A brief introduction to the complement system

“A brief introduction to the complement system” Euro Diagnostica International Autoimmunity Symposium September 17th, 2012. Malmö, Sweden Tom Eirik M...
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“A brief introduction to the complement system” Euro Diagnostica International Autoimmunity Symposium September 17th, 2012. Malmö, Sweden

Tom Eirik Mollnes

Bordet (1895): Complement lysis 1. Bacteria + Antiserum

2. Bacteria + Antiserum (56 o C, 30´) 3. Experiment 2 + Normal serum

4. Bacteria + Normal serum

Lysis

No lysis Lysis

No lysis

Conclusion: Heat stable (Ab) and heat labile (C) factor

Complement in 1984 Meeting in Royal Society, London. Hobart M. Immunology Today, 1985;5:212.

”Many immunologists hold that complement is baffling or irrelevant or, most conveniently, both but a recent meeting emphasized that complement is interesting and that it may be important, even only as an elegant model system.”

Cascade Principles “Undetonated bombs”

P=Proenzyme E=Enzyme External activator

P1

E1

Autoactivation

Inhibition E2 P2 P2

Biological effects Local vs. systemic

E3 P3 P3 E3

”The point of

E3

no return”

P3

E2

Amplification

P3 E3

Classical pathway

Lectin pathway

Alternative pathway

Microbial surfaces Mannose, NAcGlc

Foreign surfaces

Ag-Ab complexes CRP

CPN

C1q C1r, C1s

C1INH

C3(H2O) Factor I

C4 C4a

MBL MASPs

Factor I

C4bC2

C4

C4BP

C4a

C2b

C3(H2O)B

C4bC2

C2b

P C3bBbP

C3b

C3bC3bBbP

C4b2a3b

Factor I

H

C3a

Natural fluid-phase inhibitors CR1

Ba

C3bB

C3

C4BP

MCP

D

C3(H2O)Bb

C4b2a Factor I

D

H

C5

CPN

DAF

Vitronectin Clusterin

C3aR

C5a C5b C6+C7+C8+C9 Fluidphase

Membrane C4b and C3b inhibitors

CD59

Membrane

C5b-9(m) SC5b - 9 MAC Terminal complement complex

C5aR CR3 C8 C9 C5b-7

CD59

Mollnes, Song, Lambris. Trends Immunol. 2002.

Cross-talk between cascades Complement C1-INHIBITOR

Coagulation Fibrinolysis

KallikreinKinin

Functions of Complement – Protects the host against danger – Fights infections – Cross-talks with other protective systems (e.g. TLR, B- and T-cells)

– Contributes to tissue homeostasis – Physiologic renovation (e.g. C1q/SLE) – Tissue repair and regeneration

– Consequences of activation/dysregulation – Inflammation – Tissue damage and disease

What is inflammation?

Heat

Redness Swelling

Pain

Reduced function

Danger to the host 3 Rs

Danger

Recognition Response

Host

Resolution

Danger signaling Pattern recognition receptors/molecules (PRR/PRM): - Host receptors of Innate Immunity (complement/TLR) Ligands for PRRs: - PAMP: Pathogen Associated Molecular Patterns - “external” (exogenous) danger – microbes - DAMP: Damage Associated Molecular Patterns - “internal” (endogenous) danger – host molecules

Disturbed molecular homeostasis

Recognition by Complement

Harboe and Mollnes. J Cell Mol Med. 2008.

Alternative

pathway activation

Walport MJ. N Engl J Med 2001.

Complement defence against microbes C*

1 Immune adherence CR3

C* C* M AbC*

CR2

C* C*

M

C5aR

2 Chemotaxis Phagocytosis

M

C*

M

C* C*

M

C*

M

C*

C* C*

Inflammation C* Ab C*

3 Immune regulation

M

C*

4 Bacteriolysis

Inflammatory effects mediated by C5a Histamin release

Chemotaxis

Lysosomal enzyme release Neutrophil aggregation

Cell adhesion CR3 (CD11b/18)

Smooth muscle contraction Increased permeability

C5a

CR1 and FcR expression

Reactive oxygen metabolites

Cytokines

Il-1, Il-6, IL-8, TNF

B- and T-cell responses

Arachidonic acid metabolites (LT, PG)

Platelet activating factor (PAF)

Danger signaling Complement and altered self

Complement

REG REG

REG

Cancer cell Normal cell

Apoptotic cell

Endothelial damage

Endothelium and Complement Intact endothelium – The only fully complement compatible surface? • Blocking DAF/MCP induced spontaneous leakage

Damaged endothelium

Capillary leak

– Endothelium is damaged by complement – Damaged endothelium activates complement Arteriosclerosis

