The complement Flashcards
how was the complement system originally described as in the serum
a heat-labile component of normal serum that augmented the opsonization of bacteria by a heat-stable component of serum (antibodies)
where did the name “the complement” come from
this activity exhibited by the complement helped the antibacterial activity of antibodies
T/F the complement can be activated earlier infection without antibodies
True
what is the complement
complement is a system of proteins that is activated by the presence of pathogens
how many plasma proteins makes up the complement
over 30
most of the protein components are __________ that become active only after cleavage
most of the protein components are inert enzymes that become active only after cleavage
how must the proteins interact when activated
they interact sequentially forming a self-assembling enzymatic cascade and generating biologically active molecules, important for full inflammatory response
where is one of the most important key sites for the activation of the complement
is the surface of pathogens
what must happen for the complement to be useful immunologically
it has to be activated first
what are the 3 distinct pathways through which complement can be activated
- Classical pathway
- Lectin pathway
- Alternative pathway
what is the differences between the 3 different pathways of activation for the complement
depend on different types molecules for their initiation
what are the 3 ways in which the complement system protects against pathogens
- Recruitment of inflammatory and immunocompetent cells
- opsonization of pathogens
- killing of pathogens
First way of protection: recruitment
some components of the complement act as chemoattractants to recruit phagocytic cells to sites of complement activation
Second way of protection: opsonization
generation of large amounts of activated complement proteins that bind covalently to the pathogens opsonizing them for phagocytosis
Third way of protection: Killing of pathogens
the final components of the complement activation kill (damage) microbes by creating pores in their membranes
how does the complement also activate the adaptive immunity
- opsonization by complement components allows uptake of microbes by antigen-presenting cells (APC) such as dendritic cells
- B cells have complement receptors for certain complement receptors for certain complement proteins which enhance B cell response to complement coated microbes
what letter is designated by the letter C
the native components
how were the components numbered
not in numerical order but according to the order of discovery
what was the order of discovery of the complement components
- C1
- C4
- C2
- C3
- C5
- C6
- C7
- C8
- C9
how are the products of complement cleavage designated
the products of complement cleavage are designated by added lower case letter
what is the smaller cleaved fragment designated
the smaller cleavage fragment is designated “a”
What is the larger cleavage fragment of the complement components designated
- the larger cleavage fragment is designated “b”
- i.e. C4 is cleaved to C4a and C4b
- and C4b is larger fragment
- i.e. C4 is cleaved to C4a and C4b
what is the exception to the nomenclature of the products of complement cleavage
- C2
- the larger fragment is C2a
- the one with enzymatic activity
what are the complement component of the alternative pathway
- they are designated by different capital letters
- the cleavage products are designated lower case letters “a or b”
- larger fragment of factor cleavage is Bb and smaller is Ba
how it the classical pathway initiated
the classical pathway is initiated by binding of C1q (first protein of the cascade) to the surface of a pathogen
How does C1q bind to the surface of pathogens in
- binds directly to the surface of bacterial components
- proteins, lipoteichoic acid
- Binds to C-reactive protein that initially binds to phosphocholine residues on bacterial polysaccharides
- binds to antigen-antibody complex on the pathogen surface
which pathway of C1q binding to the surface of a pathogen is the most effective
when it binds to the antibody-antigen complex
how is the lectin pathway initiated
by binding of carbohydrate-binding proteins to carbohydrates on the surface of pathogens
the carbohydrate-binding proteins in the lectin pathway include
- Mannose binding lectin (MBL)
- Ficolins
(MBL) mannose binding lectin:
a lectin that binds mannose-containing carbs on microbial surface
Ficolins
bind N-acetylglucosamine on the surface of some microbes
how is the alternative pathway of the complement be initiated
