1. REVIEW OF
COMPLEMENT
SYSTEM
KHADIZHA EMIROVA
(Russia)
Moscow State University
of Medicine and Dentistry
Named after A.I.Evdokimov

2. Complement system
 system of blood proteins with proteolytic
activity, interacting with each other and
with other proteins of the immune system
required to provide antimicrobial
protection (native and specific immunity)

3. Complement system
 Activated by the type of enzymatic
cascade reaction
 The proteins of the complement system
become immunological activity only
under pathological conditions

4. Complement: ancient defense system
Миллионы
лет назад
Alternative pathway
Lectin pathway
Classical pathway
Приобретенный иммунитет
4
dapted from Fujita T, Nature Rev Immunol 2, 346-353, 2002.

5. Activation pathway of complement activation,
and triggers

6. Complement components
Molecular
weight
Serum
concentration
(ug/ml)
Classical pathway
С1
С4
С2
С3
С5
С6
С7
С8
С9
570,000
209,000
117,000
190,000
206,000
95,000
120,000
163,000
79,000
370
430
30
1,400
75
60
55
80
160
Lectin pathway
MBL
MASP 1
MASP 2
32,000
90,000
74,000
0,5-5,0
1,6-7,5
NC
100,000
25,000
223,000
200
1-5
25
Component
Alternative pathway
B
D
P
Bellanti; IMMUNOLOGY;: Clinical Applications in Health and Disease, 2012

7. Complement system
Белки системы комплемента обозначаются «С» с порядковыми
номерами от 1 до 9 и буквами латинского алфавита (B, D или P)
Субъединицы и фрагменты, образующиеся при расщепление
компонентов комплемента, обозначаются порядковыми номерами
с малыми буквами (С2а, С3b и т.д.)
Активированную форму комплемента обозначают штрихом
сверху над указанием компонента комплемента с его субкомпонентами
(C3bC2a , С3bBb и т.д.)
Если активированный фрагмент компонента комплемента, теряет
свою активность, то для в обозначении добавляется «i» (С3bi)

8. Complement - always activated with further
activation of the immune system triggers
always active
C3 + H2O
An additional activation pathway
microbes
Alternative pathway
Permanent
activation of the
complement
system
antibody
microbes
Classical
Lectin
Triggers (upper respiratory tract infection,
gastroenteritis / diarrhea, pregnancy, surgery, stress,
physical activity, injury) stimulate the further
strengthening of the complement activation of the
complement
Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395; Walport MJ. N Engl J Med. 2001;344(14):1058-66; SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.; Rother RP et al.
Nature Biotech. 2007;25(11):1256-64; Meyers G et al. Blood. 2007;110(11):Abstract 3683; Hill A et al. Br. J. Hematol. 2010;149(3):414-425;

9. Main functions of the complement system
 Lysis of microbes (MAC)
 Opsonisation (C3b, C4b, C1q)
 Generation of an inflammatory reaction
(C5a, C3a, C5b-9)
– Mediator release from mast cells
– Contraction of smooth muscle cells
– Increased permeability of blood vessels
 Chemotaxis and activation of phagocytes (C5a)
 Processing of immune complexes (C3b, C4b, CR1)
 Strengthening the B- and T-cell immune responses
– Natural (endogenous) adjuvant effects via
C3d-CD21 and iC3b-CR3
2.
CR1, complement receptor type 1
1.
Holers VM et al. Immunol Rev. 2008;223:300-316.
2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;4:372-378.

10. Complement cascade provides a variety of potential
therapeutic targets
Proximal
Classical
pathway
C4 + C2
Lectin
pathway
CD55
C3
C4b2a
C1qrs
C4a
C2b
C3
C3H2O
D+B
C3bBb
Ba
CFI/MCP
C3b
C3a
C3bBb3b
C5 convertase
C5
C5a
CR3
CFI, CFH
C4b2a3b
Potent anaphylatoxin
Chemotaxis
Cell activation
Pro-inflammatory
Pro-thrombotic
C3bi
C5b
C6
C7
C8
C9
C5b-9 terminal complement complex
C3H20
Tickover
C3b
C3
C4b
Weak anaphylatoxin
Terminal
CD55,
CFH
Alternative
pathway
Microbial opsonisation
Immune complex
clearance
C5 convertase
Cell lysis
Cell activation
Pro-inflammatory
Pro-thrombotic

