academic trainees meeting 5 th may 2011
Download
Skip this Video
Download Presentation
Academic Trainees Meeting – 5 th May, 2011

Loading in 2 Seconds...

play fullscreen
1 / 38

Academic Trainees Meeting – 5 th May, 2011 - PowerPoint PPT Presentation


  • 93 Views
  • Uploaded on

Academic Trainees Meeting – 5 th May, 2011. Interesting aspects of complement regulation……. Matthew Pickering Wellcome Trust Senior Fellow in Clinical Science Consultant Rheumatologist. Complement activation protein deficiency. Classical pathway. C3. Terminal pathway. Infection.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Academic Trainees Meeting – 5 th May, 2011' - happy


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
academic trainees meeting 5 th may 2011
Academic Trainees Meeting – 5th May, 2011

Interesting aspects of complement regulation……

Matthew Pickering

Wellcome Trust Senior Fellow in Clinical Science

Consultant Rheumatologist

complement activation protein deficiency
Complement activation protein deficiency

Classical pathway

C3

Terminal pathway

Infection

Recurrent infection with encapsulated bacteria e.g. pneumococci, Haemophilus influenzae

Recurrent Neisseria infections

SLE-like illness

Vasculitis, glomerulonephritis

complement dysregulation
Complement dysregulation

Terminal pathway dysregulation

C1 inhibitor deficiency

[classical pathway dysregulation]

Alternative pathway dysregulation

renal thrombotic microangiopathy

Atypical haemolytic uraemic syndrome

Paroxysmal nocturnal haemoglobinuria

Hereditary angioedema

Dense deposit disease,

disorders of complement
Disorders of complement

‘too little’ complement

Tell us what might happen if we therapeutically inhibit complement

Activation protein deficiency

‘too much’ complement’

Provide diseases in which complement inhibiting therapies ought to be effective

Regulatory protein deficiency

complement activation

C3bBb

Complement activation

Bacterial

Carbohydrate, ficolins

‘always on’

immune complexes

classical pathway

lectin pathway

alternative pathway

C3

C5a

C4b2a

C5 activation

C3b

‘C3b

amplification loop’

C3b

C3b

C3b

C3b

MAC

FOREIGN SURFACE

MAC = membrane attack complex

complement regulation

C3bBb

C1 inhibitor

C4bp

Complement regulation

Factor H

C1 inhibitor

classical pathway

lectin pathway

alternative pathway

C3

Factor H

C4b2a

C3b

Factor I

iC3b

C3b

Factor I

MAC

CD59

CD46

CR1

DAF

(CD55)

Factor H

iC3b

MAC = membrane attack complex

complement dysregulation and disease
Complement dysregulation and disease:
  • Physiological control of complement activation

REGULATORS

ACTIVATORS

Loss of function

Gain of function

The balance is influenced by mutations (extreme) and

and/or polymorphisms (‘fine tuning’)

what does factor h do
What does factor H do?
  • Critical negative regulator of the alternative pathway and C3b amplification loop
  • What happens to C3 levels in individuals with complete genetic deficiency of CFH?
    • Uncontrolled spontaneous activation of the alternative pathway and secondary consumption of C3
why is factor h important
Why is factor H important?
  • It is associated with human disease:

‘protective’ and ‘at risk’

polymorphisms

common

mutations

rare

Dense deposit disease

dense deposit disease
Dense deposit disease
  • Electron-dense transformation of the glomerular basement membrane

Glomerular C3 staining in DDD

DDD retinopathy

dense deposit disease1

C3 nephritic factor

C3bBb

Anti-factor H

Dense deposit disease
  • Associated with plasma C3 activation:

Factor H

C3

B, D

C3b

dense deposit disease2

600

400

Plasma C3 - mg/l

200

0

wild-type

Cfh-/-

Dense deposit disease
  • Animal models:
    • Spontaneous porcine factor H deficiency and gene-targeted factor H-deficient mice
      • Profound plasma C3 depletion – 5% of normal C3 levels
      • Spontaneous renal disease – ‘murine/porcine DDD’

