Mim: Complement System

Front 1

what is a complement?

Back 1

Complement is:
-system of plasma proteins some of which are INACTIVE proteases activate by cleavage
-a triggered enzyme cascade with downstream amplification
-components are cleaved into 2 pieces
-- 'b' (binding- BIG)
-- 'a' (soluble mediator-smalle) chemotactic

Front 2

what are the functions of a complement system? (list of 6)

Back 2

1. phagocytosis by opsonization
-coats the pathogen with a molecule (b) that will facilitate uptake of that pathogen by phagocytic cells

2. promote inflammation
-recruits inflammatory cells by liberated soluble chemotactic factors (a)

3. kills microorganisms
-forms a membrane attack complex that inserts a pore into the pathogen's membrane leading to death by osmotic lysis (can also kill host cells-pathological)

4. B cell activation and maturation

5. Immune complex removal
-solubilizes and facilitates the removal of antibody attached to foreign molecule complex, filtered by the kidney

6. T cell activity modulation/maturation

Front 3

The 3 Pathways and noteworthy characteristics

Back 3

Classical Pathway
-ONLY one of these that is acquired* and therefore initiated by antibody participation

2. MB-Lectin Pathway

3. Alternative Pathway

All 3 use the same TWO amplification steps, C3 and C5 convertase
-BUT, the alternative pathway uses a slightly structurally different C3 convertase

Upon generation of the C3 convertase, the 3 pathways converge into a common pathway until their termination

Front 4

Classical/Acquired Pathway Initiation

Back 4

requires deposition of IgM or IgG antibody on the surface of a pathogen

C1 is the first component of the complement that binds. Then it undergoes a conformational change, and generates an active serene protease that cleaves C4 into C4a (soluble) and C4b (binds to surface of pathogen)

Front 5

C1q

Back 5

first component of complement classical pathway to bind

binds to IgM Fc and IgG Fc but also directly to some bacterial surfaces to initiate pathway

activates serine proteases to cleave C4 and C2

Front 6

MB-Lectin Pathway Initiation

Back 6

mannose-binding lectin binds mannose on pathogen surfaces

uses MASP-1 and MASP-2 instead of C1, which cleave C4 and C2

Front 7

What can antibodies do and what can't they do?

Back 7

they have no inartistic killing activity!
this is where the complement cascade comes in

Front 8

what classes of antibody activate complement?

Back 8

IgM, IgG3, IgG1, IgG2

Front 9

why doesn't complement function at mucosal surfaces?

Back 9

don't want to damage our barrier epithelial
-a consequence of complement activation is tissue damage
-this is also why the primary antibody that protects surfaces (IgA) is noninflammatory

complement only functions inside the body (blood, interstitial space)
-inactivated in tears, saliva, mucins

Front 10

IgM and IgG initiation of the classical pathway

Back 10

although they are found circulating in the blood, they re unable to activate complement there. In solution, IgM is planar. In this conformation the complement binding site on the Fc region is masked and IgM cannot fix complement.

it is not until the antibody binds a pathogen and undergoes a conformational change, from planar to more crab-like, that the C1 binding site is exposed

ONLY ONE IgM is required for activation, while TWO are required for IgG (and the 2 IgG molecules must be sufficiently close enough to be bridged to each other.

Front 11

activation of alternative pathway

Back 11

very different from the other 2 pathways

most primitive and undergoes constant turnover

activation is triggered by pathogen surface recognition

spontaneous hydrolysis of C3

Front 12

where do all 3 pathways converge?

Back 12

C3

Front 13

what does the assembly of the C3 Convertase generate?

