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J A Schifferli - One of the best experts on this subject based on the ideXlab platform.
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Immune Adherence and clearance of hepatitis b surface ag ab complexes is abnormal in patients with systemic lupus erythematosus sle
Clinical and Experimental Immunology, 2008Co-Authors: N Madi, G Steiger, J Estreicher, J A SchifferliAbstract:Complement levels and complement receptor 1 (CR1) on erythrocytes (E) are reduced in systemic lupus erythematosus (SLE). To see whether these abnormalities are responsible for defective transport and elimination of Immune complexes (IC) from the circulation, patients with active SLE (14) and normal volunteers (14) were injected with preformed IC (hepatitis B surface Ag/Ab). Two minutes after injection only 25.9 +/- 19.1% (mean +/- 1 s.d.) of the circulating IC were bound to E in the SLE patients as compared to 63 +/- 3.7% in the normal subjects (P = 0.0001). For SLE patients, the reduced Immune Adherence was best explained by a combination of complement depletion and low CR1 binding capacity (tau = 0.80, P = 0.0001). The disappearance of IC as estimated from the area under the elimination curve was faster in SLE than in controls (P = 0.02), and correlated with CR1 (tau = 0.54, P = 0.0001) and Immune Adherence observed in vivo (tau = 0.33, P = 0.013). Finally, Immune Adherence was absent and IC disappeared very rapidly in a patient with C2 deficiency and an SLE-like disease. These observations suggest that in SLE the defective Immune Adherence reaction might be responsible for the accelerated disappearance of IC from the circulation.
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defective Immune Adherence and elimination of hepatitis b surface antigen antibody complexes in patients with mixed essential cryoglobulinemia type ii
Journal of Immunology, 1991Co-Authors: N Madi, G Steiger, J Estreicher, J A SchifferliAbstract:Mixed essential cryoglobulinemia type II (monoclonal Ig/polyclonal IgG) is characterized by systemic vasculitis caused by the deposition of circulating Immune reactants that include the monoclonal component. Such reactants may include Immune complexes (IC) formed from exogenous Ag. IC binding to E C receptor type 1 appears to play a role in transport and buffering of such IC (Immune Adherence: IA). To define the mechanisms responsible for Immune deposition, 7 patients with cryoglobulinemia type II (IgM kappa/polyclonal IgG) and 14 normal volunteers were injected i.v. with hepatitis B surface Ag/antibody complexes. Two minutes after injection, only 19.4% (mean) of the circulating complexes were bound to E in patients as compared with 63.1% in normal subjects. This IA correlated directly with C4 and inversely with the IgM rheumatoid factor (RF) titer. Disappearance of IC was faster in patients (mean elimination rate: 15.7%/min) than in normal subjects (9.3%). In vitro experiments demonstrated that C depletion, interference with IC opsonization by monoclonal IgM RF, and decreased binding of opsonized IC in the presence of monoclonal RF are each associated with decreased IA. These observations suggest that, in patients with cryoglobulinemia type II, monoclonal IgM RF and low C contribute to reducing IA of circulating IC that might be rapidly trapped in tissues, resulting in injury.
John P Atkinson - One of the best experts on this subject based on the ideXlab platform.
