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15 Cards in this Set

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What is classical pathway of complement?
What is alternative pathway of complement?
classical--initiated when immunoglobin binds to antigen.

alternative--"always" on. pre-existing-->eliminates certain groups of pathogens.
What are the main components of the classical pathway?
-C1(q,r,s)
-C2-C9
What is structure and role of C1q?
Role--
Molecule binds IgG-->Fc of IgG undergoes conformational change, increasing affinity for binding C1q-->C1q undergoes conformational change-->causes C1r to self-cleave and activate-->C1r cleaves/activates C1s

Structure--
18 subunits--can bind 6 molecules of IgG! 6 globular proteins connected by fibers of a triple helix.

C1q is part of C1 complex, which is: C1q, C1r (2), C1s(2), and Ca+.
What is mechanism of classical pathway?
Pathogen cell enters-->IgG binds "site 1" on pathogenic cell-->C1 complex binds IgG (C1q of C1 binds Ch2 on IgG)-->C1q undergoes conformational change-->C1r cleaves/activates itself-->C1r cleaves/activates C1s-->C1s cleaves C4 and C2-->C4b, C2a form C4,2 complex (one C1s--form lots of C4,2 complexes--"amplification")-->C4, 2 complex binds to "site 2" on pathogenic cell-->C4,2 cleaves C3 into C3a and C3b fragments-->One C3b binds to cell surface, another binds to C4,2 complex-->forms C4,2,3 complex-->new complex is specific for C5-->cleaves C5 into C5a and C5b fragments-->C5b, C6-C9 get together and form MAC (C6-C9 have post-trans modification--mannose cov. bound to tryptophan)-->MAC binds to "site 3" on path. cell-->MAC opens channels on path cell-->kills cell by lysis!
What are the main components of the alternative pathway?
-C3-C9
-B,D,H,I,P
What is mechanism of alternative pathway?
i. C3 reacts with water to make C3—H2O.
ii. C3—H2O complexes with B and D to make C3 convertase. D is activated and becomes an active proteolytic enzyme.
iii. C3 convertase cleaves C3 to make C3a and C3b. C3b can either not bind to a surface, bind to a non-activating surface, or bind to an activating surface.
1. C3b can react with water and be inactivated by H and I.
2. C3b can bind to a non-activating surface and be inactivated by H and I.
3. C3b can bind to a pathogenic surface and allow the alternative pathway to continue.
iv. C3b bound to a pathogenic surface acquires a site specific for factor B. D joins the complex to activate B. B’s activation launches the alternative pathway.
v. Bb binds to C3b to form the C3b-Bb complex, which is specific for C3.
vi. C3b-Bb activates C3.
vii. The newly formed C3b can bind to a surface for immune adherence or bind to C3b-Bb to form the C3bn-Bb complex, which is specific for C5.
viii. P joins the unstable C3bn-Bb complex to form the stable C3bn-P-Bb complex, which cleaves C5.
ix. The rest of the alternative pathway follows just as the classical pathway does.
Know the role of proteolysis in the complement pathway
. Proteolysis is required at every step in the both the classical and alternative pathways. Cleaved proteins become active and in turn activate the next proteins in the cascade.
What are the roles of C3b, C3a, and C5a in classical pathway?
C3b--"immune adherence"-- binds to pathogen cell AND receptors on leukocytes/macrophages-->pathogenic cell phagocytized!

C3a (4a, 5a)--"anaphylatoxins"--increase vasc. permeability, smooth muscle contraction, and his release.

C5a--"anaphylatoxin"--also, a "chemotactic factor"-->induces migration of leukocytes to infection.
-->makes a "cloud" around the bacteria--directs WBC's to site.
What is the role of the thioester in complement in classical pathway?
-Thioester is post-translational modification--links cysteine and glutamine.
-Present on certain complement proteins (C3 and C4)
-When C3, C4 are cleaved/activated-->His moves to cleave thioester-->makes unstable bond b/w his and glutamine-->unstable bond reacts easily with any "R-OH" structures-->If H20, will form inactive protein (favored if not close to any surface)-->if protein or sugar, will become bound to C3b, C4b (favored if close to surface)-->can react w/protein/sugar on nearby surfaces-->how C3b, C4b can bind to bacteria!
What is role of C3?
C3 has lots of jobs:
1) binds B and D
2) is cleaved into C3a->anaphylatoxin
C3b-->discriminate b/w friendly/unfriendly surfaces
-->binds to receptors on leuks/pathogens-->"immune adherence"
-->makes covalent links to tons of sufaces
-->binds to C4,2--changes its specificity
-->binds to Bb--makes C3bBb complex
-->binds directly to C3bBb complex--changes its specificity

HUGE role in both pathways!
How is complement pathway regulated?
1) C3, C4 are unstable--don't last long after being cleaved.

2) C3a-C5a, Ba--inactivated by removal of C-terminal arginines by serum carboxypeptidase B.

3) Factors H/I--inhibit C3b
Decay Accelerating Factor--prevents C3b from binding to healthy cells (erythrocytes) and having them destroyed-->these cells have decay-acc. factor, which accelerates C3b destruction by H, I.
What is role of Membrane attack complex (MAC)?
Binds to pathogenic cell-->opens channels in its surface-->lysis!
What is role of Decay-accelerating factor?
-Keeps C3b from destroying good, healthy cells!
-erythrocytes (and most cells in blood) have this factor attached to membranes-->accelerates rate of destruction of C3b by H and I.
What is role of C-reactive protein?
-present in severe inflammations.
CRP can substitute for IgG in activating the classical pathway.
It binds to a pathogen and then binds to C1q, starting the classical pathway cascade.
What the heck is paroxysmal nocturnal hemoglobinuria? What causes it?
--Lack of Decay-accelerating factor

Infection present in body-->urine turns red at night!

Why?

-Pathogen from infection creates tons of C3b-->"immune adherence" happens-->erythrocytes have no decay accelerating factor-->RBC's are lysed by leukocytes-->heme released-->red urine!