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Flashcards in 7 - Complement Deck (38)
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1
Q

Complement
Define

A
  • *System** or Cascade of
  • *Plasma Proteins** produced mainly by the LIVER

Acts to complement actions of AB’s in:
destruction of bacteria // ridding body of foreign antigens

Can cause:
local leakiness in BV –> swelling / pain / loss of fxn / inflammation

Regulation is KEY

2
Q

What ACTIVATES the Complement?

A

Variety of Stimuli:
Immunoglobulins // Lipid A

Ploynucleotides // C-Reactive Protein

Viruses / Polysaccharides / lipopolysaccharides

3
Q
  • *Complement System**
  • *Acts on What?**
A

Acts on:

  • *BIOMEMBRANES** leading to:
  • *Cytolysis**

Production of MEDIATORS of Inflammatory response

Assistance in Particle OPSONIZATION + CLEARANCE

4
Q

Three Complement Pathways

A

Classical = Cl –> Ig

Lectin = MBL –> Mannose Residues

Alternative = C3b –> deposits on pathogen surface

5
Q

Classical Pathway

Can also be activated by:
Soluble Ab-Ag Complexes, not just membrane bound antigens

A

Antigen-Antibody Complexing:
Either:
2 Adjacent IgG** Molecules OR **1 IgM Molecule
VVVVV
Induces binding of the C1 molecule through the C1q
VVVV
C1q attaches to the:
CH2 domain of IgG or CH3 domain of IgM
VVVV
C1r is activated –> cleaves C1s
VVVV
C1 converts into an enzyme whose substrates are C4 + C2

6
Q

Classical Pathway Photo

A

Soluble Ab-Ag Complexes can ALSO activate Classical Pathway

NOT just Membrane-bound antigens

7
Q

Terminal Phase
of the Complement Cascade

A
  • *MAC**
  • *Membrane Attack Complex**

Bound C5b protein recruits:
C6 / C7 / C8 / C9
VVV
Multiple C9 units form a Multimer –> extends ACROSS Lipid Bilayer
VVVV
Forms a PORE that can pass water & ions
VVVV
Pathogen cell SWELLS & LYSIS

8
Q
  • *Lectin Pathway
  • differences from Classical Pathway***
A

Cell-Surface Protein recognizes & BINDS:
SUGARS or OLIGOSACCHARIDES
generally to help mediate Cell-Cell interactions

unlike the CLASSICAL pathway, does NOT start with
AB recognition of a pathogen

Instead it imploys:
MBL = Mannose Binding Lectin
to recognize pathogens
VVV
Binds Terminal Mannose (Mannan) Residues of
Oligosaccharades on surfaces of Bacteria

9
Q

Ficolin

A

LECTIN PATHWAY

Plasma Proteins that are SIMILAR to MBL in structure

Bind to different species of Bacteria
N-acetylglucosamine, lipoteichoic acid

Coating them = OPSONIZATION
then causing:
Complement Proteins to Attack

10
Q

Lectin Pathway
INITIATION PHASE

A

MBL circulates bloodstream, in complex with MASPs
(Mannose-Associated Serine Proteases)
Which resembles the C1 component of the classical pathway

MASP-2 cleaves C4 / C2 –> forming C4B2a
analogous classical
VVVVV
Converges with the Classical Pathway
VVVV
Cleavage of C3 / C5 –> MAC formation

11
Q

The 3 Different COMPLEMENT INITIATORS

A

Classical = IgM

Lectin = Mannose

Ficolin = NAG / Lipoteichoic Acid

ALL HAVE:
Serine Protease Activity

12
Q

Alternative Pathway
Complement INITIATION

A

Small amounts of C3b are formed SPONTANEOUSLY in circulation
@ a low rate

They recognize a variety of foreign substances = Initiation Phase

Serum protein factor B binds to –> C3b
VVVV
is then cleaved to Bb, by c3 convertase
VVVV
C5 is cleaved & C5b is bound
VVVV
MAC FORMATION
(Convergence w/ classical & lectin paths)

13
Q

Review of Each Complement Pathway

A
14
Q

REGULATION
Of Complement

A

Host needs to conserve complement components
despite activation, need to have a RESERVE agaisnt other pathogens

Some cleavage products can strongly activate inflammation
and damage the host

  • *Dysregulation of complement** is involved in several Immune diseases:
  • *RA** / Macular Degeneration
15
Q

REGULATION
of the Classical Pathway

A

C1 Esterase Inhibitor = C1INH
VVVV
Binds to C1r & C1s –> PREVENTING complement activation

Several diff. proteins cause dissociation of C4b2a & STOP cascade:
C4BP // DAF // CR1/CD35 // MCP

Factor 1 cleaves C4b after C2a leaves
which HALTS the cascade

16
Q

Regulation of the

ALTERNATIVE PATHWAY

A

FACTOR H
Binds to C3bBb complex –> displaces Bb
Factor 1
causes celavage of C3b –> STOPS pathway

