- classical - alternative - common

1. C5 convertase cleaves C5 2. C5a is released; C5b forms focal point for MAC 3. C5b fuses with C6 and C7 4. Complex attaches to target cell membrane 5. C8 and C9 bind, forming transmembrane channel 6. Cell lyses

12) Complement Flashcards by Samantha Boyer

3 C’ pathways

classical
alternative
common

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current definition of complement

a system of plasma proteins which mediate a variety of inflammatory effects in addition to bacteriolysis

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discovered classical pathway

1894
Pfeiffer

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discovered alternative pathway

1954
Pillemer

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Ab dependent and independent C’ pathways

classical: dependent
alternative: independent

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pathway that evolved earlier
more primitive

alternative

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why does complement become functional in a cascade?

too destructive to exist in plasma in activated form

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3 general functions of C’ system

lysis of bacteria/enveloped viruses
opsonization (phagocytes have receptors for C3)
anaphylatoxins cause inflammation (vasodilation, permeability, chemotaxis)

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requirements for classical pathway

antigenic surface
Ab bound to antigenic surface (1 IgM, or 2 IgGs closeby)

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IgG subclasses best at fixing C’

IgG3
IgG1
IgG2
IgG4 (not at all)

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3 units/phases of classical pathway

recognition unit (C1 binding, activation)
activation unit
MAC

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trimolecular complex that initiates classical pathway

components?

C1q
C1r
C1s

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Classical Pathway Steps
(Not including common pathway)

C1q binds Fc of Ab bound to antigenic surface
C1 is activated, and molecule twists
Activated C1r then activates C1s
C1s activates C4, and then (with C4) C2
Complex C42 forms and attaches to the surface —the C3 convertase
C3 convertase cleaves C3
C3a is released; C3b binds to membrane surface (C5 convertase proximal, opsonin distal)

Common pathway begins

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Common Pathway Steps

C5 convertase cleaves C5
C5a is released; C5b forms focal point for MAC
C5b fuses with C6 and C7
Complex attaches to target cell membrane
C8 and C9 bind, forming transmembrane channel
Cell lyses

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Alternative Pathway Steps
(Not including common pathway)

Spontaneous cleavage of C3; C3b binds surface
C3b binds factor B and factor D
New C3b binds membrane surface proximally; binds properdin to stabilize C5 convertase (distal binding is opsonin)

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best C1q binding configuration

IgM + IgG3

C1s activates —–, which is required to then activate —–

C4
C2

determines whether C3b is an opsonin or part of C5 convertase

whether it attaches to membrane proximal or distal to C42/C3bBD

how does MAC cause lysis?

water flows in
K+ flows out
Na+ flows in
gross swelling of cell
contents leak out

empty cell sack is phagocytized

requirements for the alternative pathway

surface with repeating polysaccharide units (bacteria, fungi, viruses)
spontaneous cleavage of C3 (0.2-0.4% total C3/hour)

functions of anaphylatoxins C3a and C5a

degranulation of masts (histamine) - smooth muscle contraction, permeability
induce local edema - fluid contains more Ab and C’
chemotaxis

examples of C’ system regulators

C1 esterase inhibitor
Beta 1 H
DAF
cAb inhibitor
anaphylatoxin inhibitor
S protein
C8 binding protein
C3b inhibitor

indications for C’ lab tests

suspected hyper-utilization due to complement-activating disease
suspected hyposynthesis due to genetic deficiency

3 parts of C’ panel

total hemolytic complement (CH50 assay)
C3 quantitative
C4 quantitative

only pathway measured by total hemolytic complement

classical + common

method used for C3 and C4 quantitation

nephelometry measures presence only, not function

measures rate of Ag-Ab complex formation by measuring amt of light scattered as they are formed

C3/C4 nephelometry

special C' assays done in reference labs

- all complement components, immunochemical or functional - C1 esterase inhibitor, immunochemical or functional

measures ability of test sample to lyse 50% of sheep rbcs coated with rabbit anti-srbc

CH50 total hemolytic complement

CH50 steps

- mix srbc-Ab with standard, control or pt serum - incubate - centrifuge - read hemolysis at 415 nm - calculate CH50 value

CH50 precautions

- collect on ice; C1q and C5 are heat-labile - reconstitute reagents with cold water - follow procedure exactly - pipette carefully

causes of elevated complement levels

- acute inflammatory conditions (acute phase proteins) - rheumatic diseases - viral hepatitis - MI - cancer - DM - pregnancy - sarcoidosis - amyloidosis - thyroiditis - IBD - typhoid - pneumococcal pneumonia

causes of decreased complement levels

- hypercatabolism (severe rheumatic disease, subacute bacterial endocarditis, HBV, GN sepsis, malaria, cryoglobulinemia) - liver disease (decreased synth) - protein malnutrition - genetic deficiency

seriousness of genetic C' defiency depends on...

whether component is involved in 1 pathway or the common pathway

sx of genetic C' deficiency

recurrent infections

deficiency of C1 esterase inhibitor

hereditary angioedema (HANE)

uncontrolled activation of C4 and C2, resulting in local edema life threatening if in larynx

hereditary angioedema (HANE)

HANE tx

- synthetic C1 esterase inhibitor - non-masculinizing androgenic steroids