expression of heterologous CSRGs. We demonstrated that Tei15* and Dbv4 StrR-like PSRs, although orthologous, were not completely interchangeable: tei15* and dbv4 were only partially able or unable to cross-complement N. gerenzanensis knocked out in dbv4 and A. teichomyceticus knocked out in tei15*, implying that the DNA-binding properties of these PSRs are more different in vivo than it was believed before. At the same time, the unrelated LuxR-like PSRs Tei16* and Dbv3 were able to cross-complement corresponding N. gerenzanensis knocked out in dbv3 and A. teichomyceticus knocked out in tei16*. Moreover, the heterologous expression of dbv3 in A. teichomyceticus led to a significant increase in teicoplanin production. Although the molecular background of these events merits further investigations, our results contribute to a deeper understanding of GPA biosynthesis regulation and offer novel biotechnological tools to improve their production.
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Wei, Qingcong, Dan Wang, Kaijin Wei, Bin Xu, and Jin Xu. "The Mechanism of Elizabethkingia miricola Infection of the Black Spotted Frog as Revealed by Multi-Omics Analysis." Fishes 9, no. 3 (February 28, 2024): 91. http://dx.doi.org/10.3390/fishes9030091.
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Elizabethkingia miricola (E. miricola) is a significant pathogen that causes the crooked head disease in black spotted frogs. This disease has plagued numerous frog farms in China and has resulted in substantial losses to the frog farming industry. Nonetheless, the exact mechanism that causes the disease in frogs remains unknown. In this study, transcriptomic and microbiomic analyses were conducted to analyze frog samples infected with E. miricola to reveal the infection mechanism of the pathogen. Liver transcriptomic analysis indicated that the livers of infected frogs had 1469 differentially expressed genes when compared with an uninfected group. These DEGs are mainly involved in immunity and metabolism, including neutrophil extracellular trap formation, the NOD-like receptor signaling pathway, leukocyte transendothelial migration, chemokine signaling pathway, Fc gamma R-mediated phagocytosis, and “metabolism”-related pathways such as the pentose phosphate pathway, carbon metabolism, glycerophospholipid metabolism, and glycerolipid metabolism. Similarly, 4737 DEGs were found in the kidney of infected frogs. These DEGs are mainly involved in immunity, including neutrophil extracellular trap formation, the NOD-like receptor signaling pathway, B cell receptor signaling pathway, C-type lectin receptor signaling pathway, complement and coagulation cascade, and Toll-like receptor signaling pathway. Ten immune-associated DEGs were screened in liver and kidney DEGs, respectively. And it was hypothesized that E. miricola infection could influence the host immune response. Microbiome analysis results showed that some opportunistic pathogens such as Citrobacter, Shigella, and Providencia were significantly elevated (p < 0.05) in infected frogs. Additionally, functional prediction confirmed that most of the microbiota in infected frogs were linked to metabolism-related KEGG pathways. In this study, the screened genes linked to immunity showed an association with the gut microbiome. The majority of these genes were found to be linked with the abundance of opportunistic pathogens. The results showed that E. miricola infection led to the downregulation of immune and metabolic-related genes, which led to the inhibition of immune function and metabolic disorder, and then increased the abundance of opportunistic pathogens in the gut microbiota. The findings of this study offer a preliminary foundation for comprehending the pathogenic processes of E. miricola infection in black spotted frogs.
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Fleming, Patrick, Maggie Cheung, and David Sokol. "Complement-Mediated Thrombotic Microangiopathy: A Murky Presentation of a Rare Disease Entity." Blood 132, Supplement 1 (November 29, 2018): 5005. http://dx.doi.org/10.1182/blood-2018-99-119893.