by binding of spontaneously derived plasma C3b to pathogen surfaces
In each pathway, sequential reactions lead to the generation of a protein complex called________
C3 convertase
The C3 convertase remains bound to the surface of the _______
pathogen
C3 convertase cleaves C3 to yield large amounts of ______
- C3b and C3a
- C3b: the main effector molecule of the complement system
- C3a: a mediator of inflammation
The C3b molecule acts as an
opsonin - binnds covalently to the pathogen surface
A pathogen opsonized with C3b becomes a
target for destruction through phagocytosis
when C3b acts as an opsonin how does it bind to the pathogen
it binds covalently to the pathogen surface
after opsonizing a pathogen with C3b what happens to the pathogen
it becomes a target for destruction through phagocytosis
C3b binds ______ convertase to produce C5 convertase
C3
what happens to C5 convertase after it is formed from C3b binding to C3 convertase
C5 convertase is converts C5 into C5a and C5b
what is important about C5a
it is an inflammatory peptide
what action does C5b have
C5b initiates the last event in the complement system activation
After C5b initiates the last events of activation of the complement system activation the activation culminates in the formation of
MAC: membrane attack complex
what is the most potent activators of the classical complement pathway in most domestic species
IgM and to a lesser extent IgG
when one IgM or several IgG molecules bind to an antigen, the _______ of the antibody can bind to the complement component ___________
Fc portionn
C1 (C1qr2s2)
what is the back bone of C1 made of
C1q
how many globular head domains does C1q have that are connected by linear tails
six
what are the two proteins that are associated with the tail domains of C1q
- two copies of
- C1r
- C1s (serine proteases)
when is C1 activated
C1 is activated when two globular heads of C1q bind two adjacent Fc regions of antibodies bound to an antigen
what does the binding of C1q binding to antibodies activate
- C1q binding to antibodies activates the protease activity of C1r
- C1r then cleaves itself
The active C1r then cleaves the adjacent_____ molecules, which activates the serine protease activity of _____
The active C1r then cleaves the adjacent C1s molecules, which activates the serine protease activity of C1s
The activated C1s cleaves the complement protein _______ to _____ and _____
The activated C1s cleaves the complement protein C4 to C4a and C4b
what does the C4b covalently attach to after it is formed from C1s cleaves C4
C4b covalently attaches (through reaction with hydroxyl or amine groups) to the surface of the microbe or Ab-Ag complex
what is the next step after C4b is attached to the surface of the microbe
- C1s cleaves C2 into C2b and the larger C2a
- C4b then binds to C2a forming C2b2a on the surface of the microbe
C4b2a is the classical pathway to________
C3 convertase
what is the function of C3 convertase
cleaves C3 into C3a and C3b
what is the most abundant complement protein
C3
what happens to C3b after C3 is cleaved by C3 convertase
C3b being the larger fragment attaches to the surface of the microbe
what is it called when the C3b from the C3 cleavage by C3 convertase binds to the surface of the microbe
opsonisation
Since the binding of C3b to the surface opsonisation of the microbe what goal of the complement activation does this achieve
it marks the microbe for destruction by phagocytes
C3b forms a complex with C3 convertase (C4b2a) to form
the classical pathway C5 convertase (C4b2a3b)
C5 convertase cleaves C5 into
C5a and C5b
what piece of the C5 cleavage products remains with the C5 convertase (C4b2a3b) and how is the MAC involved
- C5b stays associated with the C5 convertase (C4b2a3b)
- this complex that is formed plays a role in the formation of the membrane attack complex MAC
what is the activation of the complement through the lectin pathway
it is an independent innate immune response
what does lectin bind to
lectin bind particular carbohydrate (sugar) residues
_______ and _______ are found in plasma and can recognize microbial-specific carbohydrates on the surface of microbes
MBL and Ficolins are found in plasma and can recognize microbial-specific carbohydrates on the surface of microbes
what are the physiological characteristics of MBL
MBL is a tetrameric member of the C-type lectin family and has structural similarities with C1q
What does MBL recognize on the in the cell walls of bacteria and fungi, as well as on some protozoa and in envelopes of some viruses