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role of complement receptor 1 cr1 cd35 on epithelial cells a model for understanding complement mediated damage in the kidney
Molecular Immunology, 2015Co-Authors: Anuja Java, Kathryn M Liszewski, Dennis E Hourcade, Fan Zhang, John P AtkinsonAbstract:The regulators of complement activation gene cluster encodes a group of proteins that have evolved to control the amplification of complement at the critical step of C3 activation. Complement receptor 1 (CR1) is the most versatile of these inhibitors with both receptor and regulatory functions. While expressed on most peripheral blood cells, the only epithelial site of expression in the kidney is by the podocyte. Its expression by this cell population has aroused considerable speculation as to its biologic function in view of many complement-mediated renal diseases. The goal of this investigation was to assess the role of CR1 on epithelial cells. To this end, we utilized a Chinese hamster ovary cell model system. Among our findings, CR1 reduced C3b deposition by ∼ 80% during classical pathway activation; however, it was an even more potent regulator (>95% reduction in C3b deposition) of the alternative pathway. This inhibition was primarily mediated by decay accelerating activity. The deposited C4b and C3b were progressively cleaved with a t½ of ∼ 30 min to C4d and C3d, respectively, by CR1-dependent cofactor activity. CR1 functioned intrinsically (i.e, worked only on the cell on which it was expressed). Moreover, CR1 efficiently and stably bound but didn't internalize C4b/C3b opsonized Immune complexes. Our studies underscore the potential importance of CR1 on an epithelial cell population as both an intrinsic complement regulator and an Immune Adherence receptor. These results provide a framework for understanding how loss of CR1 expression on podocytes may contribute to complement-mediated damage in the kidney.
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Lack of Evidence from Studies of Soluble Protein Fragments that Knops Blood Group Polymorphisms in Complement Receptor-Type 1 Are Driven by Malaria
2012Co-Authors: Patience B. Tetteh-quarcoo, John P Atkinson, Richard E Hauhart, Waihong Tham, Alan F Cowman, Christoph Q Schmidt, Haydyn D T Mertens, Arthur Rowe, Alexandra J. Rowe, Paul N BarlowAbstract:Complement receptor-type 1 (CR1, CD35) is the Immune-Adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non-infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McCa/b may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs) 15–25 of its ectodomain. These eleven modules encompass a region (CCPs 15–17) key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24–25. All four CR1 15–25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15–25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (KD = 0.8–1.1 µM) and C4b (KD = 5.0–5.3 µM). They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles.
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plasmodium falciparum uses a key functional site in complement receptor type 1 for invasion of human erythrocytes
Blood, 2011Co-Authors: John P Atkinson, Richard E Hauhart, Mara Guariento, Waihong Tham, Christoph Q Schmidt, Patience B Tettehquarcoo, Sash Lopaticki, Paul N BarlowAbstract:The Plasmodium falciparum adhesin PfRh4 binds to complement receptor type-1 (CR1) on human erythrocytes and mediates a glycophorin-independent invasion pathway. CR1 is a complement regulator and Immune-Adherence receptor on erythrocytes required for shuttling of C3b/C4b-opsonized particles to liver and spleen for phagocytosis. Using recombinant CR1 constructs, we mapped the recognition site for PfRh4 to complement control protein modules 1 to 3 (CCP1-3) at the membrane-distal amino terminus of CR1. This region of CR1 binds to C4b and C3b and accelerates decay of both classic pathway and alternative pathway C3 and C5 convertases. CCP1-3 competed for PfRh4 binding to erythroid CR1 and inhibited the PfRh4-CR1 invasion pathways across a wide range of P falciparum strains. PfRh4 did not bind significantly to other CR1 constructs, including CCP15-17, which is 85% identical to CCP1-3. PfRh4 binding to CR1 did not affect its C3b/C4b binding capability, and we show evidence for a ternary complex between CCP1-3, C4b, and PfRh4. PfRh4 binding specifically inhibited CR1's convertase decay-accelerating activity, whereas there was no effect on factor H-mediated decay-accelerating activity. These results increase our understanding of the functional implications of CR1 engagement with PfRh4 and highlight the interplay between complement regulation and infection.
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structure of the c3b binding site of cr1 cd35 the Immune Adherence receptor
Cell, 2002Co-Authors: Brian O Smith, John P Atkinson, Rosie L Mallin, Malgorzata Krychgoldberg, X Wang, Richard E Hauhart, Krystyna Bromek, Dusan Uhrin, Paul N BarlowAbstract:Abstract Complement receptor type 1 (CR1 or CD35) is a multiple modular protein that mediates the Immune Adherence phenomenon, a fundamental event for destroying microbes and initiating an immunological response. It fulfills this role through binding C3b/C4b-opsonized foreign antigens. The structure of the principal C3b/C4b binding site (residues 901–1095) of CR1 is reported, revealing three complement control protein modules (modules 15–17) in an extended head-to-tail arrangement with flexibility at the 16-17 junction. Structure-guided mutagenesis identified a positively charged surface region on module 15 that is critical for C4b binding. This patch, together with basic side chains of module 16 exposed on the same face of CR1, is required for C3b binding. These studies reveal the initial structural details of one of the first receptor-ligand interactions to be identified in immunobiology.