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Abstract Complement-mediated thrombotic microangiopathy (TMA), also known as atypical hemolytic uremic syndrome (aHUS) is a rare, hereditary, progressive, life-threatening disorder caused by a disruption in regulation of the alternative pathway of the complement system. Eculizumab, a terminal complement inhibitor, has emerged as a first-line therapy, however data are limited to small case series (Brocklebank et al., 2017). Here, we present a diagnostically challenging case of complement-mediated TMA, who received eculizumab therapy with excellent hematologic response. A 68-year-old female with history of possible Sjogren's syndrome, migraine disorder, chronic fatigue syndrome, inflammatory colitis, hypertension, and poor medical follow up presented with 6-day history of severe fatigue, hematochezia, decreased urine output, dyspnea with exertion and anginal chest pain. 2 weeks prior, patient endorsed "flu-like" illness and had diffuse myalgias without fevers. Further history revealed ibuprofen usage of 800-1200 mg/day for several years. Shortly after admission, patient became severely agitated and confused with an attempt to elope from hospital. During diagnostic workup, labs were significant for hemoglobin 5.6 g/dL, platelets 57,000/uL, serum creatinine 6.6 mg/dL, BUN 101 mg/dL. Peripheral smear showed schistocytes and tear drop cells, low platelets without clumping, and hypochromic normocytic red cells. LDH of 2152 U/L, haptoglobin <34 mg/dL, and GI PCR was panel negative for E. coli O157 and Shiga-like toxin producing E. coli. She was presumed to have thrombotic thrombocytopenic purpura (TTP) as she presented with 4 of the 5 characteristic pentad, including microangiopathic hemolytic anemia, acute renal failure, thrombocytopenia, and severe neurologic findings. Patient received several PRBC transfusions, five plasma exchange treatments, hemodialysis and corticosteroids. She had initial improvement in platelet count and decrease in LDH with plasma exchange, however plateaued by day 5. Further testing revealed low complement C3 level of 51 mg/dL, low complement C4 level of 22.7 mg/dL, and pre-PLEX ADAMSTS13 level of 93%, suggesting complement-mediated TMA as the correct diagnosis. Patient was subsequently transferred to tertiary care center for initiation of eculizumab. Genetic testing was completed, notable for decreased Factor H and a heterozygous missense mutation in complement factor H of uncertain significance, only having been previously reported in a single patient with aHUS (Fremeaux-Bacci et al., 2013). She achieved excellent hematologic response with eculizumab evidenced by improved platelet count, haptoglobin, decreased LDH, however she unfortunately remained dialysis-dependent. Thrombotic microangiopathy (TMA) syndromes are overlapping entities which can be categorized by primary vs secondary etiology. Primary syndromes include TTP (hereditary or acquired), Shiga-toxin mediated HUS, drug-induced TMA and complement mediated TMA. Secondary causes include pregnancy-associated (pre-eclampsia/HEELP syndrome), malignancy, systemic infection, severe hypertension, autoimmune disorders like SLE, and complications from organ transplantation. When evaluating a patient with suspected TMA, it is important to correctly categorize their disease to guide appropriate treatment. Complement-mediated TMA results from a hereditary deficiency of regulatory proteins that restrict activation of alternative complement pathway. These proteins include complement factor H (CFG) and its related proteins (CFHRs), membrane cofactor protein (MCP), CFI. Instead, it may result from an autoantibody inhibiting CFH of CFI. The consequence of this up-regulation is uncontrolled damage to vascular endothelium and renal cells, which manifests as a characteristic pentad. In our case, a CFH gene mutation was identified and history revealed a flu-like illness preceding her hospitalization. It is plausible that this illness may have served as a "second-hit" via complement-amplification. (Asif et al., 2017). Alternatively, in this patient with history of inflammatory colitis and reported Sjogren's syndrome, subclinical autoimmune disorder may also have served as a trigger. This case presentation serves as a reminder to not overlook the "zebra" that is complement-mediated TMA, to allow for prompt initiation of eculizumab therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Fu, Xiaoping, Jianjun Deng, Haixia Yang, Taro Masuda, Fumiyuki Goto, Toshihiro Yoshihara, and Guanghua Zhao. "A novel EP-involved pathway for iron release from soya bean seed ferritin." Biochemical Journal 427, no. 2 (March 29, 2010): 313–21. http://dx.doi.org/10.1042/bj20100015.
