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Complement Cascade

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The Complement cascade The complement system is a heat labile component of blood that confers bactericidal Carboxypeptidase properties. The functions of complement include the attraction of inflammatory cells, C1qr2s2 C4 MBL/MASPs C3 opsinization to promote phagocytosis, immune complex clearance and direct Chemotaxis and microbial killing through the formation of the membrane attack complex (MAC). Pathway Pathway activation of Three pathways lead to complement activation; the classical pathway initiated by activation Serpin antibodies bound to the surface of foreign bodies and the alternative and lectin activation C3a inflammatory cells, pathways that provide an antibody independent mechanism for complement inducing cytokine activation induced by the presence of bacteria and other micro-organisms. C4a Serpin production, and mast C4b The classical pathway (in light-blue): C1 the first molecule in the classical (C1 inhibitor) cell degranulation, which complement cascade comprises C1q and two molecules of C1r and C1s. C1q binds C3 convertase results in enhanced target bound antibody leading to the activation of C1s. C1s cleaves C4 present in the vascular permeability plasma releasing C4a and C4b. C4b binds C2, which is subsequently cleaved by C2 C2a C4b2a C1s. This results in the release of C2b and C2a. C2a remains associated with C4b and local blood flow. to form the classical pathway C3 convertase (C4b2a). C2a in the convertase complex C5 convertase cleaves C3 releasing C3a and C3b. The latter binds to the C3 convertase complex to form C4b2a3b, the classical pathway C5 convertase. This complex cleaves C5 C2b C3b C4b2a3b Vitronectin, clusterin leading to the release of C5a and C5b. Opsonin C4bp, Factor I, (plasma proteins) and MCP, DAF and CRI CD59 on host cells. The lectin pathway (in white): Mannan-binding lectin (MBL) and MBL-associated serine proteases (MASPs) are involved in the initial step of the lectin pathway of complement activation. The binding of MBL to mannose and N-acetyl glucosamine in micro-organisms leads to the activation of MASPs, which subsequently cleave C4 Hydrolyzed Membrane attack complex and C2. Following these cleavage events, complement pathway activation continues C3 C3i + Factor B Pathway C5 C5b as in the classical pathway. ‘Tickover’ cross-talk + C6 + C7 + C8 + C9 The alternative pathway (in dark-blue): The alternative pathway of complement activation is in a constant state of low-level activation (known as tickover). C3 is Compromised bacterial hydrolysed in the plasma to C3i, which has many of the properties of C3b. C3i then C5a binds the plasma protein, Factor B. Bound Factor B is cleaved by Factor D to produce function due to pore formation Ba and Bb. Ba is released and the remaining complex comprised of C3iBb forms the alternative pathway C3 convertase. Most of the C3b generated by the convertase is Factor I, MCP C3iB hydrolysed. However, if C3b comes into contact with an invading micro-organism it Bacterial lysis binds and amplification of the alternative pathway is promoted by the binding of C3b Stabilized to Factor B. The plasma protein, properdin stabilizes the C3 convertase to prolong activity. C3b produced in this pathway also yields the C5 convertase, C3bBb3b, which Ba Factor