BIOLOGY 151 LECTURE 11                         The Complement                                  PARUNGAO-BALOLONG 2011Sunda...
WHAT YOU NEED TO KNOW              RECALL: Functions &              Components of the              Complement             ...
RECALL...           PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
Complement...      Paul Erlich (1890s)            describe how cells respond to a range of different            threats   ...
PATHWAYS OF ACTIVATION                                       PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
THE COMPLEMENT CASCADE                            PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
FUNCTIONS AND COMPONENTS                            OF THE COMPLEMENT         Synthesized mainly by         liver hepatocy...
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
STRUCTURE OF                             C1q                          http://student.ccbcmd.edu/                          ...
SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE           CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION                            ...
SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE           CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION                            ...
SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE           CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION                            ...
CLASSICAL PATHWAY            http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/            c1act.html        ...
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
C3 MOLECULES & THIOESTER BONDS                             PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
HYDROLYSIS OF C3 BY C3 CONVERTASE C4b2a                                   PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
ALTERNATIVE PATHWAY (PROPERDIN PATHWAY)          a primitive defense system, a bypass          mechanism that does not req...
COMPONENTS: ALTERNATIVE PATHWAY                              (PROPERDIN PATHWAY)        C3: The initial recognition event ...
COMPONENTS: ALTERNATIVE PATHWAY                              (PROPERDIN PATHWAY)        Factor D (C3 proactivator        c...
COMPONENTS: ALTERNATIVE PATHWAY                              (PROPERDIN PATHWAY)        Factor D             When stabiliz...
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
PARUNGAO-BALOLONG 2011        The mannose-binding lectin pathway        does not depend on antibody for its         MBL, l...
PARUNGAO-BALOLONG 2011        The mannose-binding lectin pathway        When the MBL complex binds to a      The MBL pathw...
The three complement pathways converge at the membrane-        attack complex            PARUNGAO-BALOLONG 2011Sunday, Mar...
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
Late steps of                                      complement                                      activation and         ...
EFFECTOR ACTIONS OF COMPLEMENT                                PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
Antibody-mediated mechanisms             PARUNGAO-BALOLONG 2011                                      for combating infecti...
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
Scanning electron                                      micrographs of E. coli                                      showing...
MICROBIAL EVASION             PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
The                                                                      complement                                       ...
REGULATION        Inclusion of highly labile components    A series of regulatory proteins        that undergo spontaneous...
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
REGULATION: RECEPTORS        Many of the biological activities of the complement system depend on the        binding of co...
ROLE OF COMPLEMENT IN                           B CELL ACTIVATION                                                 PARUNGAO...
COMPLEMENT & DISEASES            Complement deficiencies                  genetic deficiencies in classical pathway compon...
COMPLEMENT & DISEASES              Pathologic effects of a normal complement system                    The immune complexe...
Sunday, March 13, 2011
What is the rate-limiting step                         in the complement cascade?                         C4. The liver ca...
WRAPPING UP!!!         The complement system comprises a group of serum         proteins, many of which exist in inactive ...
WRAPPING UP!!!         The classical pathway is initiated by antibody binding         to a cell target; reactions of IgM a...
WRAPPING UP!!!          Interactions of complement proteins and protein fragments          with receptors on cells of the ...
