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REVIEW OF COMPLEMENTSYSTEM
KHADIZHA EMIROVA (Russia) Moscow State Universityof Medicine and DentistryNamed after A.I.Evdokimov
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)
Complement system
Activated by the type of enzymatic cascade reaction
The proteins of the complement system become immunological activity only under pathological conditions
Classical pathway
520
170
- 155
450
– 36
0
420
400
– 35
0
300
- 225
120 Миллионы
лет назад
Lectin pathway
Alternative pathway
Приобретенный иммунитет
Complement: ancient defense system
4Adapted from Fujita T, Nature Rev Immunol 2, 346-353, 2002.
Activation pathway of complement activation, and triggers
Complement componentsComponent Molecular
weight
Serumconcentration
(ug/ml)
Classical pathwayС1С4С2С3С5С6С7С8С9
570,000209,000117,000190,000206,00095,000
120,000163,00079,000
37043030
1,40075605580
160
Lectin pathwayMBLMASP 1MASP 2
32,00090,00074,000
0,5-5,01,6-7,5
NC
Alternative pathwayBDP
100,00025,000
223,000
2001-525
Bellanti; IMMUNOLOGY;: Clinical Applications in Health and Disease, 2012
Complement systemБелки системы комплемента обозначаются «С» с порядковыми
номерами от 1 до 9 и буквами латинского алфавита (B, D или P)
Субъединицы и фрагменты, образующиеся при расщеплениекомпонентов 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)
always active
Complement - always activated with further activation
of the immune system triggers
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;
Permanent activation of the
complement system
Alternative pathway
An additional activation pathway
Lectin Classical
microbesC3 + H2O microbesantibody
Triggers (upper respiratory tract infection, gastroenteritis / diarrhea, pregnancy, surgery, stress, physical activity, injury) stimulate the further strengthening of the complement activation of the complement
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
CR1, complement receptor type 1
1. Holers VM et al. Immunol Rev. 2008;223:300-316. 2. 2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;4:372-378.
CFI, CFH
C5b-9 terminal complement complex
C6 C7
C8 C9
Cell lysisCell activation
Pro-inflammatoryPro-thrombotic
C5
C5bC5a
Potent anaphylatoxinChemotaxis
Cell activationPro-inflammatory
Pro-thrombotic
C3a C3bi
C3
C3b CR3Microbial opsonisation
Immune complex clearance
Weak anaphylatoxin
Lectin pathway
Lectin pathway
Classical pathway
Classical pathway
C1qrs
C4 + C2
C4a C2b
C4b2a
C4b
Alternative pathway
Alternative pathway
C3b
Ba
D + B
C3bBb
C3bBb3b
C5 convertase
C4b2a3bC5 convertase
Complement cascade provides a variety of potential therapeutic targets
Term
ina
lP
rox
ima
l CD55
CFI/MCP
CD55, CFH
C3H2OC3H20
Tickover
C3
C3
Membrane Attack Complex (MAC)
MAC
Разрушающаяся чужеродная клетка
Natural regulators of complement
12
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
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
«Свой» защита клеток хозяина
Zipfel PF, Skerka C. Nature Rev Immunol. 2009.
Benefits and harms of complement
acquired regulators
No regulators or defective regulators
No regulators or defective regulators
Измененный «свой» невоспалительное удалениеизмененных клеток хозяина
«Чужой»активация комплемента и удаление
инфекционных микроорганизиов
Complement
Неадекватное действиерегуляторов ведет к
повреждению клеток хозяина
Поврежденный «свой»
Неэффективное удаление измененныхклеток хозяина может
вести к патологии
Измененный «свой»
Активация комплемента и удаление инфекционных
микроорганизмов
Похожий на «своего»
no regulators regulators
regulators
pathologicalterms
physiological
terms
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)
‘Self’ ‘Non-self’
Non-activator surface Activator surface
C3b
#3#2#1
#3#2#1
C3b
B
H
GAG, glycosaminoglycan
iC3b
C3b
FHB
C3b
Polyanions (GAGs, sialic acid, phospholipids)
I
1)2)
3)
Factor H1) Inhibits factor B binding to C3b 2) Accelerates the decay of C3bBb3) Cofactor for factor I in cleaving C3b to iC3b → inhibition of phagocytosis and
killing by MAC
Bb
C3
C1q
B
Target
MACC3b
D
C4b 2aC3b Bb
Amplification
Protected ‘self’ (non-activating surface)
MAC, membrane attack complex; GAG, glycosaminoglycan
Loss of protection → attack against self tissues (innate autoreactivity)
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
iC3b C3b C3b
Bb
C6 C7 C9
C5b
C8
CD59CD55(DAF)
CD35(CR1)
CD46(MCP)
CR1, complement receptor type 1;MCP, membrane cofactor protein;DAF, delay-accelerating factor; MAC, membrane attack complex
C3bBb C3b,B
The complement system
Lectin pathway
C3b+
C5C6C7C8C9
Lysis
C3bi CR3
MicrobesD, P
C4b2aC4, C2C1rs
C1q
Ag-Ab, CRP
MASP1, 2, 3
MBL
Microbes
DAF, CR1
H
DAF
C4bp
C1 INH
CD59
H
I
Classical pathway Alternative pathwayMPGN
HUSNeisseria meningitidis
Bacterialinfections
LED
HAE
Bacterialinfections
PNH
Neisseria meningitidis
Bacterial infections
LAD
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
C3
Failure in control
→ HAE
→ DDD (MPGN2), partial lipodystrophy, AMD
→ aHUS
→ aHUS
→ aHUS
→ PNH
C1-INH
Factor H (N-terminus)
Factor H (C-terminus)
Factor I
CD46 (MCP)
CD55, CD59
→ ‘innate autoreactivity’
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
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
Dysregulation of complement activation:
STEC-HUS, atypical HUS and TTP
Marina Noris, Federica Mescia and Giuseppe Remuzzi Nat Rev Nephrol, 2012
Eculisumab
The only drug of complement-inhibiting antibodies for the treatment
of atypical HUS, PNG
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
Overview of complement-modulating agents under developmentIngibitor name (Company)
Mechanism of action Stage of development
FCFD4514S (Genentech) Monoclonal antibody Fab fragment against
factor D Phase Ib/II in AMD
CR2-fH (TT30) (Taligen Therapeutics/Alexion)
Fusion protein linking CFH regulatory domain to the part of complement receptor CR2 that binds C3b, thereby delivering CFH to sites of
complement activation Phase I in PNH
PMX53 (Promcs/Cephalon) C5a receptor antagonist Phase Ib/IIa in RA
CCX168 (ChemoCentryx) C5a receptor antagonist Phase II in ANCA-associated renal vasculitis
Mubodina (ADIENNE)Recombinant human minibody against C5 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
Examples of complement-related disorders with different
potential requirements concerning drug administration
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
Q & A