Factor H deficiency

Wild-type

C3 staining

dense deposit disease3
Dense deposit disease
  • What have the animal models taught us?
    • The renal disease does not develop if activation of C3 is blocked
    • The renal disease does develop if C5 activation is blocked
      • Dense deposits still develop
      • Glomerular inflammation reduced but not absent
  • Murine dense deposit disease is dependent on the ability to activate C3 but not C5

Glomerular basement membrane deposits in mice with combined deficiency of factor H and C5

Pickering MC, et al. PNAS 2006 103(25):9649-54.

human complement deficiency

C3

Factor I

Factor H

absent

low

low

C3b

iC3b, C3d

Human complement deficiency

Deficiency

State:

Plasma C3:

Recurrent infection

Associations:

immune complex-mediated renal disease

e.g. MPGN type I

Dense deposit

disease

Pickering MC, Cook HT. Clin Exp Immunol. 2008 51(2):210-30.

plasma c3 regulation

Factor H

C3bBb

Plasma C3 regulation
  • Continuous activation of C3 occurs in plasma through the C3 ‘tick-over’pathway

C3c

C3d

C3

iC3b

Factor B

Factor D

Factor I

C3b

C3b

dense deposit disease4

injections

200

150

100

0

24

48

72

Plasma C3 levels (mg/l)

50

0

hours

Dense deposit disease
  • Administration of factor I to mice with combined deficiency of H and I restores GBM C3 staining

Rose KL et al. J Clin Invest. 2008 118(2):608-18.

why is factor h important1
Why is factor H important?
  • It is associated with human disease:

‘protective’ and ‘at risk’

polymorphisms

common

mutations

rare

Atypical haemolytic uraemic syndrome

Dense deposit disease

atypical haemolytic uraemic syndrome
Atypical Haemolytic uraemic syndrome

Alternative pathway dysregulation

  • Associated with:
  • COMPLEMENT MUTATIONS
  • Loss of function mutations in regulators
  • Factor H
    • Mutations
    • Hybrid gene (copy number variation)
  • Factor I
  • MCP (CD46)
  • Gain of function mutations in activation proteins
  • C3
  • Factor B
  • ACQUIRED COMPLEMENT DYSREGULATION
  • Anti-factor H autoantibodies

renal thrombotic microangiopathy

Atypical haemolytic uraemic syndrome

atypical haemolytic uraemic syndrome factor h mutations

C3

MAC

C5a

C3bBb

B, D

C5 activation

C3b

C3b

C3b

C3b

C3b

iC3b

Atypical Haemolytic uraemic syndrome – factor H mutations

C3 regulation

Surface recognition

Factor I

C3b

CD46

HOST SURFACE

RENAL ENDOTHELIUM

murine model of factor h associated atypical haemolytic uraemic syndrome

100

75

Plasma C3 - mg/l

50

25

0

Cfh-/-

Cfh-/-FH16-20

Murine model of factor H-associated atypical haemolytic uraemic syndrome
  • Gene-targeted factor H-deficient mice transgenically expressing a mutant mouse factor H protein (FH16-20)

Mutated mouse FH16-20

wild-type mouse CFH

Renal histology in Cfh-/-.FH16-20

murine model of factor h associated atypical haemolytic uraemic syndrome1
Murine model of factor H-associated atypical haemolytic uraemic syndrome
  • Use this model to determine contribution of C5 activation to renal injury
  • Spontaneous renal disease does not occur in C5-deficient Cfh-/-FH16-20 animals
murine model of factor h associated atypical haemolytic uraemic syndrome2
Murine model of factor H-associated atypical haemolytic uraemic syndrome
  • Cfh-/-FH16-20 animals are hypersensitive to experimentally triggered renal injury – this injurious response is C5 dependent

C3

C9

atypical haemolytic uraemic syndrome therapy
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
  • Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma Therapy-sensitive / -resistant Atypical Hemolytic Uremic Syndrome (aHUS)
    • Successful outcomes announced in ASN 2010 meeting
    • http://clinicaltrials.gov/ct2/results?term=eculizumab
why is factor h important2
Why is factor H important?
  • It is associated with human disease:

