Academic trainees meeting 5 th may 2011
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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.

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Academic Trainees Meeting – 5 th May, 2011

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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 age related macular degeneration

Factor H and Age-related macular degeneration


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

  • C3C3FF ‘at risk’

  • Factor BBf32Q ‘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


    Factor h and susceptibility to meningococcal infection

    Factor H and susceptibility to meningococcal infection

    Meningococcal sepsis


    The factor h family

    The factor H family


    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 2006European Americans4.7%

    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


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