11. Membrane Attack Complex (MAC)
MAC
Разрушающаяся
чужеродная клетка

12. Natural regulators of complement
Oppression and control of the
complement
Activation of the complement
CFH
C3
CFI
Factor B
MCP (CD46)
Factor D
ТHBD
antiCFH аt
DAF (СD55)
Protectin (СD59)
Noris M, et al. Clin J Am Soc Nephrol. 2010;5:1844–1859
Noris et al NEJM 2009 Oct 22; 361(17):1676-87
12

13. Dual role of complement in the development
of immunological inflammation
 Too much
– Causes inflammation and tissue damage
(C5a and MAC)
 Too little
– Failure in the clearance of damaged tissue
or microbes
→ debris or microbial components persist
→ (auto)immune responses develop

14. Benefits and harms of complement
«Свой»
Измененный «свой»
защита клеток хозяина
невоспалительное удаление
измененных клеток хозяина
regulators
«Чужой»
regulators
активация комплемента и удаление
инфекционных микроорганизиов
no
regulators
physiological
Complement
terms
pathological
terms
No regulators or
defective
regulators
Неадекватное действие
регуляторов ведет к
повреждению клеток хозяина
Поврежденный «свой»
No regulators or
defective
regulators
acquired
regulators
Неэффективное удаление измененных
клеток хозяина может
вести к патологии
Измененный «свой»
Активация комплемента и
удаление инфекционных
микроорганизмов
Похожий на «своего»
Zipfel PF, Skerka C. Nature Rev Immunol. 2009.

15. Mechanisms of discrimination between
self and non-self by complement
 Protective coating by sialic acid, phospholipids and
GAGs
(glycophorin-sialic acid on RBCs, heparan sulphate on
endothelial cells)
H
B
C3b
C3b
#3
#1
#2
#3
#1
#2
Non-activator surface
‘Self’
GAG, glycosaminoglycan
Activator surface
‘Non-self’

16. Protected ‘self’ (non-activating surface)
1)
B
2)
Factor H
FH
I
3)
1) Inhibits factor B binding to C3b
2) Accelerates the decay of C3bBb
3) Cofactor for factor I in cleaving C3b to iC3b
→ inhibition of phagocytosis and
killing by MAC
Polyanions
(GAGs, sialic acid, phospholipids)
Loss of protection → attack against self tissues (innate autoreactivity)
C3
Amplification
B
D
C1q
MAC
Target
MAC, membrane attack complex; GAG, glycosaminoglycan

17. Mechanisms of discrimination between
self and non-self by complement
 Membrane regulators of complement activation
– CR1 (CD35)
– MCP (CD46)
– DAF (CD55)
– Protectin (MAC inhibitor, CD59)
I
Bb
C9
C6 C7
iC3b
C3b
C3b
C5b
C8
CR1, complement receptor type 1;
MCP, membrane cofactor protein;
DAF, delay-accelerating factor;
MAC, membrane attack complex
CD46
(MCP)
CD35
(CR1)
CD55
(DAF)
CD59

18. The complement system
Classical pathway
Bacterial
infections
MPGN
HUS
LED
Ag-Ab, CRP
Neisseria meningitidis
C4bp
C1q
C1rs
C4, C2
H
C3
D, P
C3bBb
C3b,B
C4b2a
C1 INH
MASP1, 2, 3
DAF
DAF, CR1
H
HAE
MBL
Microbes
Bacterial
infections
Lectin pathway
Alternative pathway
PNH
CD59
Ag-Ab, antigen-antibody; CRP, C-reactive protein; MBL, mannan-binding lectin;
MASP, mannose-associated serine protease; DAF, delay-accelerating factor;
MPGN, membranoproliferative glomerulonephritis; aHUS, atypical haemolytic
uraemic syndrome; HAE, hereditary angio-oedema;
PNH, paroxysmal nocturnal haemoglobinuria
Microbes
LAD
C3b
C3bi
CR3
+ I
Bacterial infections
C5
C6
Neisseria meningitidis
C7
C8
C9
Lysis