Norimasa Tsutsumi - One of the best experts on this subject based on the ideXlab platform.
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nosocomial transmission of varicella to a healthcare provider positive for anti varicella zoster virus antibodies nonprotective positivity with an Immune Adherence hemagglutination assay
Journal of Infection and Chemotherapy, 2011Co-Authors: Shigemi Hitomi, Toyoichiro Kudo, Hiroshi Koganemaru, Norimasa TsutsumiAbstract:A 24-year-old male healthcare provider, having attended a varicella patient 2 weeks before, developed varicella himself. He had shown a positive result for anti-VZV antibodies measured with an Immune Adherence hemagglutination assay (1:4) 1 year before. The present case shows that a positive result with this assay does not necessarily indicate protection against VZV infection.
Paul N Barlow - One of the best experts on this subject based on the ideXlab platform.
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Lack of Evidence from Studies of Soluble Protein Fragments that Knops Blood Group Polymorphisms in Complement Receptor-Type 1 Are Driven by Malaria
2012Co-Authors: Patience B. Tetteh-quarcoo, John P Atkinson, Richard E Hauhart, Waihong Tham, Alan F Cowman, Christoph Q Schmidt, Haydyn D T Mertens, Arthur Rowe, Alexandra J. Rowe, Paul N BarlowAbstract:Complement receptor-type 1 (CR1, CD35) is the Immune-Adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non-infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McCa/b may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs) 15–25 of its ectodomain. These eleven modules encompass a region (CCPs 15–17) key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24–25. All four CR1 15–25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15–25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (KD = 0.8–1.1 µM) and C4b (KD = 5.0–5.3 µM). They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles.
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plasmodium falciparum uses a key functional site in complement receptor type 1 for invasion of human erythrocytes
Blood, 2011Co-Authors: John P Atkinson, Richard E Hauhart, Mara Guariento, Waihong Tham, Christoph Q Schmidt, Patience B Tettehquarcoo, Sash Lopaticki, Paul N BarlowAbstract:The Plasmodium falciparum adhesin PfRh4 binds to complement receptor type-1 (CR1) on human erythrocytes and mediates a glycophorin-independent invasion pathway. CR1 is a complement regulator and Immune-Adherence receptor on erythrocytes required for shuttling of C3b/C4b-opsonized particles to liver and spleen for phagocytosis. Using recombinant CR1 constructs, we mapped the recognition site for PfRh4 to complement control protein modules 1 to 3 (CCP1-3) at the membrane-distal amino terminus of CR1. This region of CR1 binds to C4b and C3b and accelerates decay of both classic pathway and alternative pathway C3 and C5 convertases. CCP1-3 competed for PfRh4 binding to erythroid CR1 and inhibited the PfRh4-CR1 invasion pathways across a wide range of P falciparum strains. PfRh4 did not bind significantly to other CR1 constructs, including CCP15-17, which is 85% identical to CCP1-3. PfRh4 binding to CR1 did not affect its C3b/C4b binding capability, and we show evidence for a ternary complex between CCP1-3, C4b, and PfRh4. PfRh4 binding specifically inhibited CR1's convertase decay-accelerating activity, whereas there was no effect on factor H-mediated decay-accelerating activity. These results increase our understanding of the functional implications of CR1 engagement with PfRh4 and highlight the interplay between complement regulation and infection.
