bio 151 lec 11 complement
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BIOLOGY 151 LECTURE 11
The Complement
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WHAT YOU NEED TO KNOW
RECALL: Functions & Components of the Complement
Activation and Regulation of the Complement Cascade
Biological Consequences
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PARUNGAO-BALOLONG 2011RECALL...Sunday, March 13, 2011
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 2011
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PATHWAYS OF ACTIVATION
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THE COMPLEMENT CASCADE
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FUNCTIONS AND COMPONENTS OF THE COMPLEMENT
trigger inflammation
attract phagocytes
opsonize antigens
cause cell lysis
activate naïve B-lymphocytes
remove immune complexes
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:
larger fragments: bind to the target near the site of activation
smaller fragments: local inflammation PARUNGAO-BALOLONG 2011
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STRUCTURE OF C1q
http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/c1act.html
assembly of C1 during classical pathway
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SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION
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SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION
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SCHEMATIC DIAGRAM OF INTERMEDIATES IN THE CLASSICAL PATHWAY OF COMPLEMENT ACTIVATION
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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
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C3 MOLECULES & THIOESTER BONDS
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HYDROLYSIS OF C3 BY C3 CONVERTASE C4b2a
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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)
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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
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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)
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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 pathway) PARUNGAO-BALOLONG 2011
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The mannose-binding lectin pathway
does not depend on antibody for its activation; originates with host proteins (MBL) binding microbial surfaces
MBL, an acute phase protein, binds to mannose residues, and to certain other sugars on many pathogens
MBL, like C1q, is a two- to six-headed molecule that forms a complex with two protease zymogens (MASP-1 and MASP-2)
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The mannose-binding lectin pathway
When the MBL complex binds to a pathogen surface, MASP-2 is activated to cleave C4 and C2
A C3 convertase is formed from C2a bound to C4b
The MBL pathway is of importance in innate host defense mechanisms in early childhood
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The three complement pathways converge at the membrane-attack complex
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Late steps of complement activation and formation of the MAC (membrane attack complex)
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EFFECTOR ACTIONS OF COMPLEMENT
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Antibody-mediated mechanisms for combating infections by extracellular bacteria
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Scanning electron micrographs of E. coli showing (a) intact cells and (b, c) cells killed by complement-mediated lysis
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MICROBIAL EVASION
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formation of larger viral aggregates - reduce the net number of infectious viral particles
a coating of Ab and/or complement to the surface of a viral particle
blocking attachment to susceptible host cells - facilitate binding of the viral particle to cells
possessing Fc or CR1 - lysing most enveloped viruses
The complement system neutralizes viral infectivity Electron micrographs of negatively stained preparations of EB virus
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REGULATIONInclusion of highly labile components that undergo spontaneous inactivation if they are not stabilized by reaction with other components
A series of regulatory proteins (regulators of complement activation [RCA] gene cluster - chromosome 1 in humans)
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REGULATION: RECEPTORSMany of the biological activities of the complement system depend on the binding of complement fragments to complement receptors, which are expressed by various cells
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ROLE OF COMPLEMENT IN B CELL ACTIVATION
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COMPLEMENT & DISEASESComplement 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)
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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
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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 depletion
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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
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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
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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
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NEXT MEETING: CELL-MEDIATED
EFFECTOR RESPONSE
Sunday, March 13, 2011