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The Complement System. Fill free to ask questions during my lectures. In addition, I would also be happy to answer any questions after class. My office is in Room 441 BSB. My email address is boacklrj@musc.edu and my phone number is 792-2550. Robert J. Boackle, Ph.D. .

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slide1

The Complement System

Fill free to ask questions during my lectures.

In addition, I would also be happy to answer any questions after class. My office is in Room 441 BSB. My email address is boacklrj@musc.edu and my phone number is 792-2550.

Robert J. Boackle, Ph.D.

Please be sure to study the chapter on Complement

slide2

Complement

A series of Blood Serum

components which exist

in a NON-ACTIVE state

slide3

The Primary Functions

of the Complement System

The Primary Functions

of the Complement System

1) Quickly Neutralize anything that activates complement by permanently coating the activator

2) Enhance the Phagocytosis of that complement-coated substance

3) Directly damage that complement-coated membrane (e.g., if the activator is a susceptible microbe)

slide4

Complement Components

are produced Primarily by

“HEPATOCYTES”

MACROPHAGES and many different cell types

also produce complement components

slide5

COMPLEMENT

Fast Acting (2 min)

Potent

Tightly Controlled

Cascading/Amplifying

Sequence

slide6

1) FRAGMENTATION

2) CONFORMATIONAL

CHANGE

3) ACTIVATION

slide7

Activation by Immune Complexes

The Classical Pathway

(Most Powerful Pathway)

slide8

Lectin Pathway

weakest pathway

MBLMASP1 + MASP2

C4b, C3b, iC3b, C3dg, C3d

Immune Adherence

Enhanced Phagocytosis

C3a, C5a

Anaphylotoxins

Chemotactic Factors

Membrane

Attack

Complex

Membrane Damage & Potential for Cell Lysis

Classical Pathway Activation by Immune Complexes

C1

C4 C2

C3

C5

C6

C7

C8

C9

Membrane

damage

)

(

(Amplification Loop -

Alternative Pathway)

C3b, Factor B, Factor D

slide9

C3

C5

C6

C7

C8

C9

C3

C5

C6

C7

C8

C9

(Amplification Loop)

Cascading - Amplifying Sequence

At many steps, especially at C1 and C3

C1

C4 C2

C3

C5

C6

C7

C8

C9

Control at these two steps is important.

C4 C2

C3

C5

C6

C7

C8

C9

C4 C2

C3

C5

C6

C7

C8

C9

slide11

(Native C1)

The first Complement Component, C1 = Macromolecular C1qr2s2

C1q

C1r2 and C1s2

slide12

C1

C1q Globular Heads

bind to the exposed Fc region of IgM, IgG3 or IgG1 Immune Complexes, but not to IgA nor IgG4

slide13

= Catalytic

Domain

Activated C1s

Activated C1s

C1r

C1 Structure, after C1 activation

slide14

Movement

within the

Hinge

Region

CH2 CH3

CH2 CH3

IgG3 or IgG1

slide15

IgG3 or IgG1

ANTIBODIES

Movement

within the

Hinge

Region

Antigenic

determinant

CH2 CH3

Foreign

(Antigenic)

cell/viral surface

CH2 CH3

C1q globular heads bind CH2 gamma,

but only if the Fab regions have

bound antigen and moved

so as to expose the CH2 gamma

Antigenic

determinant

slide16

C1

At least two or more IgG antibodies are required but only one IgM (5 Fc regions)

At least two adjacent IgG

CH2 CH3

CH2 CH3

IgG3 or IgG1

Antigenic Surface

slide17

C1q conformationalchanges are induced after binding to adjacent IgG antibodies on the antigenic surface; Followed by C1r2 then C1s2 activation

At least two adjacent IgG

CH2 CH3

CH2 CH3

IgG3 or IgG1

Antigenic Surface

slide18

At least two adjacently deposited IgG antibodies are needed to bind C1, but the more deposited IgG on the antigenic surface the better the interaction with C1 becomes. This requirement for sufficiently deposited levels of antibody insures that complement is not inadvertently activated.

However, pathogens that either mutate their immunogenic epitopes or slough their epitopes defeat or circumvent the proper action of the classical complement pathway.

