The Complement System Flashcards
Quiz 2
What is the complement system?
A series of proteins that are secreted mostly by the liver. When in inactive form, they circulate in the blood, interstitial fluid, and other fluids
What is Opsonization
Coating of pathogens with proteins (opsonin)
How do the Phagocytes recognize the opsonins during opsonization?
phagocytes have receptors and this increases phagocytosis
What are two examples of opsonins
antibodies and complement proteins
What are the three proteins that C1 is made of
C1q, C1r, and C1s
What is the function of C1q
Binds to the antigen: antibody complexes and pathogen surfaces
List the 8 complement proteins that are activating enzymes
C1r, C1s, C2a, Bb, D, MASP-1, MASP-2, MASP-3
Describe C1 from the Classical Pathway
-C1q recognizes microbial surface OR binds to antibodies
-C1r and C1s are inactive proteases bound to C1q
Describe the start of the complement system with the classical pathway
-First, the pathogen infects
-antibodies that are already present (from previous infection) will then bind to the pathogen
-when C1q binds to the antibody, it will activate C1r which will cleave C1s
-C1s is then activated and will cleave C4 and C2
-C4b binds C2
-C4b2a (classical C3 convertase) cleaves C3 and activates C3
-C3b opsonizes the pathogen surface
what is the function of C1r
cleaves C1s to active protease
What is the function of C1s
Cleaves C4 and C2
What is the function of C4b
covalently binds to pathogen and opsonizes it. Binds C2 for cleavage by C1s
What is the function of C4a
Peptide mediator of inflammation (weak activity)
What is the function of C2a
active enzyme of classical pathway C3/C5 convertase: cleaves C3 and C5
What is the function of C3b
Binds to the pathogen surface and acts as opsonin. Initiates amplification via the alternative pathway. Binds C5 for cleavage by C2a
What is the function of C3a
Peptide mediator of inflammation (intermediate activity)
What is the purpose of anaphylatoxins
-vasodilators: (increase vascular permeability) gets cells to site
-can act as chemokines (attract immune cells)
-induce mast cell degranulation (Histamine release)
-THE END GOAL: inflammation
What are the two complement proteins that are anaphylatoxins
C4a and C3a
what induces anaphylactic shock?
anaphylatoxins induce shock (the same as an allergic reaction)
How does C3b opsonization work?
-C3 contains 2 disulfides
-highly reactive thioester (ThioEster Domain TED)
-The TED domain is how C3b binds to the pathogen surface
What happens if the TED domain of C3b binds to water
It will become inactive as a way to protect the immune system
Give a classical pathway summary (very brief)
-Starts with C1
-Recognizes antibody or cell wall/lipids of bacteria
-lead to a protease cascade
-releases anaphylatoxins (induce inflammation)
Create C3 convertase (C4b2a)
What does the lectin pathway recognize to begin process
-senses unique carbs on the pathogen surface
How does the Lectin pathway sense unique carbs on pathogens?
Bacteria and yeast have terminal mannose while vertebrates do not and this allows them to distinguish between the species
What are the four different pattern recognition receptors from the Lectin Pathway?
-Major one: mannose-binding lectin (MBL)
-the other three are ficolins (L-, M-, H-ficolin)
What do the Lectin Pathway pattern recognition receptors bind to?
carbohydrates
What type of carbohydrates do MBL bind to
-mannose
-fucose
-N-acetylglucosamine (bacterial cell wall)
What type of carbohydrates do Ficolins bind to
acetylated sugars (bacterial cell wall)
What is Affinity
Strength of interaction between two molecules (usually represented by Kd)
What is avidity
OVerall strength of multiple interactions between two molecules (represented by Keq)
How does avidity work
-binding at one site brings the otehr two sites into closer contact
-this increases the chance that they will interact (kon)
-if one site dissociates, the other site(s) can stay bound
-for dissociation to occur, all sites must dissociate simultaneously
How does avidity apply to the lectin pathway?
MBLs and ficolins have the ability to bind free sugars therefore with avidity, the sugars need to be a certain distance/ pattern for good binding and this is why we only see binding on the surfaces
What does MASP stand for
MBL-associated serine proteases
What are the role of MASP-1,-2, and -3
-They are a complex with MBL
-upon binding of MBL, MASP-1 cleaves and activates MASP-2
-MASP-2 cleaves C4 and C2 to form C4b2a C3 convertase (the same as classical pathway)
What are the two MASP that ficolins use
MASP-1, and -2
What are the two ways the alternative pathway form
-way 1: C3b deposition from lectin or classical pathway (C3 convertase is now C3bBb)
-way 2: spontaneous activation, C3 undergoes spontaneous hydrolysis to C3(H2O) therefore convertase is now C3(H2O)Bb
What is dangerous about the alternative pathway?
spontaneous activation could lead to attacking host cells
How can the alternative pathway be prevented from attacking the host cell
-with the use of regulatory proteins
-Properdin (factor P) is released by neutrophils and binds pathogen surfaces to stabilize the C3bBb convertase and requires neutrophil activation AND a pathogen surface
What are the four components of the alternative pathway
C3, Factor B, Factor D, and Properdin (P)
What is the function of Bb in the alternative pathway
Bb is the active enzyme of the C3 convertase C3bBb and the C5 convertase C3b2Bb
What is the function of Factor D
plasma serine protease, cleaves B when it is bound to C3b to Ba and Bb
What is the function of Properdin
Plasma protein that binds to bacterial surfaces and stabilizes the C3bBb convertase
What do all three pathways generate
a C3 convertase
What is the C3 convertase for the lectin pathway
C4b2a
What is the C3 convertase for the classical pathway
C4b2a
What is the C3 convertase for the alternative pathway
C3bBb
What happens when C3b binds to C3 convertase
generates C5 convertase
What is the C5 convertase for lectin pathway
C42a3b
What is the C5 convertase for the classical pathway
C4b2a3b
What is the C5 convertase for the alternative pathway
(C3b)2Bb
What are the three outcomes of complement activation
-small cleavage products induce inflammation
-receptors recognize C3b for phagocytosis
-Membrane attack complex (MAC) formation
Explain the process of small cleavage products inducing inflammation
-small complement-cleavage products act on blood vessels to increase vascular permeability and cell-adhesion molecules
-increase permeability allows increased fluid leakage from blood vessels and extravasation of immunoglobulin and complement molecules
Describe the Membrane attack complex (MAC) formation
-C5b binds C6 and C7
-C5b67 complexes bind to membrane via C7
-C8 binds to the complex and inserts into the cell membrane
-C9 molecules bind to the complex and polymerize
-10-16 molecules of C9 bind to form a pore in the membrane
What other things are bound by the complementary system
-apoptotic cells
-virus-infected cells
-Cancerous cells
What is Factor H binding protein an example of?
One way pathogens have evolved around the complement system
What is the factor H binding protein?
-hHBP is an integral membrane protein of N. meningitidis
-binds serum factor H
-factor H’s role is to protect host from complement
-now it protects the pathogen (basically makes the pathogen look ‘host-like’)
