4. Complement
Complement is made of_________________ that work together. One activates another, and that activates another. It works in a cascade-type manner outside of the cell.
20-30 different proteins
There are __ways of activating complement. But they all have the same terminal steps and the same functions in the immune system.
3 Classical, Alternative, and Lectin pathway
The membrane attack complex is C5b_____.
6789.
Classical pathway is part of the ______immune response
Adaptive (anything dealing with antibodies is adaptive b/c it is antigen specific)
Complement produces______ to enhance inflammation and recruit other immune cells
Anaphylatoxins
The classical pathway produces ____ and ______.
Anaphylatoxins: C3a, C4a, and C5a Opsonins: C3b and C4b
What is an antigen-antibody complex
Antibodies bound to an antigen
C5_ is the beginning of the membrane attack complex (MAC)
B
In C2, the "a"piece is _____ and _____to the pathogen or other component. The "b" piece is ____, ____, and _____.
Bigger, binds Smaller, soluble, floats away
C5b_ to the pathogen and C5a ___ as an _____.
Binds (to pathogen, starting its own complex, MAC), leaves, anaphylatoxin
C1 enzymatic activity is activated when_____
C1 binds to 2 or more Fc regions of antibody bound to antigen
In terms of regulation of complement, in the classical pathway ____controls the cleavage of C4, inhibiting activation of the classical pathway.
C1 inhibitor = C1INH
Inhibit activation of the classical pathway - controls cleavage of C4 and C2
C1 inhibitor = C1INH
What is C1INH and what does it do?
C1 inhibitor; controls cleavage of C4 in the classical pathway, thereby inhibiting activation of the classical pathway
The classical pathway starts when the____ complex binds 2 different __portions of antibodies that are bound to antigen and then __ is activated
C1, Fc (the stalk of two antibodies), C1
When C2 is cleaved by C1 what portion binds to C4b?
C2a
The alternative pathway is initiated by spontaneous cleavage of ______. Something about the surface/environment of the pathogen allows ____ to be cleaved rapidly. The pathway involves cleavage and enzymatic activation of proteins, leading to generation of ______. It can end in formation of the ____. The alternative pathway produces ___ and ___, which are anaphylatoxins AND ____ which is an opsonin.
C3 (C3b binds pathogen), C3, C5 convertase MAC - C5b678(9)n C3a and C5a C3b
What initiates the alternative pathway?
C3 (although in classical it is cleaved by C3 convertase, C3 is inherently unstable and is spontaneously cleaved) The surface around pathogens increases cleavage of C3 A small amount of C3b is in circulation
What is another name for C4b2a?
C3 convertase
C4b2a cleaves____making _____
C3, C4b2a3b
When C3 is mutated this leads to the inability to breakdown ___ by factor ____.
C3, H
The anaphylatoxins produced by complement to enhance inflammation are ____, ____, and ________.
C3a, C4a, C5a The "a" fragments don't just "float way" some actually have a function. These promote inflammation.
Which complement proteins act as opsonins (enhance phagocytosis by coating pathogen)
C3b and C4b
Hint: in the classical pathway only ____ is out of order.
C4
When C1 is activated it cleaves ____ and ____
C4, C4 b binds to pathogen C2, C2a binds to C4b making C4b2a
When C4 is cleaved by C1 what portion of C4 binds to the pathogen?
C4b
In the second step of the classical pathway, when C2a binds to C4b what does it make?
C4b2a
The C5 convertase is
C4b2a3b (it is its own complex)
C4b2a3b cleaves ______ . And C4b2a3b is known as_____.
C5, C5 convertase
C6 binds ____; C7 binds_____; C8 binds____; multiple C9s bind______; to complete the formation of the MAC C5b678(9)n
C5b, C5b6, C5b67; C5b678
The membrane attack complex (MAC) is ____?
C5b678(9)n
Complex______ called the membrane attack complex (MAC) can form holes/pores in membranes. This works on gram____bacteria and not gram____bacteria. It also works on enveloped viruses, parasites, and anything with a membrane. The end result is the lysis of the pathogen.