IgG3 or IgG1

Antigenic Surface

slide19

Active Host Enzymes now on the Antigen

C1r2-C1s2

C1q

CH

2

Flexibility of C1q

FOREIGN SURFACE

slide20

C4

Activated

C1S

2

FOREIGN SURFACE

slide21

C1S

2

C4b

Short-lived Active Binding Site

FOREIGN SURFACE

slide22

C1S

2

C4b

Covalent Binding

FOREIGN SURFACE

Virus Neutralization

slide23

C4b that did not bind to the antigen

is quickly degraded

FACTOR I

(protease)

C4 Binding

Protein

C4b

If C4b Remains Unbound

Note:Bordetellapertussis accumulates serum C4 Binding Protein, resulting in Factor I-mediated inactivation of bound C4b on its surface

slide24

C4

C4

C4a

C1s

C1r2

2

C4b

C1q

C4b

C4b

C4b

Antigenic Surface

slide25

C2

C2

C2b

C2a

C1s

C1r2

C2b

2

C4b2a is a

C3 Convertase

enzyme complex

C1q

C2a

C2a

C2a

C4b

C4b

C4b

Antigenic Surface

slide26

C4b2a is a C3 convertase enzyme

C1s is no longer needed.

C1 Inhibitor travels between

the now loosened C1q stems and

Irreversibly binds and

inactivates C1r and C1s

C2a

C4b

ANTIGEN

slide27

Native C3

C2

C4b

GLY- CYS - GLY- GLU - GLU -THR

S

C

O

slide28

Both C4b and C3b

are covalently bound

to the antigen via the

short-lived active binding site.

C3b

C4b

ANTIGEN

GLY- CYS - GLY- GLU - GLU -THR

H

S

C

O

ANTIGEN

slide29

Regions on C4b and C3b

become “Exposed.”

Host Phagocytes attach

to these regions on

the deposited complement

C3a does not bind to antigen, it is released

C3b

C3a

C3b may also

attach

covalently to

C4b on

C4b2a

C3a

C3b

C2a

C4b

As soon as C4b and C3b are

Covalently bound

to the antigenic surface

w

w

V

V

Antigenic Surface

slide30

PMN or any Phagocyte

Immune Adherence & Enhanced Phagocytosis

of the complement-coated antigen

One of the “major” functions of complement is to enhance Phagocytosis

C3b

C3b

C3b

C2a

C2a

C4b

C4b

w

w

w

w

Antigenic Surface

each activated complement component has at least one inhibitor or inhibitory mechanism
Each activated complement componenthas at least one inhibitoror inhibitory mechanism

Complement Regulation

The powerful fast-acting complement system must be controlled at each step or disease ensues due to non-productive depletion of complement.

slide32

C1 Inhibitor

Release of

Ab

Release of

C1

Dissolution of

Immune Complexes

C3b

C3b

C3c

C3b

C3c

C3b

C2a

C2a

iC3b

C3d

C4b

C4b

Antigenic Surface

Inactivation and removal of C1 occurs as C4b and C3b deposit on the Fab (CH1) or on the antigenic determinants and disrupt the immune complexes, which in turn cause a loosening of the C1qr2s2 complex and allows entrance of C1-Inhibitor.

C1-Inhibitor binds and then removes the inactivated C1r and C1s. However, when low levels of deposited IgG are present, the entire C1qr2s2 complex is removed by the action of C1-Inhibitor. Trace amounts of heparin bind to C1q and facilitate the C1-inhibitor mediated inactivation of activated C1r2 and C1s2 and the removal of C1qr2s2 thereby allowing a more efficient maintenance/usage of the (residual) complement components.

slide33

Deficiencyof

Early Complement Components

(C1r, C1s, C4 or C2)

Insufficient complement activation on the antigen-

No loosening of the Immune Complexes

SLE and/or Glomerulonephritis-

Inability to clear immune complexes

faster than they are forming

Possible consequences

slide34

C1r

C1s

Complement Regulation

Activated C1, when not bound to immune complexes is rapidly inhibited by

C1q

C1- Inhibitor

Prevents Auto-activation of Native C1 by Activated C1

slide35

Activated C1, when not bound to immune complexes is rapidly inhibited by

C1r

C1s

C1- Inhibitor

Complement Regulation

C1q

In the absence of sufficient control by C1-Inhibitor, activated C1r in one (released) activated C1 will activate C1r in other Native C1 (C1 auto-activation) resulting in escalating C1 auto-activation, C4 and C2 consumption and continual depletion of C1-Inhibitor.