D by invading leads to the production of C5a and C5b. Note, C3b generated in the classical micro-organisims pathway feeds into the alternative pathway to amplify the activation of complement. Factor H C3iBb Inhibitors of the complement system (in yellow): The complement system is regulated to protect the host. Complement inhibitors include the plasma serine DAF and CR1 proteinase inhibitor serpin (C1 inhibitor). The plasma proteins, Factor I and C4 C3 convertase C6 binding protein (C4-bp), inhibit the activity of the classical C3 convertase. Classical C5b pathway activation is also inhibited by the surface bound proteins, decay accelerating C9 factor (DAF), CR1 and membrane co-factor protein (MCP). The alternative pathway C8 is regulated by Factor H, DAF and CR1, which inhibit the C3 convertase of the C7 alternative pathway. Factor I promotes the catabolism of C3i and C3b (Factor H and C3 C3b C3bBb3b MCP act as co-factors). C5 Convertase Opsinization (C3bi breakdown product is C3a also an opsonin), Clearance of immune www.abcam.com Factor I complexes and B cell priming. Complement antibodies from Abcam: See more products at: www.abcam.com/immunology Product Clonality Applications Host Cross- Datasheet Product Clonality Applications Host Cross- Datasheet reactivity www.abcam.com/ab… reactivity www.abcam.com/ab… Classical pathway Alternative pathway C1q [7H8] M ELISA, Flow Cyt, IHC-FoFr, Factor B P IHC-Fr Shp Hu 64515 IHC-Fr, IP, WB Rat Ms 11861 Factor D [008-01] M ELISA, WB Mm Hu 36383 C1r P DID, Ie, RID, RIe Shp Hu 8781 Factor P [10-18] M ELISA, FuncS, IHC-Fr Mm Hu 58984 C1s P DID, Ie, RID Shp Hu 8782 Properdin, B factor [008-02] M ELISA, WB Mm Hu 17932 C2 P ELISA, WB Rb Hu, Ms, Rat, Dog and Zfsh 58389 SC5b9 [3R2/0] M ELISA, Flow Cyt, IHC-Fr, WB Mm Hu 59024 C3 / C3b [755] M IP, WB Mm Hu 11871 C3 [11H9] M Flow Cyt, IHC-Fr, IP, WB Rat Ms 11862 Regulatory / Inhibitors C3a / C3a des Arg [013-16] M ELISA, WB Mm Hu 36385 C4 binding protein P IHC-Fr Shp Hu 53894 C3a Receptor [hC3aRZ1] M Flow Cyt, IHC-Fr Mm Hu 59554 CD59 [MEM-43] M Flow Cyt, FuncS, ICC/IF, IHC-Fr, C3c (FITC) P Flow Cyt, IHC-Fr Rb Hu, Ms, Rat, Gt, Cow, Dog, Pig, IHC-P,IP, WB Mm Hu 9182 Pig, Sh, Cat, Gpig, Mink and Kg 4212 Clusterin (Apolipoprotein J) P WB Rb Hu 42673 C3d P ELISA, ICC, IHC-P Rb Hu 15981 Complement Receptor 1 C4 [16D2] M Flow Cyt, IHC-Fr, IP, WB Rat Ms 11863 (CR1) (CD35) [RLB25] M IHC-Fr, IHC-P Mm Hu 49520 C4a [99-H7] M ELISA, WB Mm Hu 63796 Decay Accelerating Factor C4b P ELISA, WB Chk Hu 48582 (DAF) (CD55) [BRIC110] M Flow Cyt, ICC/IF Mm Hu 53353 C4c / C4b (FITC) P IHC-Fr Rb Hu 4216 ECT P WB Rb Hu, Ms and Mk 15053 C4c P ID, WB Chk Hu 61965 Factor H P DID, Flow Cyt, Ie, RID, RIe Shp Hu, Ms, Rat, Hrs, Dog, Cat C4d P Flow Cyt, ICC/IF,IHC-Fr, IHC-P, WB Rb Hu 36075 and Gpig 8842 C5 / C5a P WB Rb Hu 46168 Factor I [061-01] M ELISA, WB Mm Hu 52244 C5 P IHC-Fr, WB Rb Ms 11898 Membrane Co-Factor Protein C5/C5b P WB Rb Hu 46153 (MCP) (CD46) [MEM-258] M Flow Cyt, IP, WB Mm Cow and Hu 789 C5a / C5a des Arg [2952] M ELISA, WB Mm Hu 11878 Properdin [HYB 039-06] M AP, ELISA, WB Mm Hu 25850 C5b-9 [aE11] M ELISA, IHC-Fr, WB Mm Hu, Bb and Pig 15984 Serpin (C1 Inactivator) M IHC-P, WB Mm Hu 54898 C5R1 [P12/1] M Flow Cyt, IHC-Fr, WB Mm Hu and RhMk 33212 Vitronectin [EP873Y] M ICC/IF, IHC-P, WB Rb Hu, Ms and Rat 45139 GC1q R [60.11] M ELISA, Flow Cyt, IP, WB Mm Hu, Ms and Rat 24733 