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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
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COMPLEMENT RECEPTORS Tímea Berki and Ferenc Boldizsár Signal transduction Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
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TÁMOP-4.1.2-08/1/A-2009-0011 Basic functions of the complement Opsonization: enhancing phagocytosis of antigens Chemotaxis: attracting macrophages and neutrophils Lysis: rupturing membranes of foreign cells Clumping of antigen-bearing agents Altering the molecular structure of viruses Transport of immuncomplexes by RBCs
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TÁMOP-4.1.2-08/1/A-2009-0011 Opsonins Acute phase proteins like mannose- binding lectin (MBL), C-reactive protein (CRP) C3b, C4b complement factors Surfactant proteins in the alveoli SP-A and SP-D The antibody molecule IgG can function as an opsonin
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TÁMOP-4.1.2-08/1/A-2009-0011 Secreted Pattern Recognition Receptors (PRRs) Complement receptors, collectins Pentraxin proteins such as serum amyloid and C-reactive protein Lipid transferases Peptidoglycan recognition proteins (PGRs) and the LRR, XA21D are all secreted proteins One very important collectin is mannan- binding lectin (MBL), a major PRR of the innate immune system that binds to a wide range of bacteria, viruses, fungi and protozoa. MBL predominantly recognizes certain sugar groups on the surface of microorganisms but also binds phospholipids, nucleic acids and non-glycosylated proteins
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TÁMOP-4.1.2-08/1/A-2009-0011 Role of complement receptors Complement receptors are responsible for detecting pathogens by mechanisms not mediated by antibodies Complement activity is not antigen sensitive, but can be triggered by specific antigens Therefore complement (a group of proteins in the serum that help achieve phagocytosis and lysis of antigens) is also part of the innate humoral immune system
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TÁMOP-4.1.2-08/1/A-2009-0011 Complement receptors CR #Name Cluster of differentiation (CD) CR1-CD35 CR2-CD21 CR3Macrophage-1 antigen or „integrin alphaMbeta2”CD11b+CD18 CR4Integrin alphaXbeta2 or „p150,95”CD11c+CD18 -C3a receptor- -C5a receptorCD88
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TÁMOP-4.1.2-08/1/A-2009-0011 Complement receptors CR1 CR2 CR3 CR4 CR2 CR3 CR4 CRIg SIGNR1 C3aR C5aR C1qR CD46 CD55 CD59 C3aR C5aR C1qRP Antigen recognition and uptake Pathogen recognition and/or clearance Modulation of T H 1/T H 2 commitment Antigen recognition and uptake Cytokine modulation and APC maturation CR1 Inhibits cell proliferation Expressed on <15% Unknown Expressed on <5% Cytokine modulation Expressed on activation T-cell trafficking Upregulated by activation Cytokine modulation CD46 CD55 CD59 Activation/proliferation, cytokine modulation and lineage commitmentAPC T cell
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TÁMOP-4.1.2-08/1/A-2009-0011 CR1 Erythrocyte complement receptor 1 (CR1, CD35): Also known as C3b/C4b receptor and immune adherence receptor It is found on erythrocytes, leukocytes, glomerular podocytes, and splenic follicular dendritic cells The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement
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TÁMOP-4.1.2-08/1/A-2009-0011 Role of CR1 CR1 serves as the main system for processing and clearance of complement opsonized immune complexes It has been shown that CR1 can act as a negative regulator of the complement cascade, It mediates immune adherence and phagocytosis and inhibits both the classic and alternative pathways The number of CR1 molecules decreases with aging of erythrocytes (100-1000/cell) in normal individuals and is also decreased in pathological conditions such as SLE, HIV infection, some HAs and other conditions featuring immune complexes
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TÁMOP-4.1.2-08/1/A-2009-0011 CR2 Complement component receptor 2 (CR2, CD21): Also known as, 3d /Epstein Barr virus receptor CR2 on mature B cells form a complex with two other membrane proteins, CD19 and CD81(=TAPA-1). The CR2- CD19-CD81 complex is often called the B cell co- receptor complex, because CR2 binds to antigens through attached C3d (or iC3b or C3dg) when the membrane IgM binds to the antigen. This results in the B cell having greatly enhanced response to the antigen. Complement receptor 2 has been shown to interact with CD19. Epstein Barr Virus (EBV) binds to B cells at CR2 during infection of these cells. Yefenof et al. (1976) found complete overlapping of EBV receptors and C3 receptors on human B cells.
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TÁMOP-4.1.2-08/1/A-2009-0011 C5aR C5a receptor : C5a receptor : also known as complement component 5a receptor 1 (C5AR1) or CD88 is a G protein-coupled receptor for C5a
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TÁMOP-4.1.2-08/1/A-2009-0011 Overview of complement receptor (CR) and Toll-like receptor signalingTLRCR3C5aR C3b gC1qR C1q CD46 iC3b C5 BacteriaViruses Erk1/2 PI3K TLR4-induced IL-12 inhibited by posttranscriptional mechanism TLR4-induced IL-12 inhibited by posttranscriptional mechanism Nucleus IL-12p35 IL-12/IL-23p40 IL-23p19 IL-27p28 IRF-1, IRF-8 IRF-1, IRF-8 C5a
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TÁMOP-4.1.2-08/1/A-2009-0011 Toll-like receptors-pattern recognition Peptidoglycan (G+) Lipoprotein Lipoarabinomannan (Mycobacteria) LPS (Leptospira) LPS (Porphyromonas) GPI (Trypanosoma cruzi) Yymosan (Yeast) dsRNAFlagellin Unmethylated CpG DNA TLR2TLR1TLR5TLR3TLR9TLR6TLR2 Lipoteichoic acids (G+) RVS F protein LPS (G-) TLR4CD14 MD-2
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TÁMOP-4.1.2-08/1/A-2009-0011 Toll-like receptors (TLRs) They are single, membrane-spanning, non- catalytic receptors that recognize structurally conserved molecules derived from microbes They receive their name from their similarity to the protein coded by the Toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard. The gene in question, when mutated, makes the Drosophila flies look unusual, or 'weird'. The researchers were so surprised that they spontaneously shouted out in German "Das ist ja toll!" which translates as "That´s wild!"
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TÁMOP-4.1.2-08/1/A-2009-0011 MyD88 TRIF TLR3TLR7TLR2 PKA TAK1 PKR MKKs lBlB lBlB p50 p65 MyD88 LPS TLR4 MD2 LBP dsRNA TBK1 IKK MDA-5 RIG-1 IPS1 TLR9 JAK2 mTOR PI3K CD14 TLR types
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