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