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COMPLEMENT RECEPTORS TÁMOP-4.1.2-08/1/A-2009-0011 Basic Functions of the Complement

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COMPLEMENT RECEPTORS TÁMOP-4.1.2-08/1/A-2009-0011 Basic Functions of the Complement 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 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 Tímea Berki and Ferenc Boldizsár Signal transduction COMPLEMENT RECEPTORS 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 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 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 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 TÁMOP-4.1.2-08/1/A-2009-0011 Complement receptors Cluster of CR # Name differentiation (CD) CR1 - CD35 CR2 - CD21 CR3 Macrophage-1 antigen or „integrin alphaMbeta2” CD11b+CD18 CR4 Integrin alphaXbeta2 or „p150,95” CD11c+CD18 - C3a receptor - - C5a receptor CD88 TÁMOP-4.1.2-08/1/A-2009-0011 Complement receptors APC T cell CR1 CR1 Inhibits cell proliferation Expressed on <15% CR2 Antigen recognition and uptake CR2 CR3 CR3 Unknown CR4 Expressed on <5% CR4 Pathogen recognition CRIg and/or clearance SIGNR1 Cytokine modulation C3aR Expressed on activation C3aR Modulation of T 1/T 2 H H T-cell trafficking commitment C5aR C5aR Upregulated by activation Antigen recognition C1qR C1qRP Cytokine modulation and uptake CD46 CD46 Activation/proliferation, Cytokine modulation CD55 CD55 cytokine modulation and and APC maturation lineage commitment CD59 CD59 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 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 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. TÁMOP-4.1.2-08/1/A-2009-0011 C5aR C5a receptor : also known as complement component 5a receptor 1 (C5AR1) or CD88 is a G protein-coupled receptor for C5a TÁMOP-4.1.2-08/1/A-2009-0011 Overview of complement receptor (CR) and Toll-like receptor signaling Bacteria Viruses C5 C3b iC3b C5a C1q CR3 TLR C5aR gC1qR CD46 TLR4-induced IL-12 inhibited PI3K by posttranscriptional mechanism Erk1/2 IRF-1, IRF-8 IL-12p35 IL-12/IL-23p40 Nucleus IL-23p19 IL-27p28 TÁMOP-4.1.2-08/1/A-2009-0011 Toll-like receptors-pattern recognition Peptidoglycan (G+) Lipoprotein Lipoarabinomannan (Mycobacteria) LPS (Leptospira) LPS (Porphyromonas) Lipoteichoic acids (G+) GPI (Trypanosoma cruzi) RVS F protein Unmethylated Yymosan (Yeast) dsRNA LPS (G-) Flagellin CpG DNA TLR1 TLR2 TLR2 TLR6 TLR3 CD14 MD-2 TLR4 TLR5 TLR9 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!" TÁMOP-4.1.2-08/1/A-2009-0011 TLR types LPS TLR2 LBP TLR4 MD2 CD14 dsRNA MyD88 MyD88 TLR9 TLR7 TLR3 RIG-1 MDA-5 JAK2 IPS1 PI3K IKKe TBK1 mTOR MyD88 TRIF PKA TAK1 PKR MKKs lkB p50 p65 p38 JNK .
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