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1、Chapter 14 Effector Mechanisms of Humoral Immunity,Overview of Humoral Immunity,Neutralization of Microbes and Microbial Toxins,Antibody can bind to microbial structures interfere with the ability of the microbes t interact with cellular receptors. Allosteric effects of antibodies: very few antibody
2、 molecules may bind to a microbe and induce conformational changes in surface molecules of microbe. Antibody mediated neutralization of microbes and toxins requires only the antigen-binding regions of the antibodies.,Antibody-Mediated Opsonization and Phagocytosis,Fc Receptors,1. Each of the leukocy
3、tes FcRs contains one Fc-binding polypeptide chain, called the a chain, which is a member of the Ig superfamily and determine the affinity and specificity.,2. Three distinct types of Fcg receptors: Fcg RI (CD64), expressed on macrophages and neutrophils, a high-affinity (10-8-10-9M). receptor for Ig
4、G1 ane G3.,g chain of the receptor contains an ITAM. Transcription of FcgRI gene is stimulated by IFN-g,2) Low- affinity receptors(10-6M): FcgRII(CD32),FcgRII: is expressed on macrophages and binds IgG1 and IgG3. There are three different isoforms of FcgRII: A,B, C FcgRIIA: on neutrophils and mononu
5、clear phagocytes. FcgRIIA and IIC contain ITAMs and deliver activating signal.,2) Low- affinity receptors: FcgRII(CD32),FcgRIIB is expressed exclusively by lymphocytes, especially on B cells, which cotain an inhibitor motif.,3) Low- affinity receptors: FcgRIIIA, two separate genes code for this mole
6、cular in humans.,FcgRIIIA isoform, the product of the A gene, expressed mainly on NK cells. Receptor clustering induced by IgG1 and IgG3 activates NK cells, thereby mediating antibody-dependent cell-mediated cytotoxicity. FcgRIIIB, the product of the B gene, is a glycosylphosphatidylinositol (GPI)-
7、linked protein expressed on neutrophils. It does not mediate phagocytosis or trigger neutrophil activation.,3 FceRI: IgE receptor(10-10M), expressed mainly on mast cells and basophils.,Antigen mediated cross linking of Ig E that is prebound to FceRI results in activation and degranulation of the mas
8、t cells or basophils. Is also expressed on eosinophils, where it can mediate IgE-directed ADCC.,4. FcaR(CD89): an IgA receptor expressed on neutrophils, monocytes, and eosinophils.,Fc Receptors,Antibody-Dependent Cell-Mediated Cytotoxicity,NK cells eosinophils,The Complement System:,Activation of co
9、mplement invovles the sequential proteolysis of proteins to generate enzymes with proteolytic activity. The products of complement activation become covalently attached to microbial cell surfaces, and other antigens. Complement activation is inhibited by regulatory proteins that are present on norma
10、l host cells and absent from microbes.,Pathway of Complement Activation:,Classical Pathway,1) Activator: IgG , IgM and antigen complex 2) Component: C1-C9 3) Procedure:,Recognization,Activation,Membrane attack,识别阶段：主要参与的补体分子是C1,Ag-Ab complex C1q C1r活化C1s 活化,I,II,IgA and IgE cannot activate complemen
11、t,IgM CH3区，IgG CH2区,C1 Molecular:,Multimeric protein complex composed of C1q, C1r, and C1s,1C1q, 2C1r, 2C1s C1q An umbrella-like radial array of six chains Binds to the antibody Fc region of m and g chain. Is a hexamer（六聚体）,C1r and C1s are serine esterase（丝氨酸酯酶）,Recognition Procedure:,Generation of
12、C3-convertase Generation of C5-convertase,Activation:,C4,Generation of C3-convertase,Activation:,I、C1s活化剪切C4为C4a和C4b，C4b共价结合到细胞膜上：,Generation of C3-convertase,C4b,Mg+,C4a,C2,C4b2b is C3 convertase,II、C1s活化剪切C2为C2a和C2b，C4b与C2b形成C3转化酶（C4b2a):,C3 molecular:,C3b formed the internal thioester（硫酯键） bond a
13、nd formed covalent amide （氨基化合物）or ester linkages with the antigen-antibody complex or with the adjacent surface of a cell.,Generation of C5-convertase,C4b,Mg+,C4a,C2a,C3,C4b2b3b is C5 convertase; it leads into the Membrane Attack Pathway,C3 molecular:,The central component in three pathways of comp
14、lement activation. C3 is degraded to generate biologically active products and the subsequent covalent attachment of a product of C3.,2. The Alternative Pathway,Component:,Components of the alternative pathway,C3,B,D,P,Spontaneous C3 activation,C3,H2O,B,D,C3,Generation of C3 convertase,This C3 b mol
15、ecule has a very short half life,B,D,If spontaneously-generated C3b is not degraded,C3-activation the amplification loop,C3,C3a,B,D,C3,C3-activation the amplification loop,C3a,C3a,C3,B,D,C3-activation the amplification loop,C3a,C3a,C3a,C3-activation the amplification loop,C3a,C3a,C3a,C3-activation t
16、he amplification loop,C3b stabilization and C5 activation,C3,C5,B,D,P,This leads to membrane attack pathway,Binding of microbial polysaccharides to circulating lectins such as MBL. Not to depend on antibody for its activation To be activated by mannose-binding lectin (MBL, an acute phase protein produced in inflammatory response) to mannose residues on glycoprotein or carbohydrates on the surface of microbes Details of the lectin pathway remai