MBL recognizes Mannose, Fucose, N-acetylgucosamine that are present in the cell walls of bacteria and fungi as well as on some protozoa and in envelopes of some viruses
What happens to MBL when it binds to a microbial cell wall
conformational changes occur which promote activation of MBL-associated serine proteases (MASPs) via autocatalysis
what is the function of MASPs
- it cleaves C4
- into C4a and C4b
- it also cleaves C2
- into C2a and C2b
after MASPs cleaves C4 and C2 what happens to the larger portions
C4b complexes with C2a to create C3 convertase (C4b2a), which is assembled on the surface of the microbe
In the lectin pathway what is the function of the C3 convertase (C4b2a)
C3 convertase cleaves C3 into C3a and C3b leading to deposition of C3b on the surface of microbes
in the lectin pathway C4b2a complexes with C3b to create ______, a _______ convertase, which initiates the terminal membrane attack pathway
in the lectin pathway C4b2a complexes with C3b to create C4b2a, a a C5 convertase, which initiates the terminal membrane attack pathway
How does the activation of the complement through the alternative pathway differ from the other pathways
- it does not require recognition of a microbial surface by antibodies or lectin
- it utilizes the nonspecific, low-level hydrolysis of C3
why is C3 important to the activation of the complement
- it is the most abundant complement protein
- also a key player in all pathways
how does the complement activation begin in the alternative pathway
- spontaneous cleavage of C3
- this produces C3a and C3b components
in the alternative pathway what happens to the C3b from the spontaneous cleavage of C3
C3b binds to a microbial surface or is degraded
What happens in the alternative pathway if a C3b binds to a healthy host cell membrane
it is rapidly degraded to prevent any further complement activation
how is C3b degraded when it binds to a healthy cell membrane in the alternative pathway
-Sialic acid residues on cell membranes promote binding of C3b to factor H (a negative regulator of complement activation)
What is the function of factor H and I
inactivate and degrade inappropriately bound C3b
why is it that when C3b binds to a microbe membranes and cell walls it is not degraded
- Microbial membranes and cell walls are typically rich in Polysaccharides that do not contain sialic acid
- additionally C3b bound to a microbial surface cannot be degraded by factor H and I
what is the next step in the alternative complement pathway after C3b binds to the microbial surface
C3b binds Factor B to form C3bB complez
what happens to C3bB after it is formed in the alternative complement pathway
C3bB complex is then cleaved by factor D
what are the two products of the C3bB complex cleavage by factor D in the alternative complement pathway
- Ba is released
- active C3bBb remains
what is C3bBb in the alternative complement pathway
C3bBb is the alternative C3 convertase
what is the purpose of this alternative C3 convertase in the alternative complement pathway
- Alternative C3 convertase can efficiently cleave plasma C3 and create more C3b that gets deposited onto microbial surfaces
- this is also known as an amplification loop
The alternative C3 convertase is unstable in the alternative complement pathway what is used to stabilize it
Factor P (properdin)
What happens after the Alternative C3 convertase cleaves C3 in the alternative complement pathway
C3b complexes C3bBb to form C3bBb3b
In the alternative complement pathway the formation of C3bBb3b is the:
alternative C5 convertase
What is the function of the alternative C5 convertase in the alternative complement pathway
Alternative C5 convertase cleaves C5 producing C5b initiating the terminal MAC formation
What is the goal of the Terminal membrane attack pathway
the goal of the terminal membrane attack pathway is to construct a protein complex that makes a hole in the target membrane and thus can directly lyse and kill the microbe
what protein is formed in the Terminal membrane attack pathway
the Membrane attack complex (MAC)
What product from each pathway initiates the formation of the MAC
- Classical: C5 convertase (C4b2a3b)
- Lectin pathway: C5 convertase (C4b2a3b)
- Alternative pathway: Alternative C5 convertase (C3bBb3b)
what is the first step in the MAC formation
C5b recruits C6 and C& to the target membrane forming the C5b67 complex
In the MAC formation what happens after C5b67 complex is formed
C8 binds to the C5b67 complex unfolding a hydrophobic region that wedges into the target membranes
In the MAC formation what happens after the C8 binds to C5b67 and inserts itself into the cell membrane
