The complement system

Francesco Tedesco

Istituto Auxologico Italiano Milano

PROTEINS OF THE COMPLEMENT SYSTEM

Components Regulators Receptors

Serum Soluble C1q, MBL,Ficolins Collectins C1INH

C1r, C1s, MASPs, FD C4bp, FH, FI, P

C2, B C3a/C5a INA

C3, C4, C5 Vitronectin

C6, C7, C8, C9

Membrane

Associated

CR1 C1qR

DAF, MCP C3aR, C5aR

HRF, CD59 CR1, CR2

CR3, CR4

Clusterin

Modified from Kohl et al. Immunol. Res. 2006

MBL Ficolins CollectinsC1q

RECOGNITION MOLECULES OF THE C SYSTEM

Immune complexes

Pentraxins

PAMP DAMP

ECM

Repeated simple sugars

PAMP DAMP

DEFENSE COLLAGENS

Pulmonary SPD

MBL

Globular domains

Collagen-like

domains

Ficolin CL-11

Globular domains

Collagen-like

domains

C1q

C1q COOH

C1q COOH

C1q COOH

C1q COOH

C1q COOH

COLNH2

COLNH2

COLNH2

COLNH2

COLNH2

13

22

149

147

48

C1q COOH

C1q COOH

C1q COOHCOLNH2

17

NH2

EMI

EMINH2

COILED-COIL REGIONSEGF

LZ

PRECEREBELLIN

MULTIMERIN

EMILIN

27

C1q COOHCOLNH2 C1q (A, B, C)

H1B27

AdipoQ

COLLAGEN X (a1)

COLLAGEN VIII (a1, a2)

SACCULAR COLLAGEN

C1q COOHNH2

48

C1qTNF4C1q

Activation occurs through a series of enzymatic reaction

characterized by limited proteolysis of the substrates and

proceeds in a cascade fashion

FUNCTIONAL PROPERTIES OF THE C SYSTEM

Neutralization of the target

Activation

ALTERNATIVE

PATHWAY

LECTIN

PATHWAY

CLASSICAL

PATHWAY

C3b C3H2OMBL-Ficoline

CollectineC1q

P

B

D

MASP

C4

C2C2

C4

C1s

C1r

C 3

C3bC3a

ACTIVATION PATHWAYS OF THE C SYSTEM

C3bC3a

C5a C5

C 3

CYTOLYSIS

MAC

C6

C7

C8

C9

EFFECTOR PHASE OF THE C SYSTEM

C5b

CR1OPSONIZATIONC3aR

C5aR

Recruitment and Activation

of myeloid derived leukocytes

Recruitment of myeloid

derived suppressor cells

Modified from Lea and Johnson, Immunobiology 2012

EGF

Factor I/membrane attack complex C6/7 (FIMAC)

Complement control protein(CCP)

Thrombospondin type-1 (TSP1)

Epidermal growth factor (EGF)-likeLow-density lipoprotein-receptor class A (LDLRA)

Membrane attack complex (MAC) proteins/perforin

C9

C8a/C8

C7

C6

Cytolytic

EGF

EGF

EGF FI

MAC

FI

MAC

EGF FI

MAC

FI

MAC

C3bC3a

C5a C5

C 3

C6

C7

C8

C9 SC5b-9

INFLAMMATION

EFFECTOR PHASE OF THE C SYSTEM

C5b

SCb-9

CONTROL

C5a

SC5b-9

400x

Dobrina et al, Blood 2002

SC5b-9 CONTROLC5a

Dobrina et al, Blood 2002

FREQUENCY OF AUTOIMMUNE DISEASES

ASSOCIATED WITH INHERITED C DEFICIENCIES

Impaired clearance of immune complexes

Impaired removal of apoptotic cells

Defective B-cell tolerance

Increased expression of IFN-α by activated plasmacytoid dendritic cells

%

FREQUENCY OF INFECTIONS ASSOCIATED WITH

INHERITED C DEFICIENCIES

S. Pneumoniae

H. Influenzae

Neisseria meningitides

%

• Occurrence of the first episode of meningitis at

the median age of 14 years as opposed to the age

of 2-3 years of the normal population

• high rates of recurrences with 2 or more episodes

of meningitis

• mild clinical course of infection with a low

mortality rate

• the disease is frequently caused by rare

meningococcal serogroups (x, y, w135)