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Iron in phytoferritin from legume seeds is required for seedling germination and early growth. However, the mechanism by which phytoferritin regulates its iron complement to these physiological processes remains unknown. In the present study, protein degradation is found to occur in purified SSF (soya bean seed ferritin) (consisting of H-1 and H-2 subunits) during storage, consistent with previous results that such degradation also occurs during seedling germination. In contrast, no degradation is observed with animal ferritin under identical conditions, suggesting that SSF autodegradation might be due to the EP (extension peptide) on the exterior surface of the protein, a specific domain found only in phytoferritin. Indeed, EP-deleted SSF becomes stable, confirming the above hypothesis. Further support comes from a protease activity assay showing that EP-1 (corresponding to the EP of the H-1 subunit) exhibits significant serine protease-like activity, whereas the activity of EP-2 (corresponding to the EP of the H-2 subunit) is much weaker. Consistent with the observation above, rH-1 (recombinant H-1 ferritin) is prone to degradation, whereas its analogue, rH-2, becomes very stable under identical conditions. This demonstrates that SSF degradation mainly originates from the serine protease-like activity of EP-1. Associated with EP degradation is a considerable increase in the rate of iron release from SSF induced by ascorbate in the amyloplast (pH range, 5.8–6.1). Thus phytoferritin may have facilitated the evolution of the specific domain to control its iron complement in response to cell iron need in the seedling stage.
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Chatterjee, Priyadarshini, Amma Agyemang, Marat Alimzhanov, Soren Degn, Ronald Herbst, Tze Tan, Elizabeth Alicot, and Michael Carroll. "Intersection of Complement C4 and Interferon Alpha pathways in B cell tolerance (171.32)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 171.32. http://dx.doi.org/10.4049/jimmunol.188.supp.171.32.
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Abstract Humoral autoimmunity is an important hallmark of autoimmune diseases like lupus. Factors that allow self-reactive B cells to escape negative selection stages and become activated remain poorly defined. Using a novel B cell receptor knock-in mouse strain 564Igi, we define a complement-dependent pathway by which B cell tolerance is upheld. Interestingly, the 564-autoantibody could bind SSB/La, a common lupus antigen, establishing the physiological relevance of this model. Deficiency in complement C4 caused a breakdown in the elimination of autoreactive B cell clones at the transitional stage, as demonstrated by their continued maturation, their ability to respond to a range of stimuli, entry into follicles (lack of follicular exclusion) and formation of germinal centers with a higher propensity. All results taken together indicate that the complement system must be intact for B cell tolerance to be upheld. Strikingly, the dysregulation of autoreactive B cells in C4-deficient mice was not B cell intrinsic, as a C4-sufficient myeloid compartment could re-establish efficient B cell selection. Our current model holds that poor clearance of apoptotic debris in the absence of C4 chronically activates myeloid cells to release cytokines, like IFNα, in excess and reduce the stringency of tolerance at the transitional stage. In support of our hypothesis, IFNα receptor blockade was found to restore negative selection of B cells in C4-deficient 564Igi mice.
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Alic, Lejla, Nikolina Papac-Milicevic, Darina Czamara, Ramona B. Rudnick, Maria Ozsvar-Kozma, Andrea Hartmann, Michael Gurbisz, et al. "A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes." Proceedings of the National Academy of Sciences 117, no. 18 (April 22, 2020): 9942–51. http://dx.doi.org/10.1073/pnas.1913970117.
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Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis.
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Fu, Qiaoyu, Junming Jiang, Xubo Li, Zhe Zhai, Xuemei Wang, Chongrui Li, Qiaoling Chen, et al. "Activation of MyD88-Dependent TLR Signaling Modulates Immune Response of the Mouse Heart during Pasteurella multocida Infection." Microorganisms 11, no. 2 (February 4, 2023): 400. http://dx.doi.org/10.3390/microorganisms11020400.
