"complement"

Front 1

What is classical pathway of complement?
What is alternative pathway of complement?

Back 1

classical--initiated when immunoglobin binds to antigen.

alternative--"always" on. pre-existing-->eliminates certain groups of pathogens.

Front 2

What are the main components of the classical pathway?

Back 2

-C1(q,r,s)
-C2-C9

Front 3

What is structure and role of C1q?

Back 3

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+.

Front 4

What is mechanism of classical pathway?

Back 4

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!

Front 5

What are the main components of the alternative pathway?

Back 5

-C3-C9
-B,D,H,I,P

Front 6

What is mechanism of alternative pathway?

Back 6

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.

Front 7

Know the role of proteolysis in the complement pathway

Back 7

. 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.

Front 8

What are the roles of C3b, C3a, and C5a in classical pathway?

Back 8

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.

Front 9

What is the role of the thioester in complement in classical pathway?

Back 9

-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!

Front 10

What is role of C3?

Back 10

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!

Front 11

How is complement pathway regulated?

Back 11

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.

Front 12

What is role of Membrane attack complex (MAC)?

Back 12

Binds to pathogenic cell-->opens channels in its surface-->lysis!

Front 13

What is role of Decay-accelerating factor?

Back 13

-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.

Front 14

What is role of C-reactive protein?

Back 14

-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.

Front 15

What the heck is paroxysmal nocturnal hemoglobinuria? What causes it?

Back 15

--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!