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structure of the c3b binding site of cr1 cd35 the Immune Adherence receptor
Cell, 2002Co-Authors: Brian O Smith, John P Atkinson, Rosie L Mallin, Malgorzata Krychgoldberg, X Wang, Richard E Hauhart, Krystyna Bromek, Dusan Uhrin, Paul N BarlowAbstract:Abstract Complement receptor type 1 (CR1 or CD35) is a multiple modular protein that mediates the Immune Adherence phenomenon, a fundamental event for destroying microbes and initiating an immunological response. It fulfills this role through binding C3b/C4b-opsonized foreign antigens. The structure of the principal C3b/C4b binding site (residues 901–1095) of CR1 is reported, revealing three complement control protein modules (modules 15–17) in an extended head-to-tail arrangement with flexibility at the 16-17 junction. Structure-guided mutagenesis identified a positively charged surface region on module 15 that is critical for C4b binding. This patch, together with basic side chains of module 16 exposed on the same face of CR1, is required for C3b binding. These studies reveal the initial structural details of one of the first receptor-ligand interactions to be identified in immunobiology.
N Madi - One of the best experts on this subject based on the ideXlab platform.
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Immune Adherence and clearance of hepatitis b surface ag ab complexes is abnormal in patients with systemic lupus erythematosus sle
Clinical and Experimental Immunology, 2008Co-Authors: N Madi, G Steiger, J Estreicher, J A SchifferliAbstract:Complement levels and complement receptor 1 (CR1) on erythrocytes (E) are reduced in systemic lupus erythematosus (SLE). To see whether these abnormalities are responsible for defective transport and elimination of Immune complexes (IC) from the circulation, patients with active SLE (14) and normal volunteers (14) were injected with preformed IC (hepatitis B surface Ag/Ab). Two minutes after injection only 25.9 +/- 19.1% (mean +/- 1 s.d.) of the circulating IC were bound to E in the SLE patients as compared to 63 +/- 3.7% in the normal subjects (P = 0.0001). For SLE patients, the reduced Immune Adherence was best explained by a combination of complement depletion and low CR1 binding capacity (tau = 0.80, P = 0.0001). The disappearance of IC as estimated from the area under the elimination curve was faster in SLE than in controls (P = 0.02), and correlated with CR1 (tau = 0.54, P = 0.0001) and Immune Adherence observed in vivo (tau = 0.33, P = 0.013). Finally, Immune Adherence was absent and IC disappeared very rapidly in a patient with C2 deficiency and an SLE-like disease. These observations suggest that in SLE the defective Immune Adherence reaction might be responsible for the accelerated disappearance of IC from the circulation.
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defective Immune Adherence and elimination of hepatitis b surface antigen antibody complexes in patients with mixed essential cryoglobulinemia type ii
Journal of Immunology, 1991Co-Authors: N Madi, G Steiger, J Estreicher, J A SchifferliAbstract:Mixed essential cryoglobulinemia type II (monoclonal Ig/polyclonal IgG) is characterized by systemic vasculitis caused by the deposition of circulating Immune reactants that include the monoclonal component. Such reactants may include Immune complexes (IC) formed from exogenous Ag. IC binding to E C receptor type 1 appears to play a role in transport and buffering of such IC (Immune Adherence: IA). To define the mechanisms responsible for Immune deposition, 7 patients with cryoglobulinemia type II (IgM kappa/polyclonal IgG) and 14 normal volunteers were injected i.v. with hepatitis B surface Ag/antibody complexes. Two minutes after injection, only 19.4% (mean) of the circulating complexes were bound to E in patients as compared with 63.1% in normal subjects. This IA correlated directly with C4 and inversely with the IgM rheumatoid factor (RF) titer. Disappearance of IC was faster in patients (mean elimination rate: 15.7%/min) than in normal subjects (9.3%). In vitro experiments demonstrated that C depletion, interference with IC opsonization by monoclonal IgM RF, and decreased binding of opsonized IC in the presence of monoclonal RF are each associated with decreased IA. These observations suggest that, in patients with cryoglobulinemia type II, monoclonal IgM RF and low C contribute to reducing IA of circulating IC that might be rapidly trapped in tissues, resulting in injury.