‘protective’ and ‘at risk’

polymorphisms

common

mutations

rare

Atypical haemolytic uraemic syndrome

Dense deposit disease

factor h and amd the y402h polymorphism
Factor H and AMD – the ‘Y402H’ polymorphism

From Sofat et al., Atherosclerosis 213 (2010) 184-90

factor h and age related macular degeneration1
Factor H and Age-related macular degeneration

Alternative pathway dysregulation

  • Associated with:
  • Polymorphic variants in:
  • Regulators
  • Factor H Y402H ‘at risk’
          • V62I ‘protective’
  • activationproteins
  • C3 C3FF ‘at risk’
  • Factor B Bf32Q ‘protective’

Ocular drusen

Age-related macular degeneration

factor h and age related macular degeneration2
Factor H and Age-related macular degeneration

62Valine

62Isoleucine

Age-related macular degeneration

Functional differences in

the Valine62Isoleucine CFH

polymorphism

62Isoleucine more efficient

at preventing red cell lysis

14nM vs. 22.6nM at 50% lysis

complement dysregulation and eye disease age related macular degeneration
Complement dysregulation and eye disease – age-related macular degeneration

Factor H 402Y*

Factor H 62I

Factor B 32Q

C3S

CFHR1/3 deletion*

Factor H 402H*

Factor H 62V

Factor B 32R

C3F

Factor H null alleles

C3 3923∆DG

‘protective’

polymorphisms

‘at risk’

polymorphisms

mutations

alternative pathway activation

DDD retinopathy

Ocular drusen

Age-related macular degeneration

Dense deposit disease

*functional consequences not understood

why is factor h important3
Why is factor H important?
  • It is associated with human disease:

‘protective’ and ‘at risk’

polymorphisms

common

Age-related macular degeneration

Meningococcal sepsis

mutations

rare

Atypical haemolytic uraemic syndrome

Dense deposit disease

why are the factor h related proteins important
Why are the factor H-related proteins important?
  • They are associated with human disease:

‘protective’ and ‘at risk’

polymorphisms

common

mutations

rare

the factor h family copy number variation
The factor H family: copy number variation

CFH

CFHR4

CFHR2

CFHR5

Most frequent CFH-CFHR allele

CFH

CFHR3

CFHR1

CFHR4

CFHR2

CFHR5

CFHR1-3 deletion allele polymorphism (common)

Deletion homozygotes: African American 16%

Hageman et al, Ann. Medicine 2006 European Americans 4.7%

Others (uncommon - <1%)

CFH

CFHR1

CFHR4

CFHR2

CFHR5

CFH

CFHR3

CFHR2

CFHR5

CFH

CFH

CFHR3

CFHR3

CFHR1

CFHR3

CFHR4

CFHR1

CFHR2

CFHR4

CFHR5

CFHR2

CFHR5

CFH

CFHR3

CFHR1

CFHR1

CFHR4

CFHR2

CFHR5

why are the factor h related proteins important1
Why are the factor H-related proteins important?
  • They are associated with human disease:

‘protective’ and ‘at risk’

polymorphisms

CFHR1-3 deletion allele polymorphism

associated with protection against AMD

Mol Immunology 44 (2007):3921.

common

Age-related macular degeneration

complement therapeutics
Complement therapeutics

Pathologies in which complement is activated

complement therapeutics1
Complement therapeutics

Examples of the many complement inhibitors in development

Eric Wagner and Michael Frank Nature Reviews 2010, vol. 9, 43-56.

thanks
Thanks
  • Elena Goicoechea de Jorge
  • Katherine Vernon
  • Mitali Patel
  • Kirsten Rose
  • Talat Malik
  • Sharmal Narayan
  • Marieta Ruseva
  • Tamara Montes
  • Lola Sanchez-Nino
  • Danielle Paixao-Cavalcante
  • Fadi Fakhouri
  • Terence Cook
  • Marina Botto
  • Santiago Rodriguez de Cordoba
  • Veronique Fremeaux -Bacchi
  • Patrick Maxwell
  • Danny Gale
ad