c1 inhibitor deficiency genetic 1 silent gene 25 of normal c1 inh 2 dysfunctional gene product
C1 Inhibitor DeficiencyGenetic:1. Silent Gene - 25% of Normal C1 INH2. Dysfunctional Gene Product

In Both Cases

C1 Inhibitor Function is down

and C4 levels are lower than normal

Acquired:

Lymphoproliferative Disorders

slide37

Angioneurotic edema (Angioedema)

NO Control over unbound activated C1 resulting in total depletion of C4 and C2 and most importantly temporary depletion of C1-inhibitor, resulting in lowered control over Kallikrein and subsequent Bradykinin formation.

PlasmaPrekallikrein circulates complexed with high molecular weight kininogen. (Kallikrein activity is controlled by C1 INHIBITOR), Uncontrolled Activated Kallikrein cleaves kininogen to releaseBradykinin.

slide38

Complement and Breast Cancer

  • In Breast Cancer
  • Elevated Ca++ levels are often observed that may slightly disrupt C1qr2s2, making it more difficult to activate complement on an antibody-coated cancer cell surface
  • Poor specific antibody responses (to cancer cells)
  • Elevated levels of complement inhibitory molecules on the surface of the cancer cells
  • Small levels of complement deposition actually cause surviving cancer cells to become more resistant to apoptosis.
complement c3b c4b neutralizes endotoxin
COMPLEMENT (C3b & C4b)Neutralizes Endotoxin

Changes the nature of the substance..no longer endotoxin

Neutralizes Viruses

Virus no longer binds to the target host cell properly

slide40

C5a is a “very strong Chemotatic Factor”

C5a

C5b

C5a

C5 joins the complex after one or two C3b molecules bind.

C5

C3b

C2a

C3b

C4b

ANTIGEN

slide41

TISSUE

INFECTION

PMN

C5a

P

M

N

C5b

C3a

C3b

Concentration Gradient of C5a and C3a

c3a c5a
C3a&C5a

PMN

PMN

C5a

PMN

C3a

Complement Coated Antigen

c3a c5a1
C3a & C5a

UP-REGULATION -- Higher Expression

of Complement Receptors on PMN

PMN

tissue infection

Complement Coated Antigen

TISSUE INFECTION

PMN

P

M

N

ARTHUS

REACTION

Infected Tissue

slide45

C3a and C5a bind to Mast Cells and Basophiles

Then Mast Cells and Basophiles release Histamineand Heparin

Mast Cell

C3a

C5a

slide46

Histamine Release

C3a

Mast Cell

C5a

slide49

Classical Pathway

C1

C4 C2

C3

C5

C6

C7

C8

C9

“Membrane damage”

LectinPathway

Alternative Pathway

(Amplification Loop)

Membrane

Attack

Complex

(MAC)

C5-9

slide50

Membrane Attack Complex, C5-C9

C5b

C5b

Transmembrane

Channel

C6

C6

C7

C7

C8

Cell Membrane

Polymerized C9

C8 enters the membrane,

then the polymerized C9 causes the lesion.

Then the cell swells.

slide54
Protective Mechanisms on Host Cell MembranesHost Cells Must Protect Themselves from Inadvertent Complement Attack
slide55

Over-expressed on host cells that are located in inflamed areas or on Cancer Cells

Complement Receptor 1CR1 (CD35)Decay Accelerating Factor DAF (CD55)Membrane Cofactor ProteinMCP (CD46)Protectin(CD59)

Protective Mechanisms onHost Cell Membranes

Xenograph Organ Transplant Research Goal: Genetically program foreign cells (animal organs) to express these “human” complement regulatory substances and defeat destruction by Ab and the Classical Complement Pathway

protective mechanisms on host cell membranes
Protective Mechanisms on Host Cell Membranes

How do these normal cell surface proteins protect host cells in areas of complement-mediated inflammation from inadvertent complement attack?As an example, we will discuss the mechanism forMembrane Cofactor ProteinMCP (CD46) and Complement Receptor One (CR1)