CHARACTERISTICS OF MENINGOCOCCAL DISEASE

IN PATIENTS WITH INHERITED DEFICIENCIES

OF LATE C COMPONENTS

CONTROL OF C ACTIVATION

LECTIN

PATHWAY

CLASSICAL

PATHWAY

MBL-Ficolins-Collectins C1q

MASP

C2C4

C1sC1r

C 3

C1 Inh

C2C4

CLINICAL FEATURES OF HEREDITARY

ANGIOEDEMA

• Recurrent nonpruritic angioedema edema of

skin and submucosal tisssue without urticaria

• Recurrent episodes of abdominal pain and

vomiting

• Life threatening laryngeal edema

C3 CONVERTASES

C3b

CD55

C3

FHFI

CD46CR2

B cells

FDC

iC3b C3d

CR3

Phagocytes

NK cells

DISEASES ASSOCIATED WITH A DEFECTIVE

CONTROL OF THE ALTERNATIVE PATHWAY

• Atypical hemolytic-uremic syndrome characterized by

abnormal clotting, hemolytic anemia,

thrombocytopenia, and kidney failure

• Dense deposit disease characterized by proteinuria,

hematuria , in about half of affected individuals

develop end-stage renal disease

• Age-related macular degeneration characterized by

drusen and neoangiogenis

C6 C7

C8 C9

C5b-9

C5

C5b

CD59

1. Complement-mediated intravascular

hemolysis

2. Thrombus formation

More frequently in cerebral, hepatic and

splenic veins

PAROXYSMAL NOCTURNAL

HAEMOGLOBINURIA

COMPLEMENT AND

ADAPTIVE IMMUNITY

Carrol and Isenman, Immunity 2012

Effect of C activation on T cell

function

Christoph Hess, Claudia Kemper – Immunity review , 45, 2016, 240–254

Local/cell surface Intracellular pathway

ADDITIONAL FUNCTIONS OF

THE C SYSTEM

C1qC1qC1q

Immune cell modulatorDendritric cells- IL-6, TNF-a, IL-10

- CD80/86

- IL-12

B cells- Negative selection

of autoreactive cells

- IgG

T cells- IFN-g

- CD8+

T proliferation

-Phagocytosis

-Apoptotic cell clearance

Macrophages

Embryo

implantationC1qC1qC1q

decidua normal uterus

Bulla et al, Mol. Immunol. 2008

brainskinkidney

C1Q PROMOTES TROPHOBLAST INVASION AND VASCULAR

REMODELING IN DECIDUA

C1Q PROMOTES TROPHOBLAST INVASION AND

VASCULAR REMODELING IN DECIDUA

C1q SYNTHESIZED BY EVT PROMOTES THEIR

DECIDUAL INVASION

Agostinis et al, JI 2010

C1q CK7

Pre-eclampticNormal

C1Q IN TROPHOBLAST SURROUNDING

SPIRAL ARTERIES

Decidua

PLACENTAL VASCULAR REMODELING

IN C1QA-/- MICE

Agostinis et al., JI 2010CK (brown)

WT C1qa-/-

labyrinth labyrinthdecidua decidua

C1q

Angiogenesis

Wound healing

C1qC1q

COMPLEMENT DEPOSITION IN HUMAN

GRANULATION TISSUE

Bossi et al PNAS, 2014

Ctrl

VEGFC1q

RAT AORTIC RING ASSAY

ECs (Griffonia Semplicifolia isolectin-B4)

PCs (NG2 Chondroitin sulfate proteoglycan)

PERICYTE ATTACHMENT

MOUSE MODEL OF WOUND HEALING

C1q-/- WT

C1q-/- + C1q

C1q

Tumor growth

C1qC1q

EXPRESSION OF COMPLEMENT COMPONENTS IN

TUMOUR TISSUES

Bulla et al Nature Communications, 2016

EFFECTS OF C1Q ON TUMOUR

GROWTH AND SURVIVAL

Bulla et al Nature Communications, 2016

ANGIOGENESIS AND LUNG METASTASES IN TUMOUR-

BEARING MICE

THERAPEUTIC CONTROL OF

C-MEDIATED TISSUE INJURY

ALTERNATIVE

PATHWAY

LECTIN

PATHWAY

CLASSICAL

PATHWAY

Activating surfaces

C3b C3H2O

Carbohydrates

MBL-FicolinsImmune complexes

C1q

P

B

D

MASPs

C4

C2C2

C4C1s

C1r

C 3

C3bC3a

C5a

MAC

C7

C8

C9

C5b6C6

C5

SC5b-9

C3aR

C5aREculizumab

Pexelizumab

MubodinaaptamerARC1905

Compstatin

CH

3

CH

3

CH

2

CH

2

MB12/22

CH

3

CH

3

CH

2

CH

2

HP

HP

MT07

ANTI-C5 RECOMBINANT

ANTIBODY VARIANTS

Macor et al, Arthritis & Rheum 2012

BIO-DISTRIBUTION OF MT07 IN A RAT

MODEL OF ANTIGEN-INDUCED ARTHRITIS

t0 5h 2days 4days 9days 18days 30days

Macor et al, Arthritis & Rheum 2012

PREVENTION OF RAT MODEL OF ANTIGEN-

INDUCED ARTHRITIS

C3

C9

Saline MT07

Macor et al, Arthritis & Rheum 2012

ANTI-INFLAMMATORY

EFFECT OF MT07

Saline MT07

Macor et al, Arthritis & Rheum 2012

CONCLUSIONS

Complement has evolved as a highly sophysticated

system able

• to play an important role in host protection against

pathogens and endogenous danger

• to exert physiological functions that contribute to

angiogenesis and tissue development and

regeneration

• to induce tissue damage under several pathological

conditions that can be controlled by neutralizing

antibodies.