Reasons to analyse complement • Complement deficiencies – are associated with certain diseases

• Complement activation – clinical: reflects ongoing disease processes – experimental: animal and in vitro models

• Complement pharmacology – has already reached clinical medicine

CH50 - Total Complement Hemolytic Activity Detection of complement deficiency Sensitized SRBC

Serum

RRBC Mg EGTA

B D P Alternative Classical C1 C4 C2 C3 CH50 CH50 C5

C6 C7 C8 C9 Lysis (Hb release)

Total Complement System Activity Serum is added to micro-titer wells

C5

C6

C7

C8

C9 C5

C3

C6

C7

C4 C2

C1qrs

MBL

Classical pathway

C5

C3

C4 C2

IgM

C8

C9

MASP-2

P

C6

Lectin pathway

C8

C3

FB

Mannan

C7

C9

FD

LPS Alternative pathway

Enzyme immunoassay (EIA) for quantification of TCC (neoepitope) anti-C6

Av-Px Biotin

SC5b-9 anti-C9neo

mAb aE11

Complement deposition in tissue

MPGN II in factor H dysfunction TCC (C5b-9) in glomeruli

Acute Ab-mediated rejection C4d in peritubular capillaries

Complement in the future Therapeutic aspects

Makrides SC. Pharmacol Rev 1998

COMPLEMENT DISEASES

References

Acute Adult respiratory distress syndrome

Zilow et al., 1992; Rinaldo and Christman 1990; Langlois et al., 1989; Meade et al., 1994

Ischemia-reperfusion injury:

Eculizumab (Soliris®)

Myocardial infarct

Hill and Ward, 1971; Earis et al., 1985; Rubin et al., 1989;Fox, 1990; Entman et al., 1991; Kilgore et al., 1994; Homeister and Lucchesi, 1994

Skeletal muscle Lung inflammation

Rubin et al., 1989; Weiser et al., 1996 Ward, 1996, 1997; Eppinger et al., 1997

Hyperacute rejection (transplantation)

Bach et al., 1995; Baldwin et al., 1995; Sanfilippo, 1996; White, 1996; Lawson and Platt, 1996

Sepsis Cardiopulmonary bypass

Hack et al., 1989; Gardinali et al., 1992 Kirklin et al., 1983; Homeister et al., 1992

Burns, wound healing

Ward and Till, 1990; Oldham et al., 1988; Davis et al., 1987; Ljunghusen et al., 1996

Asthma Restenosis Multiple organ dysfunction syndrome Trauma, hemorrhagic shock

Regal et al., 1993; Regal and Fraser, 1996 Niculescu et al., 1987 Miller et al., 1996 Gallinaro et al., 1992;Kaczorowski et al., 1995

Guillain-Barré syndrome

Hartung et al., 1987; Sanders et al., 1986; Koski et al., 1987; Koski, 1990

Chronic Paroxysmal nocturnal hemoglobinuria Glomerulonephritis

Yomtovian et al., 1993; Shichishima, 1995; Rosse, 1997 Couser, 1993; Couser et al., 1985, 1995;Spitzer et al., 1969

C5 PNH

- Paroxysmal nocturnal hemoglobinuria

- GPI-anchor defect (e.g. DAF CD59 )

Systemic lupus erythematosus

Belmont et al., 1986; Hopkins et al., 1988; Negoro et al., 1989; Gatenby, 1991

Rheumatoid arthritis Infertility

Kemp et al., 1992; Satsuma et al., 1993;Abbink et al., 1992 D’Cruz et al., 1990, 1991;Anderson et al., 1993

Alzheimer’s disease

Johnson et al., 1992; Rogers et al., 1992; Pasinetti, 1996; Eikelenboom et al., 1994;Velazquez et al., 1997; Jiang et al., 1994; McGeer et al., 1997; Chen et al., 1996; Morgan et al., 1997

Organ rejection (transplantation)

Platt, 1996; Baldwin et al., 1995; Marsh and Ryan, 1997; Dalmasso, 1997

Myasthenia gravis Multiple sclerosis

Lennon et al., 1978;Piddlesden et al., 1996 Piddlesden et al., 1994

Biomaterials incompatibility Platelet storage

C5a C5b-9

Gyongyossy-Issa et al., 1994

Hemodialysis

Cheung et al., 1994; Himmelfarb et al., 1995; Mollnes, 1997

Cardiopulmonary bypass equipment

Craddock et al., 1977; Haslam et al., 1980;Gillinov et al., 1993; Mollnes, 1997; te Velthuis et al., 1996

Complement in summary

Ricklin D et al. Nat Immunol 2010.