19. Failure in control
→ ‘innate autoreactivity’
C1-INH
Factor H (N-terminus)
Factor H (C-terminus)
Factor I
CD46 (MCP)
CD55, CD59
→ HAE
→ DDD (MPGN2), partial
lipodystrophy, AMD
→ aHUS
→ aHUS
→ aHUS
→ PNH
HAE, hereditary angio-oedema; DDD, dense deposit disease; MPGN, membranoproliferative
glomerulonephritis; AMD, age-related macular degeneration; aHUS, atypical haemolytic uraemic
syndrome; MCP, membrane cofactor protein; PNH, paroxysmal nocturnal haemoglobinuria

20. Other diseases where complement
activation is involved
 Cold agglutinin disease
– IgM autoantibodies against RBCs
 Catastrophic antiphospholipid syndrome
– Antiphospholipid antibodies
– Thrombotic occlusion of small blood vessels, organ failure, necrosis
 Myasthenia gravis
– IgG autoantibodies against AChRs
 Multifocal motor neuropathy
– IgM anti-GM1 ganglioside antibodies
– Conduction blocks in lower motor neurons
 Neuromyelitis optica (Devic’s syndrome)
– Autoimmune attack against optic nerves and spinal cord
 Dermatomyositis
– Microangiopathy in perifascicular regions of muscles and skin
aIn
addition to atypical haemolytic uraemic syndrome, dense deposit disease, paroxysmal nocturnal haemoglobinuria,
age-related macular degeneration and hereditary angio-oedema; AChR, acetylcholine receptor

22. Dysregulation of complement activation:
STEC-HUS, atypical HUS and TTP
Marina Noris, Federica Mescia and Giuseppe Remuzzi Nat Rev Nephrol, 2012

24. Eculisumab
The only drug of complementinhibiting antibodies for the treatment
of atypical HUS, PNG

25. Approaches to target complement inhibitors to various surfaces
either in circulation or after ex vivo coating/perfusion
Ricklin and Lambris 2007 ; Monk et al. 2007; Qu et al. 2009 ;
Woodruff et al. 2011 ; Recknagel et al. 2012; Schmidt et al. 2012; D. Ricklin and J.D. Lambris 2012

26. Overview of complement-modulating agents under development
Ingibitor name
Mechanism of action
Stage of development
(Company)
FCFD4514S (Genentech)
CR2-fH (TT30) (Taligen
Therapeutics/Alexion)
PMX53 (Promcs/Cephalon)
CCX168 (ChemoCentryx)
Mubodina (ADIENNE)
Monoclonal antibody Fab fragment against
factor D
Fusion protein linking CFH regulatory
domain to the part of complement receptor
CR2 that binds C3b, thereby delivering CFH
to sites of complement activation
C5a receptor antagonist
C5a receptor antagonist
Recombinant human minibody against C5
Phase Ib/II in AMD
Phase I in PNH
Phase Ib/IIa in RA
Phase II in ANCA-associated
renal vasculitis
Preclinical
NNC 0151-0000-0000 (Novo
Nordics)
Anti-C5a receptor antibody
Phase I in SLE
Phase II in RA
Recombinant CFH (Taligen
Therapeutics/Optherion)
Restores/potentiates the action of
endogenous CFH
Preclinical
CFH from human plasma (LFB)
Restores/potentiates the action of
endogenous CFH
Preclinical
Marina Noris, Federica Mescia and Giuseppe Remuzzi Nat Rev Nephrol, 2012

27. Examples of complement-related disorders with different
potential requirements concerning drug administration

28. Conclusion
 Activation of complement in many diseases is a normal
physiological response
 There are very few diseases in which complement is not
activated
 Complement activation can be pathogenic when it is
dysregulated and persistent
 There is little rationale for complement inhibition in situations
where activation is part of the process of disease resolution
 Complement must be constantly monitored, as it is
always active and has a destructive force

29. Q&A