Mammalian cells carry SIALIC ACID on their surface,
promoting binding of Factor H so that the complement cascade STOPS ATTACK on mammalian cells

Bacterial cells LACK sialic acid, so factor B –> binds to C3b
leading to complement attack

17
Q

Regulation of the
TERMINAL COMPONENT

of the Complement Cascade

A

CD59 (mamallian membrane protein)
Binds to C5b-C8 complex –> PREVENTING C9 polymerization
this stops membrane disruption by MAC

18
Q

C1 INH

C1 Inhibitor

A

Regulator of Complement Activation

Serine Protease Inhibitor

Bints to C1r & C1s
VVVV
DISSOCIATES them from
C1q

19
Q

Factor H

A

Regulator of Complement Activation

binds C3b & DISPLACES Bb cofactor
for
Factor 1
mediated cleavage of
C3b

20
Q

C4BP

C4 Binding Protein

A

Regulator of Complement Activation

Binds C4b & DISPLACES C2 cofactor
for
Factor 1
mediated cleavage of
C4b

21
Q

MCP // CD46

Membrane Cofactor Protein

A

Regulator of Complement Activation

Found in:
Leukocytes / Epithelial Cells / Endothelial Cells

Cofactor for Factor 1
mediated cleavage of BOTH:
C3b** & **C4b

22
Q

Factor 1

uses what as COFACTORS?

A

Regulator of Complement Activation

SERINE PROTEASE
that cleaves
C3b & C4b
by using these as COFACTORS:

Factor H

MCP

C4BP

CR1

23
Q

DAF
Decay Accelerating Factor

A

Regulator of Complement Activation

Found in:
BLOOD cells / epi+endothelial cells

DISPLACES:
C2a from C4b
&
Bb from C3b

Dissociation of C3 convertases

24
Q

CD59

A

Regulator of Complement Activation

Found in, Same as DAF:
BLOOD cells // endo+epithelial cells

BLOCKS C9 binding
&
PREVENTS formation of MAC

25
Q

3 Major FUNCTIONS
of Complement

A

Opsonization

Anaphylatoxin Production

Cell Lysis

26
Q

OTHER Activities
Of Complement

A

Enhancement of B-Cell Responses

REMOVAL of Immune Complexes

REMOVAL of Necrotic Cells + Subcellular Membranes

Responses to Viruses

27
Q

Opsonization

A

1 of 3 Major Fxns of Complement

C3b + iC3b + C4b
VVVV
NEUTROPHIL + MACROPHAGE
CR1 CR3 CR4
VVVV
ENHANCED UPTAKE of PATHOGEN

28
Q

Anaphylatoxin Production

A

1 of 3 Major Fxns of Complement

C5a + C3a + C4a
are produced by complement
VVVV
Smooth Muscle Contraction
+
Mast Cell DEGRANULATION-release of Vasoactive substances
Plasma Exudation
VVV
Active Neutrophil + Macrophage

29
Q

Cell Lysis

A

1 of 3 Major Fxns of Complement

C5b - C9** = **MAC
VVV
Death of Bacterium

30
Q

C3 Deficiency
Complement Deficiencies

A

No C3b –> Terminal stage NOT activated
VVVV
SEVERE INFECTIONS + INFLAMMATION

31
Q

C1 / C2 / C4 Deficiency

Complement Deficiencies

A

NO activation of Classical Path
VVVVV
Pyogenic Infections

Autoimmune Diseases

32
Q

Properdin or Factors B / D

Complement Deficiencies

A

NO MAC FORMED
Much LESS is formed, not enough
UNDERACTIVE complement system
VVVV
SEVERE PYOGENIC INFECTIONS

33
Q

MBL DEFICIENCY
Complement Deficiencies

A

NO activation of LECTIN PATH
VVVV
BACERIAL INFECTIONS

34
Q

Lack of any of C5-C9

Complement Deficiencies

A

NO MAC FORMED
VVVV
Recurrent NEISSERIAL Infections

35
Q

Lack of C1INH (C1 Inhibitor)
Complement Deficiencies

A

ALL PATHS are OVER-ACTIVATED

Is a Serine Protease Inhibitor, will affect ALL 3 PATHWAYS
VVVV
ANGIOEDEMA

36
Q

MISSING CD59 or DAF

Complement Deficiencies

A

MAC damages HOST CELLS

vvvvv

HEMOLYSIS + THROMBOSIS

37
Q

Lack of Factor H or I

Complement Deficiencies

A

C3 UNREGULATED

vvvv

Glomerulonephritis
+
Hemolytic Uremic Syndrome

38
Q

Missing COMPLEMENT Receptor

Complement Deficiencies

A

IMPAIRED Adhesion & Migration of LEUKOCYTES

vvvvv

Recurrent BACTERIAL Infections