Cellular & Molecular Immunology 2009

Transcription

1 Cellular & Molecular Immunology 2009 Complement Nicholas M. Ponzio, Ph.D. Department of Pathology & Laboratory Medicine March 4, 2009

2 Innate and adaptive immunity

3 FAMOUS BELGIANS Jules Jean Baptiste Vincent BORDET ( )

4 Lysis of Vibrio cholera by immune serum Experiment #1 Fresh normal serum Fresh immune serum Heated immune serum no lysis lysis no lysis Since antibodies are heat stable, Bordet concluded that a heat labile substance was needed in addition to antibodies to cause lysis

5 Lysis of Vibrio cholera by immune serum Experiment #2 Proof of Principle: Heated immune serum + fresh normal serum LYSIS Conclusion: A heat labile substance in normal serum complements the ability of antibodies in immune serum to lyse targets

6 What is Complement? C is a complex series of proteins in the blood These proteins are sequentially activated (aka, fixed), and they non-specifically complement the action of antibodies In the process of being activated, the C proteins are cleaved into a major fragment and a minor fragment (aka, split product) These fragments are responsible for the observed biological functions of C

7 Biological Functions of C Opsonization and Phagocytosis Microbes coated with C components are ingested more efficiently Stimulation of Inflammation C products can induce acute inflammation Cytolysis C can cause lysis of microbes

8 To perform these functions: C activation involves the sequential proteolysis of proteins to generate enzymes with proteolytic activity C products attach to microbial surfaces or to antibodies that are bound to microbes C activation is inhibited by regulatory proteins present on host cells, but absent from microbes

9 Fig Pathways of Complement Activation

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11 Structure of Complement Component C1

12 Classical pathway of complement activation C4b2b C4b2b C2b C2b C5a

13 Structure of Complement Component C1

14 The C1 component of complement

15 Activation of complement by IgM and IgG antibodies

16 Fig Pathways of Complement Activation

17 Thioester bond of C3

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19 Alternative pathway of complement activation C5a

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22 Late steps of complement activation: Formation of the membrane attack complex (MAC)

23 Electron micrographs of Membrane Attack Complex inserted into the cell membrane

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25 MHC I MHC II

26 MHC I MHC II

27 Table 14-6 Receptors for Fragments of C3 Receptor Type 1 (CR1, CD35) Type 2 (CR2, CD21) Distribution Mononuclear phagocytes, neutrophils, B and T cells, RBCs, FDCs eosinophils, B Cells, Follicular Dendritic Cells, Function Phagocytosis; Clearance of immune complexes; Promotes dissociation of C3 convertases by acting as cofactor for cleavage of C3b, C4b Co-receptor for B cell activation; Trapping of antigens in germinal centers; Receptor for EBV

28 Table 14-6 Receptors for Fragments of C3 Receptor Type 3 (CR3, CD11b/18) Type 4 (CR4, CD11c/18) Distribution Mononuclear phagocytes, neutrophils, NK cells Mononuclear phagocytes, neutrophils, NK cells Function Phagocytosis; Leukocyte adhesion to endothelium (via ICAM-1) Phagocytosis; Leukocyte adhesion

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31 Regulation of complement activation by C1 inhibitor

32 Classical pathway of complement activation

33 Cleavage of C3b by Factor I

34 Inhibition of the membrane attack complex

35 Functions of the Complement System

36 Functions of the Complement System

37 Functions of the Complement System C3a & C5a = Anaphylatoxins

38 Functions of the Complement System

39 Additional functions of the complement system: Trapping of IC in germinal centers C receptors on Follicular Dendritic Cells bind IC and present antigen to B cells during humoral immune responses. B cell activation C3d (cleavage product of C3b) binds to C receptors on B cells, providing a signal to initiate B cell activation during humoral immune responses.

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41 Complement Deficiencies Classical Pathway: C1q, C1r, C4, C2, C3 (C2 most common) C2 & C4 -- autoimmune diseases (e.g., SLE) C3 -- gram + bacterial infections Alternative Pathway: Properdin & Factor D -- gram + infections Membrane Attack Complex (MAC): C Neisseria bacterial infections