Membrane Attack Complex (MAC) Lectin Pathway C6 P IHC-Fr, WB Rb Ms 11899 Mannan Binding Lectin A [2B4] M IA, WB Rat Ms 36670 C7 P DID, Ie, RID Shp Hu 8791 Mannan Binding Lectin C8 [056B-373] M ELISA, Flow Cyt, IHC-Fr, WB Mm Hu 59140 [HYB 131-01] M ELISA, IHC-Fr, IHC-P, WB Mm Hu 23457 C9 P ELISA, ID, IHC-Fr, IHC-P Shp Hu 53896 MASP1 P WB Rb Hu 65891 MASP1/3 P WB Rb Hu 65887 And many more... MASP2 P WB Rb Hu 65895 Mannan Binding Lectin antibody [HYB 131-01] (ab23457) C5R1 [P12/1] antibody (ab33212) Clonality Applications Host Species cross reactivity Clonality Applications Host Species cross reactivity M ELISA, IHC-Fr, IHC-P, WB Mm Hu M Flow Cyt, IHC-Fr, WB Mm Hu and RhMk Mannan Binding Lectin, MBL, belongs to the C-type family of collectins. It functions as an All cellular responses to C5a are specifically mediated by interactions with the opsonin which activates the complement system on binding to microbial polysaccharides. This membrane bound C5a receptor, a seven transmembrane GTP binding coupled image shows Mannan Binding Lectin staining in formalin fixed and PFA-fixed paraffin receptor that belongs to the rhodopsin supergene family. C5a receptor 1 embedded human liver, using ab23457 expression has been reported in myeloid blood cells, brain, liver, lung, spleen, heart, kidney, and intestinal tract. This image shows FACS analysis of C5R1 expressing cells in human peripheral blood granulocytes, using ab33212..
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  • Complement Herbert L

    Complement Herbert L

    Host Defense 2011 Complement Herbert L. Mathews, Ph.D. COMPLEMENT Date: 4/11/11 Reading Assignment: Janeway’s Immunobiology, 7th Edition, pp. 54-55, 61-82, 406- 409, 514-515. Figures: (Unless otherwise noted) Janeway’s Immunobiology, 7th Edition, Murphy et al., Garland Publishing. KEY CONCEPTS AND LEARNING OBJECTIVES You will be able to describe the mechanism and consequences of the activation of the complement system. To attain the goals for these lectures you will be able to: a. List the components of the complement system. b. Describe the three activation pathways for complement. c. Explain the consequences of complement activation. d. Describe the consequence of complement deficiency. Page 1 Host Defense 2011 Complement Herbert L. Mathews, Ph.D. CONTENT SUMMARY Introduction Nomenclature Activation of Complement The classical pathway The mannan-binding lectin pathway The alternative pathway Biological Consequence of Complement Activation Cell lysis and viral neutralization Opsonization Clearance of Immune Complexes Inflammation Regulation of Complement Activation Human Complement Component Deficiencies Page 2 Host Defense 2011 Complement Herbert L. Mathews, Ph.D. Introduction The complement system is a group of more than 30 plasma and membrane proteins that play a critical role in host defense. When activated, complement components interact in a highly regulated fashion to generate products that: Recruit inflammatory cells (promoting inflammation). Opsonize microbial pathogens and immune complexes (facilitating antigen clearance). Kill microbial pathogens (via a lytic mechanism known as the membrane attack complex). Generate an inflammatory response. Complement activation takes place on antigenic surfaces. However, the activation of complement generates several soluble fragments that have important biologic activity.