Professional Documents
Culture Documents
Matthew Pickering
Centre for Complement and Inflammation Research
Overview
Complement biology: lessons from nature
complement deficiency states
Complement therapeutics
eculizumab
Complement activation
Bacterial
immune complexes ‘always on’
Carbohydrate, ficolins
C5 activation
C3b Factor B
Factor D
C4b2a C3bBb
C3b Factor H
Factor I
Regulators of complement
activation gene cluster
(RCA)
200Kb
1q32
‘too much’
complement’
Regulatory protein
deficiency Provide diseases in
which complement
inhibiting therapies
ought to be effective
Complement activation protein deficiency
Classical pathway C3 Terminal pathway
Infection
REGULATORS ACTIVATORS
Atypical haemolytic
uraemic syndrome
Viro Pharma
Berinert™
CSL Behring
Recombinant C1 inhibitor
Rhucin™
Hereditary angioedema Pharming
Paroxysmal nocturnal haemoglobinuria
Humanised anti-C5 antibody
Terminal pathway
dysregulation
Paroxysmal nocturnal
haemoglobinuria Eculizumab - Soliris™
Alexion Pharmaceuticals
Paroxysmal nocturnal haemoglobinuria
Pathogenesis of haemolysis:
CD59 deficiency results in uncontrolled terminal pathway activation
and formation of membrane attack complex cell lysis
CD59
‘always on’
eculizumab
alternative pathway
C3
C5a
C3bBb
C5 activation
C3b Factor B
Factor D
common
mutations
rare
DDD retinopathy
Dense deposit disease
Heterogeneous light microscopic appearances
Patrick Walker et al., Modern Pathology, 20; 605-16, 2007
25% 18%
Membranoproliferative Crescentic
45% 12%
Mesangial proliferation Acute proliferative & exudative
C3 glomerulopathy
Glomerular pathology associated with deposition of complement C3
in the absence of immunoglobulins
CFHR5 nephropathy
Dense deposit disease
Impaired plasma regulation
ACTIVATION
REGULATION
FACTOR H C3
plasma regulation
surface recognition
Dense deposit disease
Impaired plasma regulation plasma regulation
surface recognition
C3 nephritic factor
C3
C3bBb Factor H
C3b B, D
Anti-factor H
Models of ‘dense deposit disease’
Animal models:
Spontaneous porcine factor H deficiency and gene-targeted factor H-deficient
mice
600
Plasma C3 - mg/l
Factor H
deficiency 400
200
Wild-type
common
mutations
rare
ACTIVATION
REGULATION
FACTOR H C3
FACTOR I FACTOR B
CD46
plasma regulation
surface recognition
Atypical Haemolytic uraemic syndrome
‘always on’
alternative pathway
C3
C5a
C3bBb
C5 activation
C3b Factor B
Factor D
100
Plasma C3 - mg/l
75
50
25
Cfh-/- Cfh-/-FH16-20
Atypical haemolytic uraemic syndrome - therapy
C5 inhibition successful in case reports – examples:
Eculizumab for aHUS – N. Engl. J. Med. 2009 360:5 pp542-543
Eculizumab for congenital aHUS – N. Engl. J. Med. 2009 360:5 pp544-6
common
mutations
rare
Meningococcal sepsis
Alternative pathway dysregulation and
disease
It is associated with renal and non-renal disease:
common
Age-related macular
degeneration Meningococcal sepsis
mutations
rare
common
mutations
rare
C3 glomerulonephritis
CFHR5 nephropathy
Familial C3 glomerulonephritis and mutation in CFH-related
protein 5
CLINICAL FEATURES
• Autosomal dominant
• Persistent microscopic
haematuria
• Episodes of synpharyngitic
macroscopic haematuria
• Progression to end stage renal
disease mainly in males
IgA Post-infectious
Am J Kidney Dis, vol 39, N 1, 2002: pp24-27
Why are the factor H-related proteins
important?
They are associated with renal disease:
common
mutations
rare
Why are the factor H-related proteins
important?
They are associated with renal disease:
mutations
rare
Complement and tissue injury
Pathologies in which
complement is activated
Antibody-mediated injury to allografts
Complement-fixing donor-specific antibodies
Associated with peritubular C4d staining
Can complement inhibition prevent / ameliorate antibody-
mediated rejection?
C1 inhibitor concentrates
Viro Pharma
Berinert™
CSL Behring
Eculizumab
Alexion Pharmaceuticals
Complement therapeutics
Examples of the many complement inhibitors in development
Eric Wagner and Michael Frank Nature Reviews 2010, vol. 9, 43-56.
Summary
Abnormal regulation of complement is associated with disease
The kidney appears to be particularly susceptible
Renal pathologies resulting directly from complement dysregulation include:
Atypical haemolytic uraemic syndrome
C3 glomerulopathies
Dense deposit disease
CFHR5 nephropathy