NEXT MEETING:                           CELL-MEDIATED                         EFFECTOR RESPONSESunday, March 13, 2011
Upcoming SlideShare
Loading in...5
×

Bio 151 lec 11 complement

1,850

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
1,850
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
169
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Bio 151 lec 11 complement

  1. 1. BIOLOGY 151 LECTURE 11 The Complement PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  2. 2. WHAT YOU NEED TO KNOW RECALL: Functions & Components of the Complement Activation and Regulation of the Complement Cascade Biological Consequences PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  3. 3. RECALL... PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  4. 4. Complement... Paul Erlich (1890s) describe how cells respond to a range of different threats proposed that cells produce more of these side chains, which eventually break off, circulate in the blood stream and attach to toxic products released by bacteria (ANTIBODIES) Jules Bordet (1900s) experiments revealed how antibodies need to recruit special allies in order to destroy specific bacteria wasn’t sealed by antibodies alone (partner up with a substance that is routinely present in the blood = COMPLEMENT) PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  5. 5. PATHWAYS OF ACTIVATION PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  6. 6. THE COMPLEMENT CASCADE PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  7. 7. FUNCTIONS AND COMPONENTS OF THE COMPLEMENT Synthesized mainly by liver hepatocytes (blood monocytes, tissue macrophages, epithelial cells of GI &GU tracts) Most circulate in the serum in functionally inactive forms as proenzymes (zymogens) ACTIVATION: trigger inflammation activate naïve B- larger fragments: bind lymphocytes to the target near the attract phagocytes site of activation remove immune opsonize antigens complexes smaller fragments: local inflammation cause cell lysis PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  8. 8. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  9. 9. STRUCTURE OF C1q http://student.ccbcmd.edu/ courses/bio141/lecguide/ unit4/innate/c1act.html assembly of C1 during classical pathway PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  10. 10. SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  11. 11. SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  12. 12. SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  13. 13. CLASSICAL PATHWAY http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/ c1act.html assembly of C1 during classical pathway http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/ c3case.html assembly of C3 convertase http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/ c5case.html cleavage of C3 and assembly of C5 convertaseSunday, March 13, 2011
  14. 14. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  15. 15. C3 MOLECULES & THIOESTER BONDS PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  16. 16. HYDROLYSIS OF C3 BY C3 CONVERTASE C4b2a PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  17. 17. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  18. 18. ALTERNATIVE PATHWAY (PROPERDIN PATHWAY) a primitive defense system, a bypass mechanism that does not require C1, C4, and C2 interaction (does not depend on antibody for its activation) Activation immunologically (e.g., by IgA and some IgG) non immunologically (e.g., by certain microbial cell surfaces, complex polysaccharides, and bacterial lipopolysaccharides) PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  19. 19. COMPONENTS: ALTERNATIVE PATHWAY (PROPERDIN PATHWAY) C3: The initial recognition event necessary for alternative pathway activation is the presence of C3, specifically C3b, which is probably continuously generated in small amounts in the circulation Factor B (C3 proactivator) C3b interacts with factor B, to form C3bB, which is a magnesium ion- dependent complex PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  20. 20. COMPONENTS: ALTERNATIVE PATHWAY (PROPERDIN PATHWAY) Factor D (C3 proactivator convertase) The complex C3bB is susceptible to enzymatic cleavage by factor D, into two fragments, Ba and Bb (Ba fragment is released) An active site is exposed in the Bb fragment, which remains bound to C3b, forming the C3bBb (amplification C3 convertase) PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  21. 21. COMPONENTS: ALTERNATIVE PATHWAY (PROPERDIN PATHWAY) Factor D When stabilized by the binding of properdin (P), which slows the dissociation of Bb, the C3bBb complex becomes a C3 convertase that cleaves C3 and generates more C3b C3b then fixes to the activator surface so that more factor B binding sites are exposed As more C3b is generated, the complex expands and becomes a C5 convertase (cleaving C5 into C5a and C5b and initiating the membrane attack PARUNGAO-BALOLONG 2011 pathway)Sunday, March 13, 2011
  22. 22. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  23. 23. PARUNGAO-BALOLONG 2011 The mannose-binding lectin pathway does not depend on antibody for its MBL, like C1q, is a two- to six-headed activation; originates with host proteins molecule that forms a complex with two (MBL) binding microbial surfaces protease zymogens (MASP-1 and MASP-2) MBL, an acute phase protein, binds to mannose residues, and to certain other sugars on many pathogensSunday, March 13, 2011