Back 13

1. Chemotactic factors (C3a, C5a, and C4a)- peptide mediators of inflammation, phagocyte recruitment

2. Opsonin (C3b)- aids in phagocytosis

3. Terminal Complement Components- lead to formation of the membrane attack complex that creates pores in the pathogen envelope resulting in osmotic lysis

Front 14

C3 Convertase

Back 14

converts C3 into C3a and C3b
-this step can be repeated thousands of times for amplification

cleavage produces 3 powerful chemotactic factors (C3a, C5a, C4a), which act on vascular epithelium to recruit neutrophils from the blood to the site of infection

also produces C3b, an opsonin

Front 15

opsonins

Back 15

molecules that bind antigens and make them a target of the immune system

Front 16

C5 convertase

Back 16

generate if C3b binds to the C3 convertase itself

makes C5a and C5b
-this is the 2nd amplification step in the pathway

C5b is deposited onto the pathogen's cell membrane and together wight he other terminal components of the cascade (C6-C9), inserts a ring structure into the membrane

Front 17

opsonins: C3b

Back 17

C3b and IgG

pathogen membrane bound C3b binds to its receptor located on macrophages and other phagocytic cells

when only C3b binds to CR1, bacteria are not phagocytksed

phagocytosis requires the binding of both C3b AND C5a (second signal)

Front 18

opsonins: IgG

Back 18

there are IgG-Fc receptors on the surface of macrophages to recognize IgG antibodies bound to specific pathogens

aggregation of immunoglobulin on bacterial surface allows cross-linking of Fc receptors
-IgG Ab binds its epitope on bacterium and IgG also binds to its Fc receptor on the macrophage

requires minimum of 2 IgG molecules

Front 19

synergistic opsonization

Back 19

deposition of BOTH C3b and IgG on the surface provides a synergistic effects and is the best way to promote phagocytosis

Front 20

MAC assembly

Back 20

termination of the complement cascade involves assembling a Membrane Attack Complex (MAC)

-begins with the C5 convertase that generates C5b
-C5b binds C6 and C7 followed by C8, which is inserted into the membrane instead of simply binding the surface
-finally, up to 16 molecules of C9 polymerize in a circle to form a pore

Front 21

Removal of immune complexes

Back 21

during an immune response, pathogen antigens and their pathogen-specific IgG antibodies form complexes that bind the C3b

RBC's have complement receptors (CR2) for C3b, which capture these large antibody:antigen complexes and remove them from circulation as they pass through the spleen and liver

resident macrophages in these areas destroy the complexes and dispose of them

Front 22

complement cascade's role in adaptive immunity

Back 22

one of the receptors for complement, CR2, is part of the B-Cell signaling mechanism

BCR bridging to Ag via CR2 delivers a powerful activation and maturation signal to the B-cell in the periphery

upon complement receptor activation, a T-cell is driven to become a regulatory T-cell

Front 23

deficiency in compliment proteins

Back 23

results in increased susceptibility to extracellular bacterial infections

deficiencies in earlier steps (leading up to generation of C3b) give rise to immune complex diseases (like lupus), where one is unable to remove immune complexes
-this should make sense since removal requires C3b

Front 24

deficiencies in terminal components of complement (C6-C9)

Back 24

make people susceptible to recurrent nisserial infections (bacterial infections)

Front 25

deficiencies in regulatory proteins

Back 25

would lead to uncontrolled activation of the complement system and hereditary angioedema (uncontrolled activation of complement cascade, leading to extreme inflammation)

Front 26

C4a

Back 26

chemotactic factor
peptide mediator of inflammation (weak activity)

Front 27

C3a

Back 27

chemotactic factor

early promotor of acute inflammation (intermediate activity

act on mast cells (degranulation) and tissues around blood vessels (recruit histamine)

Front 28

C3b

Back 28

many molecules of C3b bind to pathogen surface and act as opsonins

initiates amplification via the alternative pathway

binds C5 for cleavage by C2b

Front 29

C5a

Back 29

chemotactic factor
early promotor of acute inflammation
act on mast cells (degranulation) and tissues around blood vessels (recruit histamine)

Front 30

specific C3 convertase for classical and alternative pathways

Back 30

Classical: C4b2b and C4b2a
(made from binding of C2b onto C4b)

Alternative: C3bBb

Front 31

specific C5 convertase used

Back 31

C4b2b3b
(created when C3b binds to the C3 convertase (C4b2b))