C5b6789 Negative, positive
The alternative pathway is activated by ___,____,___, and ____. Because it is part of the innate immune response.
Cell wall components, LPS, cobra venom, viruses (motif or pattern specific not antigen specific)
The classical pathway produces 3 anaphylatoxins: ____, ____, ____. While the alternative pathway only produces 2 anaphylatoxins: ___,___.
Classical: C3a, C4a, and C5a Alternative: C3a,C5a (no C4a)
The classical pathway produces 2 opsonins: ____, and _____. The alternative pathway only produces 1 opsonin _____.
Classical: C3b and C4b Alternative: C3b (no C4b)
Macular degeneration is the leading cause of irreversible vision loss in the elderly. It is caused by the deterioration or breakdown of the macula. It causes loss of visual acuity and central vision. ____ is thought to be involved b/c mutations in complement factors have been found in a significant percent of pts.
Complement
C3a, C4a, and C5a are similar to____ in what they do.
Cytokines - recruit cells, act on vascular to promote extravasation C3a, C4a, and C5a also facilitate extravasation
Complement can ______ and _______.
Destroy invaders, signal other immune players that the war is on
C3a, C4a, and C5a are anaphylatoxins and——————.
Enhance inflammation
Complement Opsonization is similar to _____.
Fc opsonization by antibodies
The classical pathway is activated by antigen-antibody complexes; What two antibodies activate complement in this pathway?
IgA and IgG
Regulation of complement: what is Factor H and Factor I?
Inhibit C3, causes degradation of C3b it it does not bind cell surface
The alternative pathway is part of the ____ immune response
Innate
Complement can be activated by both the ____ and _____immune response. Through each immune response it is activated in a different way.
Innate, adaptive
What makes C4b2a3b?
It's made when C4b2a cleaves C3
When C2 is cleaved the two split products formed are C2a and C2b. C2a is the ______, ______ peptide, while C2b remains______.
Larger, binding Soluble
When factor h is mutated this leads to _____
Loss of factor h activity = not able to control complement through the degradation of C3b Loss of a complement inhibitor = unregulated complement activation = lots of inflammation and tissue destruction
Protectin inhibits ____ by binding C5b678 and preventing the recruitment of C9.
MAC
When C9 is mutated this leads to increase in the level of C9 available to make ____. This leads to more _____, more inflammation and ___ destruction.
MACs, lysis, tissue
C5b678(9)n is the___?
Membrane attack complex (MAC)
Evidence that complement is involved in macular degeneration is ____ and _____.
Mutations in complement factors, druses contains lots of complement proteins
Most soluble complement proteins are designated by the letter "C" followed by a number (C1, C2, C3, C4). The order of activation or involvement does_____ always follow numerical order
NOT (So this means that the number will not let you know which comes first in the cascade sequence)
In opsonization of complement, complement generates____which enhance phagocytosis by coating pathogen with opsonins. The eat me signal is produced by __ and ___ (complement proteins) which acts as opsonins. ____ and _____ have complement receptors that, when bound to opsonins, increase phagocytosis of the marked pathogen.
Opsonins, C3b C4b, macrophages neutrophils
What are the three main functions of complement?
Opsonization, Lysis, and recruit other immune cells (enhancing inflammation) All these actions lead to destroying the antigen!!
Inhibit MAC - Binds C5b678 and prevents recruitment of C9
Protectin
Complement is a very ___ response.
Rapid
The 20-30 proteins of complement are made up of _____ and ______proteins.
Serum, cell surface
When the complement is cleaved to be activated two products are produced. The piece called "a" is ______, remains_______, and ________. The piece called "b" is ____ and ______ to the pathogen or other components. There is only one exception to this type of naming.
Smaller, soluble, and floats Away Bigger, Binds
C3a, C4a, and C5a increase _______ permeability, enhance _____molecule expression. Increase the expression of adhesion molecules on _____ and act ___________ for these cells.
Vascular, adhesion Neutrophils, chemoattractants
Inhibit C3 - degradation of C3b if it does not bind the cell surfaces
Via Factor H and Factor 1
Many complement proteins are ________
Zymogens (have to be cleaved to be activated)
