The complement system Francesco Tedesco Istituto Auxologico Italiano Milano
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.