(the textbook chapter provides more complete information)

slide57

Factor I

(a serum protease)

If C3b inadvertently deposits on a host cell. Then, CR1 and or MCP as a part of that host cell membrane will serve as cofactors for serum Factor I

Inactivated iC3b Complement Cascade is stopped

MCP

MCP

MCP

HOST CELL

slide58

Alternative Complement Pathway

in the absence of Classical Pathway activation

1) Represents a first line of defense before substantial levels of Ab are produced

2) Is always ready to be activated by a susceptible surface

Always remember that the Amplification Loop of the classical pathway has the same molecular steps as the Alternative Pathway

slide59

The Alternative Pathway

Non - specific (does not require antibody)Less Efficient (requires more of the activator)Mg++ DependentBy definition does not require C1, C4 or C2although the Classical Pathway will activate it!

slide60

“Must start with a Bound C3b

That has not been inactivated”

C3b

C1

C4 C2

C3

C5

C6

C7

C8

C9

Membrane

damage

C3 Amplification Loop or

C3a, C5a

Anaphylotoxins

Chemotactic Factors

C4b, C3b, iC3b, C3dg, C3d

Immune Adherence

Enhanced Phagocytosis

Alternative Pathway

C3b, Factor B and Factor D

thus serum factor b will bind to any deposited c3b that has not been inactivated
Thus, serum FACTOR B will bind to any Deposited C3bthat has not been Inactivated

C3b

Factor B

PRO-ENZYME

now ready to become activated

Activator / Antigen

slide62

Factor D

activated

C3b

Factor Bb

Activator / Antigen

slide63

C3bBb activates more C3

“Amplification of C3b deposition”

Native C3

C3b

Factor Bb

(Activated)

Antigen

slide64

Activated Factor B when bound to

deposited C3b will now activate more native C3

Amplification Loop

C3a

C3b

NATIVE C3

Factor Bb

Enzyme

Antigen

Note that Factor Bb has enzymatic functions almost like C2a

slide65

C3 Amplification Loop

C3bBb enzyme

More C3b is Deposited

C3

C3b

C3b

Factor Bb

ANTIGEN

slide66

FACTOR B

Factor B

More Factor B binds

so more C3 can be activated

C3

C3b

C3b

ANTIGEN

slide67

Factor C3bBb activates C3 and C5

( similar to C2 )

MORE

MORE

C3b

FACTOR B

Activator / Antigen

slide68

Factor B

Adheres to deposited C3b, if C3b is bound to an antigen.

C3b

If the surface to which C3b binds has no built-in protection

against complement (like host cells do)

e.g. no CR1, MCP or DAF

that surface will activate the Alternative Pathway

(the C3b-Amplification Loop).

This includes most microbes and artificial substances,

for example “Cellophane filters used in leukophoresis”

slide69

FACTOR I

serum protease i

In addition, Factor H is the primary Inhibitor of unbound C3b

When C3b fails to bind to antigen, Factor H “quickly” binds to the C3b, this attracts the Factor I protease, then C3b is rapidly inactivated by Factor I to form iC3b

FACTOR H

C3b

slide70

Pathogens have mechanisms to circumvent the immune system.Streptococcus pyogenes

Neisseria gonorrhoeae

Candida albicans

Each of these pathogens express molecules that attract and accumulate host serum Factor H onto its microbial surface that promote a rapid serum Factor I mediated cleavage of any deposited C3b to form iC3b.[Inactivated C3b (iC3b) can not participate in the amplification loop.] As a result, less C3b is deposited on these organisms.

slide71

Factor I

If C3b becomes inadvertently bound to a host cell

or becomes bound to an antibody-coated cancer cell

Host Cell has evaded the attack no amplification loop

C3b

i

Host Cell Surface Co-Factor

either CR1 or MCP (CD46)

slide72

PMNs can endocytose small amounts of C3b or iC3b or C3d that inadvertently deposit on their surfaces

slide73

Host Cell Protective Mechanisms

Complement Receptor 1CR1 (CD35)Decay Accelerating Factor DAF (CD55)Membrane Cofactor ProteinMCP (CD46) CD46 just happens to be a receptor for measles virus (MV) MV infection may cause host immune suppression, secondary to signaling events through CD46 on dendritic cells and macrophages. Protectin (CD59).