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Pasteurella multocida (P. multocida) is an important zoonotic pathogen. In addition to lung lesions, necropsies have revealed macroscopic lesions in the heart in clinical cases. However, most previous studies focused on lung lesions while ignoring heart lesions. Therefore, to investigate the immune response of the P. multocida-infected heart, two murine infection models were established by using P. multocida serotype A (Pm HN02) and D (Pm HN01) strains. Histopathological examination revealed heterogeneous inflammatory responses, including immune cell infiltration in the epicardial and myocardial areas of the heart. Transcriptome sequencing was performed on infected cardiac tissues. To explore the traits of immune responses, we performed the functional enrichment analysis of differentially expressed genes, gene set enrichment analysis and gene set variation analysis. The results showed that the innate immune pathways were significantly regulated in both groups, including the NOD-like receptor signaling pathway, the complement and coagulation cascade and cytokine–cytokine receptor interaction. The Toll-like receptor signaling pathway was only significantly activated in the Pm HN02 group. For the Pm HN02 group, immunohistochemistry analysis further verified the significant upregulation of the hub component MyD88 at the protein level. In conclusion, this study reveals critical pathways for host heart recognition and defense against P. multocida serotypes A and D. Moreover, MyD88 was upregulated by P. multocida serotype A in the heart, providing a theoretical basis for future prevention, diagnosis and treatment research.
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Feng, Shuju, Stephen J. Eyler, Yuzhou Zhang, Tara K. Maga, Michael H. Kroll, Richard J. H. Smith, and Vahid Afshar-Kharghan. "ADAMTS13 Variants in Atypical Hemolytic Uremic Syndrome." Blood 120, no. 21 (November 16, 2012): 490. http://dx.doi.org/10.1182/blood.v120.21.490.490.
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Abstract Abstract 490 Atypical hemolytic uremic syndrome (aHUS) is a clinically defined thrombotic microangiopathic anemia (TMA) characterized by the symptom triad of renal failure, thrombocytopenia and microangiopathic hemolytic anemia in the absence of Shiga-toxin-producing bacteria as a triggering factor. Its pathogenesis is linked to dysregulation of the alternative pathway of the complement cascade, with loss-of-function mutations reported in complement regulators like factor H (CFH), membrane cofactor protein (MCP), factor I (CHI) and thrombomodulin (THBD), and gain-of-function mutations in complement activators like factor B (CFB) and complement component 3 (C3). In nearly 40% of patients, however, mutations are not identified in these genes raising the possibility of unrecognized contributory genetic causes. Genetic variants in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs) have been causally related to thrombotic thrombocytopenic purpura (TTP), another TMA characterized by the pentad of neurologic symptoms, fever, kidney failure, thrombocytopenia and microangiopathichemolytic anemia. The phenotypic similarities between aHUS and TTP can at times lead to difficulty in their clinical distinction. On this basis, we hypothesized that partial deficiency in ADAMTS13 function may coexist with abnormalities in the alternative complement pathway in patients with aHUS. To test this hypothesis, we measured ADAMTS13 functional activity in 26 patients with aHUS by fluorescence resonance energy transfer substrate-von Willebrandfactor 73mer (FRETS-VWF73) and recombinant VWF A2 domain cleavage assay. We also genotyped all patients for ADAMTS13 and alternative complement pathway genes. We transiently expressed 10 different ADAMTS13 missense variants in HEK293 cells to analyze activity and secretion of each recombinant protein. The ADAMTS13 functional activity was partially reduced (< 60%) in serum from 20 patients (77%) as measured by FRETS-VWF73 and recombinant VWF A2 cleavage assays. Genetic variants in ADAMTS13 were identified in 21 patients (81%) and included R386C, Q448E, A900V, V832M, R1060W, R7W/Q448E, A900V/Q448E, R1096H/A747V, R7W/A1033T, R7W/P618A/Q448E, R7W/P618A/A900V/Q448E, R7W/P618A/A732V/Q448E. The coexistence of both ADAMTS13 deficiency and excessive complement functional activity was present in 13 patients (50%). Activity of recombinant ADAMTS13 proteins containing the following variants was normal: R386C, Q448E, P618A, A732V, A747V, V832M, A900V, A1033T and R1060H. The R1096H variant of ADAMTS13 was associated with a reduction in functional activity by 50%. The secretion of recombinant proteins with the following variants was severely reduced: P618A, R1060H (<1%), R386C, R1096H (<10%), and A1033T (<50%) (Figures 1 and 2). This study implicates ADAMTS13 in the pathogenesis of aHUS and mandates the evaluation of ADAMTS13 in aHUS patients. Defining the role of ADAMTS13 in aHUS may aid in the development of new treatments and/or assist in clarifying whether long-term treatment with currently available anti-complement therapy is required for this disease. Disclosures: Kroll: Aplagon: Membership on an entity's Board of Directors or advisory committees; Optimer: Consultancy; Leo: Honoraria, Travel Expenses, Travel Expenses Other.