the complex recruits 10-16 copies of C9 into the membrane to create a cylindrical pore
In the MAC formation, what is the result after the cylindrical pore is formed
- Mac breaches the cell membrane of the microbe allowing water to rush into the cell
- Osmotic lysis of the microbe by sufficient number of MAC on the membrane
What is the function of the complement control proteins
the complement control proteins act to prevent the complement innate defense system from acting inappropriate targets and also from acting in perpetuity
what type of proteins can downregulate or stop the classical, lectin, and alternative pathways at key points
soluble or membrane-associated complement control proteins
how do the complement control proteins function
- Inhibit the protease activities
- or facilitate the degradation of activated complement complexes or convertases
Complement control protein “C1 inhibiter” is located
- in the plasma
- large amounts are in the serum
Complement control protein “C1 inhibitor” regulates which pathway
classical and lectin
Complement control protein “C1 inhibiter” action
- inactivates
- C1r
- C1s
- MASPs
Complement control protein “C4b-binding protein” is located
in the plasma and serum
Complement control protein “C4b-binding protein” regulated these pathways
classical and lectin
Complement control protein “C4b-binding protein” regulatory action
- Binds C4b
- accelerates the decay of the classical and lectin C3 convertase (C4b2a)
Complement control protein “Factor H and I” location
plasma and serum
Complement control protein “Factor H and I” regulates which pathway
Alternative complement pathway
Complement control protein “Factor H and I” action
- Binds C3b and accelerates decay
Complement control protein Decay-accelerating factor (CD55): location
cell membrane of erythrocytes, neutrophils, lymphocytes, monocytes, platelets, and endothelial cells
Complement control protein Decay-accelerating factor (CD55): pathway regulation
alternative
Complement control protein Decay-accelerating factor (CD55): action
accelerates decay of C3 convertase (C3bBb)
Complement control protein Complement receptor I (CD35): location
Cell membrane of erythrocytes (primates), neutrophils, lymphocytes, monocytes, and macrophages
Complement control protein Complement receptor I (CD35): pathway regulation
classical, lectin, and alternative
Complement control protein Complement receptor I (CD35): action
Binds C3b and C4b and inhibits alternative and classical/lectin C3 convertase
Complement control protein membrane cofactor protein (CD46): location
widely expressed on cell membrane of host cells
Complement control protein membrane cofactor protein (CD46): Pathway regulated
classical, lectin, and alternative
Complement control protein membrane cofactor protein (CD46): Action
Binds C3b and C4a and inhibits alternative and classical/lectin C3 Convertases
Complement control protein protectin (CD59): location
predominantly expressed on cell membrane of erythrocytes, leukocytes, and vascular endothelium
Complement control protein protectin (CD59): pathway regulated
terminal membrane attack
Complement control protein protectin (CD59): Action
Binds to C5b678 and prevents C9 recruitment and MAC formation
what is the outcome from the complement product MAC
- Direct target lysis
- Osmodysregulation and lysis of target cells
what is the outcome from the complement product C3a and C5a tissue inflammation
- Tissue inflammation
- Activation of mast-cell degranulation leadinng to release of vasoactive amines (histamine and serotonin)
what is the outcome from the complement product C3a and C5a Endothelial activation
- Endothelial activation
- increased expression of adhesion molecules
what is the outcome from the complement product C3a and C5a chemotaxis
- Promotes migration of neutrophils, eosinophils, and macrophages toward the site of complement activation
what is the outcome from the complement productC5a (C3a and C4a) leukocyte activation
upregulation of adhesion molecules, phagocytic receptors, and antimicrobial effectors by neutrophils and monocytes
what is the outcome from the complement product C3b and iC3b Opsonization
- enhancement of particle phagocytosis by macrophages and nneutrophils
what is the outcome from the complement product C3dg promotion of humoral responses
Enhanced B-cell activation, retention of antigen complexes in B-cell follicles
what is the outcome from the complement product C3b (and iC3b) immune complex clearance
Blocking of growth and facilitation of dissociation of immune complexes, immobilization and clearance of immune complexes through interaction with CR1 on erythrocytes