  24. 24. PARUNGAO-BALOLONG 2011 The mannose-binding lectin pathway When the MBL complex binds to a The MBL pathway is of importance pathogen surface, MASP-2 is in innate host defense mechanisms activated to cleave C4 and C2 in early childhood A C3 convertase is formed from C2a bound to C4bSunday, March 13, 2011
  25. 25. The three complement pathways converge at the membrane- attack complex PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  26. 26. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  27. 27. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  28. 28. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  29. 29. Late steps of complement activation and formation of the MAC (membrane attack complex) PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  30. 30. EFFECTOR ACTIONS OF COMPLEMENT PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  31. 31. Antibody-mediated mechanisms PARUNGAO-BALOLONG 2011 for combating infections by extracellular bacteriaSunday, March 13, 2011
  32. 32. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  33. 33. Scanning electron micrographs of E. coli showing (a) intact cells and (b, c) cells killed by complement-mediated lysis PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  34. 34. MICROBIAL EVASION PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  35. 35. The complement system neutralizes viral infectivity Electron micrographs of negatively stained preparations of EB virus formation of larger viral aggregates - blocking attachment to susceptible reduce the net number of infectious host cells - facilitate binding of the viral particles viral particle to cells a coating of Ab and/or complement possessing Fc or CR1 - lysing most to the surface of a viral particle enveloped viruses PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  36. 36. REGULATION Inclusion of highly labile components A series of regulatory proteins that undergo spontaneous inactivation (regulators of complement activation if they are not stabilized by reaction [RCA] gene cluster - chromosome 1 in with other components humans) PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  37. 37. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  38. 38. PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  39. 39. REGULATION: RECEPTORS Many of the biological activities of the complement system depend on the binding of complement fragments to complement receptors, which are expressed by various cells PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  40. 40. ROLE OF COMPLEMENT IN B CELL ACTIVATION PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  41. 41. COMPLEMENT & DISEASES Complement deficiencies genetic deficiencies in classical pathway components (C1q, C1r, C4, C2 and C3) deficiencies in components of the alternative pathway (properdin, factor D, C3) deficiencies in the terminal complement components (C5, C6, C7, C8, C9, Neisseria bacteria) deficiencies in complement regulatory proteins (abnormal complement activation) deficiencies in complement receptors (CR3 & CR4 – inadequate adherence of neutrophils to endothelium at tissue sites of infection) PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  42. 42. COMPLEMENT & DISEASES Pathologic effects of a normal complement system The immune complexes produced in autoimmune diseases may bind to vascular endothelium and kidney glomeruli and activate complement (MAC generation) It initiates the acute inflammatory responses that destroy the vessel walls or glomeruli and lead to thrombosis, ischemic damage to tissues, and scarring Some of the late complement proteins may activate prothrombinases in the circulation that initiate thrombosis PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  43. 43. Sunday, March 13, 2011
  44. 44. What is the rate-limiting step in the complement cascade? C4. The liver can produce a finite amount of C4 In rare cases, when an angioedema attack is treated with large amounts of FFP, symptoms may worsen because of a temporary C4 depletionSunday, March 13, 2011
  45. 45. WRAPPING UP!!! The complement system comprises a group of serum proteins, many of which exist in inactive forms Complement activation occurs by the classical, alternative, or lectin pathways, each of which is initiated differently The three pathways converge in a common sequence of events that leads to generation of a molecular complex that causes cell lysis PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  46. 46. WRAPPING UP!!! The classical pathway is initiated by antibody binding to a cell target; reactions of IgM and certain IgG subclasses activate this pathway Activation of the alternative and lectin pathways is antibody- independent. These pathways are initiated by reaction of complement proteins with surface molecules of microorganisms In addition to its key role in cell lysis, the complement system mediates opsonization of bacteria, activation of inflammation, and clearance of immune complexes PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  47. 47. WRAPPING UP!!! Interactions of complement proteins and protein fragments with receptors on cells of the immune system control both innate and acquired immune responses Because of its ability to damage the host organism, the complement system requires complex passive and active regulatory mechanisms Clinical consequences of inherited complement deficiencies range from increases in susceptibility to infection to tissue damage caused by immune complexes PARUNGAO-BALOLONG 2011Sunday, March 13, 2011
  48. 48. NEXT MEETING: CELL-MEDIATED EFFECTOR RESPONSESunday, March 13, 2011
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×