complement 2016

8/17/2019 Complement 2016

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Complement system



The complement : Facts

“The activity of blood serum that completes the action of antibody”

Lyses cells, bacteria, and viruses

Opsonization promotes phagocytosis

Removes immune complexes from circulation (Immune clearance)

and deposits them in spleen/liver



Complement is activated in many ways

Classical Pathway: begins with Ag-Ab complex

Alternative Pathway: foreign cell-surface constituents initiated

Lectin Pathway: activated by mannose-binding lectin (MBL) to microbes



Classical Pathway Begins with Ag-Ab Binding

Bacterial surface Ag-Ab binding

Binding of C1q to IgM

C1qr 2s2 is stabilized by Ca++

C1 molecule



Antibody conformation and complement

IgM C1q binding sites are unexposed(‘planar’ configuration)

IgM Exposes 3 C1q binding sites

(‘staple’ configuration)



C1s hydrolyzes C4b and C2a to form

C4b2a complex (called C3 convertase)

C4b C2a

( )

Formation of C3 Convertase

C1q binds to Ag-bound Ig

Activated C1r activates C1s



Hydrolysis of C3 by C3 Convertase (C4b2a)

In C3 convertase, C4b stabilizes and 2a hydrolyzes C3 into C3b and C3a

formation of labileThioester bond

Binding to free-OH or -NH2 groups onmembrane

C 3 C o n v e r t a s e



C4b2a3b makes C5 convertase which cleaves C5 into C5b and C5a

i nf l a

mm a t or y

r e s p on s e s

inflammatory

responsesOpsonization

Formation of C5 Convertase

inflammatory

responses



Initiated by bacterial cell wall

C3, factor B, factor D, and properdin (factor P)mediate this pathway

Ba

( C 3 b B b s t a

b i l i z e r )

M g + +

©

C3bBb (C3 convertage) amplifies C3b response

C3bBb3b acts like a C5 convertase

Alternative Pathway also activates C5 convertase



Lectin pathway also activates C5 convertase

MBL

(Mannose-binding lectin)

- acute phase protein similar to C1q

- induced during inflammation

- binds mannose, NAG, D-glucose,L-fucose pattern on microbes

C4b2a3b acts like a C5 convertase



C5b67 undergo a hydrophilic-

amphiphilic structural transition

↓

C8 induces a 10Å pore that can lyseRBCs

↓

C9 (perforin-like molecule) binding &polymerization completes MAC (70-100 Å)

Formation of C5b6789 (MAC)

A tubular functional pore (70 – 100 Å)



MAC formation on target cell surface

Complement lesionson RBC membrane

Poly-C9 complex(in v i t ro )

~100 Ȃ

Bi l i l Eff t M di t d b C l t



Inflammatory responses

Biological Effects Mediated by Complement

C3a, C4a, C5a (anaphylatoxins)

Bind complement receptors (mast cells and basophils), inducedegranulation and release of histamine

C3a, C5a, and C5b67

Induce smooth-muscle contraction, vascular permeability, extravasation,and chemo attraction



Opsonization


C3b and C4b are opsonins

Bi l i l Eff t M di t d b C l t



Immune clearance phenomenon




Regulations of complement

R l t f C l t A ti ti (RCA)



Regulators of Complement Activation (RCA)

Complement deficienc and disease



Complement deficiency and disease

@ SLE : No clearance of circulating immune complexes activate leukocytesthrough FcR to produce local inflammation

# renal deposition of immune complexes

Complement Deficiency

C3 and Factor B

C3b-inactivator, C6 and C8

Deficiencies of early C

components C1, C4, C2

C1-inhibitor

Diseases

Severe bacterial infections

Severe Neisseria infections

Systemic lupus erythematosus@ (SLE),

glomerulonephritis# and polymyositis

(inflammation in muscles)

Hereditary angioedema (inflammation of

dermis)

C3 depletion due to unregulated C3

convertase, increased infections withpyrogenic bacteria

Factor I, H deficiency

S i b l t i k t id l t tt k



Some microbes play trick to avoid complement attack

Group A Streptococcal strains inhibits C3

M+ wild type




Salmonel la enterica Short types of LPS or lipo-oligosaccharide (LOS) binds to serum amyloid P

component (SAP) to affect complement pathway






Salmonel la typhimurium Resistant strain

Microbial evasion of complement



Microbial evasion of complement

Gram negative bacteria

Gram positive bacteria



Q???

complement 2016

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