slide74

Decay Accelerating FactorDAF (CD55)Blocks the interaction of C4b and C3b with the subsequent complement componentsProtectin (CD59)Blocks the function of C8 and C9

Two additional the host cell surface Protective Mechanisms

phosphatidylinositol “anchored” to the host cell

slide75

Paroxysmal Nocturnal Hemoglobinuria (PNH)

An acquired disorder of phosphatidylinositol "anchors"on selected hemopoietic stem cell lines and their particular erythrocyte progeny. The patients develop anemia associated with the intermittent passage of dark urine. The hemoglobinuria is due to an increased susceptibility of the abnormal population of innocent bystander erythrocytes to complement-mediated lysis, when complement is activated.

The deficiency of the phosphatidylinositol anchoring system is reflected by deficiencies of DAF (CD55) and Protectin (CD59).

Type I PNH red cells have normal levels or slightly lowered levels of these two proteins and usually show normal resistance to complement-mediated hemolysis.

Type II PNH erythrocyte populations lack DAF and have intermediate sensitivity to hemolysis.

Type III PNH erythrocyte populations lack both proteins and are very sensitive to hemolysis.

slide76

C3

 chain

S

S

S

S

 chain

Covalently bound

to the antigen

C3 Convertase

C4bC2a or C3bBb

C3b

S

S

S

S

C3a

Factor I with co-factor

H or CR1 or MCP

iC3b

S

S

S

S

C3dg

C3c goes into the fluid phase

Factor I

C3c

S

S

S

S

C3d

C3g

Tissue protease or plasmin

The speed of the C3b breakdown (catabolism) depends on the nature of the substance onto which C3b covalently binds

slide77

Phagocytes

have receptors for all of the covalently-bound C3 fragments

slide78
PMN

MONOCYTES /

MACROPHAGES

PMN

MONOCYTES /

MACROPHAGES

CR3

iC3b

COMPLEMENT

RECEPTOR

EXPRESSED

ON

BINDING

SPECIFICITY

ERYTHROCYTES

PMN

MONOCYTES /

MACROPHAGES

C3b

C4b

CR1

universal

GLOMERULAR

PODOCYTES

C3d

C3dg

CR4

slide79

Complement deposition (C3b and C3d) on Antigens amplifies the stimulation of B Cells (that have CR2 and CR1, in addition to their specific Ab-receptors for the antigen) and enhances the subsequent Antibody production by a 1000 fold.

COMPLEMENT

RECEPTOR

EXPRESSED

ON

BINDING

SPECIFICITY

CR2

iC3b

C3dg

C3d

B cells

(EB virus

receptor)

Dendritic Cells

slide80

Role of

Complement Receptor 1

(CR1)

on

Erythrocytes

slide81

Complement Coated Immune Complexes are picked-up from the serum by Erythrocytes and Delivered to Phagocytes.

Complement Coated

ANTIGEN

ANTIBODY

COMPLEX

CR1

CR1

Erythrocyte

CR1

CR1

CR1

slide82

CR1

CR3

CR1

CR4

CR3

Phagocyte

CR4

CR4

CR3

CR1

CR4

CR3

Complement Coated Immune Complexes are picked up from the serum by Erythrocytes and Delivered to Phagocytes.

Complement Coated

ANTIGEN

ANTIBODY

COMPLEX

CR1

CR1

Erythrocyte

CR1

CR1

CR1

slide83

Complement Coated

ANTIGEN

ANTIBODY

COMPLEX

CR1 interaction weakens

CR1

RELEASE OF COMPLEMENT COATED

CR3

IMMUNE COMPLEXES TO PHAGOCYTE

CR1

CR4

CR3

CR1

Phagocyte

CR1

CR4

Erythrocyte

CR4

CR3

CR1

CR1

CR1

CR4

CR1

CR3

slide84

Complement Coated

ANTIGEN

ANTIBODY

COMPLEX

CR1 interaction weakens

CR1

RELEASE OF COMPLEMENT COATED

CR3

IMMUNE COMPLEXES TO PHAGOCYTE

CR1

CR4

CR3

Phagocyte

CR1

CR4

CR1

CR4

CR3

Erythrocyte

CR1

CR4

CR1

CR1

CR3

CR1

slide85

Deficiencyof

1) Early Complement Components

(C1r, C1s, C4 or C2)