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Zhu, Wenli, Zhen Wang, Suying Hu, Ye Gong, Yuanchu Liu, Huanhuan Song, Xiaoli Ding, Ying Fu, and Yaping Yan. "Human C5-specific single-chain variable fragment ameliorates brain injury in a model of NMOSD." Neurology - Neuroimmunology Neuroinflammation 6, no. 3 (April 4, 2019): e561. http://dx.doi.org/10.1212/nxi.0000000000000561.
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ObjectiveUsing phage display, we sought to screen single-chain variable fragments (scFvs) against complement C5 to treat neuromyelitis optica spectrum disorder (NMOSD).MethodsAfter 5 rounds of phage display, we isolated individual clones and identified phage clones specifically binding to C5 using ELISA. Using aquaporin-4 (AQP4)-transfected cells in vitro, we confirmed whether these scFvs prevented complement-dependent cytotoxicity (CDC) caused by the serum of patients with NMOSD and human complement (hC). We selected an NMOSD mouse model, in which intracerebral NMOSD immunoglobulin G (IgG) and hC injections induce NMOSD-like lesions in vivo.ResultsWe obtained scFvs to test specificity and blocking efficiency. The scFv C5B3 neutralized C5 in the complement activation pathway, which prevented AQP4-IgG–mediated CDC in AQP4-transfected cells. In an NMOSD mouse model, C5B3 prevented AQP4 and astrocyte loss, decreased demyelination, and reduced inflammatory infiltration and membrane attack complex formation in lesions.ConclusionsWe used phage display to screen C5B3 against C5, which was effective in inhibiting cytotoxicity in vitro and preventing CNS pathology in vivo.
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Kim, Y. U., T. Kinoshita, H. Molina, D. Hourcade, T. Seya, L. M. Wagner, and V. M. Holers. "Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein." Journal of Experimental Medicine 181, no. 1 (January 1, 1995): 151–59. http://dx.doi.org/10.1084/jem.181.1.151.
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Normal host cells are protected from the destructive action of complement by cell surface complement regulatory proteins. In humans, decay-accelerating factor (DAF) and membrane cofactor protein (MCP) play such a biologic role by inhibiting C3 and C5 convertases. DAF and MCP accomplish this task by specific mechanisms designated decay-accelerating activity and factor I cofactor activity, respectively. In other species, including mice, structural and/or functional homologues of these proteins are not yet well characterized. Previous studies have shown that the mouse protein Crry/p65 has certain characteristics of self-protecting complement regulatory proteins. For example, Crry/p65 is expressed on a wide variety of murine cells, and when expressed on human K562 erythroleukemic cells, it prevents deposition of mouse C3 fragments on the cell surface during activation of either the classical or alternative complement pathway. We have now studied factor I cofactor and decay-accelerating activities of Crry/p65. Recombinant Crry/p65 demonstrates cofactor activity for factor I-mediated cleavage of both mouse C3b and C4b. Surprisingly, Crry/p65 also exhibits decay-accelerating activity for the classical pathway C3 convertase strongly and for the alternative pathway C3 convertase weakly. Therefore, mouse Crry/p65 uses the specific mechanisms of both human MCP and DAF. Although Crry/p65, like MCP and DAF, contains tandem short consensus repeats (SCR) characteristic of C3/C4 binding proteins, Crry/p65 is not considered to be a genetic homologue of either MCP or DAF. Thus, Crry/p65 is an example of evolutionary conservation of two specific activities in a single unique protein in one species that are dispersed to individual proteins in another. We propose that the repeating SCR motif in this family has allowed this unusual process of evolution to occur, perhaps driven by the use of MCP and DAF as receptors by human pathogens such as the measles virus.