2) CR1 (on erythrocytes)

SLE and/or Glomerulonephritis-

Inability to clear immune complexes

Possible consequences

slide86

HIV-1

In addition to remaining dormant inside the DNA of host cells (such as CD4 positive cells), and continually changing its immunodominant epitopes, HIV-1 virions (when released into the serum from an infected host cells) are protected from the complement system in several ways:

slide87

HIV-1

  • 1) Acquires DAF (CD55) upon leaving the host cell
  • Attracts Factor H from serum
  • Sheds many of its trimeric gp160 spikes
  • In addition to continually changing its immunodominant epitopes, these above properties allow a percentage of HIV-1 particles to escape neutralization by antibody and complement. A low level, non-neutralizing C3b-iC3b-C3d deposition may actually help HIV-1 to be more persistent in lymph nodes.
slide88

Y

Y

HIV-1 Virion Structure

  • Actual mature HIV-1 virion has only 7-15 spikes due to shedding limits IgG aggregation
  • ~ 100 nm diameter
  • 20 faced icosahedron with 12 vertices
  • 3 envelope spikes on each face and one at each vertex = 72 spikes
    • Based on underlying structure

humanvaccine.duke.edu, 1/12/06

c5a induced granulocyte aggregation blockage of capillaries by granulocytes superoxide stimulation
C5a Induced Granulocyte AggregationBlockage of Capillaries by Granulocytes+Superoxide Stimulation

Massive Complement Activation

SHOCK

slide91

C5a Induced

Granulocyte Aggregation

RESPIRATORY DISTRESS SYNDROME

EXTENDED DAMAGE IN CARDIAC INFARCTION

RETINAL DAMAGE - TEMPORARY BLINDNESS

activation of classical and alternative pathways by biomaterials
Hemodialysis (Cellophane Filters)

Oxygenators (Silicone Polymers)

Filtration Leukopheresis (Nylon Fibers)

Contrast Media (X-Ray Examination)

ACTIVATION OF CLASSICAL ANDALTERNATIVE PATHWAYS BY BIOMATERIALS

No CR1, no MBP, so No Way To make C3b inactive

the lectin complement pathway
The Lectin Complement Pathway

Like the Alternative Pathway, this is another primitive back-up system to activate complement (and save your life), before substantial levels of specific IgG antibodies are produced.

Very Similar to C1qr2s2 and C1-Mediated Activation

slide94

MBLand Ficolins are carbohydrate binding Lectins in human serum that look like C1q, all three have a umbrella-like appearance.

slide95

However, rather than C1q, the

Lectin Complement Pathway begins with the binding of host serum glycoproteins termed:

1) Mannan Binding Lectin (MBL) or by

2) Ficolins (FCNs)

Normally, both of these lectins are at a relatively low concentrations in human serum.

slide96

MBL-MASP1, MASP2 & MASP3

C1qr2s2

FCN-MASP1, MASP2 & MASP3

Pro-enzymes

Lectin Pathway (ancient & weakest Pathway)

1) Human Mannan Binding Lectin (MBL) or

2) Human Ficolins (FCNs)

These are Human Serum Lectins, which remain

associated with serum serine proteases termed MASPs (rather than C1r and C1s).

Upon binding to microbial structures, such as

Mannan, Lipoteichoic Acid, or Peptioglycan, the MASP (pro-enzymes) proteases within the Lectin-MASP complexes become activated and in turn activate C4, C2 and C3.

Mannan is a capsular substance of pathogenic fungi and yeasts

(e.g., Cryptococcus neoformans and Candida albicans).

slide97

C1qr2s2

MBL-MASP1, MASP2 & MASP3

C4 C2

C3

C5

C6

C7

C8

C9

FCN-MASP1, MASP2 & MASP3

All three “lectins” remain associated with their respective serum pro-enzymes. After the lectins bind to their respective targeted substance, their associated activated enzymes are capable of activating early complement components.