Role of Complement in TMA-mediated diseases ... Nephrology De afbeelding kan niet worden weergegev...

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Transcript of Role of Complement in TMA-mediated diseases ... Nephrology De afbeelding kan niet worden weergegev...

  • Nephrology

    De afbeelding kan niet worden weergegev en. Mogelijk is er

    Alexion Antwerp 2012

    Role of Complement in TMA-mediated diseases Mohamed R Daha m.r.daha@lumc.nl

  • Nephrology

    De afbeelding kan niet worden weergegev en. Mogelijk is er

    Uncontrolled Complement Activation is Central to Many Diseases

    Dense deposit disease (MPGN II)

    Membranoproliferative glomerulonephritis I (MPGN I)

    IgA Nephropathy

    Antibody mediated rejection

    Age-related macular degeneration (AMD)

    Neuromyelitis optica

    Catastrophic anti-phospholipid syndrome (CAPS)

    Psoriasis

    Myasthenia gravis

    Paroxysmal nocturnal hemoglobinuria (PNH)

    Hemolytic uremic syndrome (aHUS and STEC-HUS)

    Sepsis, anaphylaxis, homeostasis

    Ischemia-reperfusion injury

    Cold agglutinin disease (CAD)

    Autoimmune hemolytic anemia (AIHA)

    Paroxysmal cold hemoglobinuria (PCH)

    Systemic lupus erythematosus (SLE)

    Rheumatoid arthritis

    Myocardial infarction

    Schrezenmeier H Transf and Apheresis Sci 2011 Dec EPub; Holers VM et al Immunol Rev 2008; 223:300-316

  • Nephrology

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    What is Complement?

  • Nephrology

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    Innate and acquired immunity

    Cells:

    NK cells macrophages dendritic cells granulocytes

    Cells:

    T lymphocytes B lymphocytes

    Soluble mediators: Cytokines

    Chemokines Defensins Pentraxins

    Complement Etc.

    Soluble products: Cytokines

    Chemokines

    Antibodies

    Innate immunity Acquired immunity

  • Nephrology

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    Biological functions of complement

    •  Direct pathogen elimination

    •  Induction of phagocytosis via opsonization

    •  Induction of inflammation and chemotaxis

    •  Interface between innate and adaptive immunity

    •  Clearance of immune complexes and self debris

  • Nephrology

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    Three activation pathways of the complement system

    C3a

    C5b-9

    Classical pathway

    Lectin pathway

    C3

    C3b

    (C1q, C1r, C1s, C4, C2)

    (MBL,Ficolins, MASPs, C4, C2)

    Alternative pathway (Properdin, factor B and D)

    Terminal pathway

  • Nephrology

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    Covalent C3 deposition

    C3b

    C3b

    Amplification

    C3b

    iC3b

    C3dg

    Terminal activation

    Cellular interactions

  • Nephrology

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    The complement system

    C3 Classical pathway

    Lectin pathway

    Alternative pathway C3b

    C3a C5b-9

    Terminal pathway

  • Nephrology

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    Regulation of Complement activation

    Regulation of Complement activation occurs at least at three levels: In the fluid Phase At the tissue level And is also determined by the integrity of the tissue itself( apoptosis or necrosis)

  • Nephrology

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    Fluid phase complement regulators

    Molecules •  C1 inhibitor •  C4 binding protein •  Factor H •  Factor I

    Level of inhibition C1r, C1s, MASP's C4b, C4b2a C3b, C3bBb C4b, C3b

  • Nephrology

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    Membrane-bound regulators of complement

    From: Kim et al,

    Clinical Immunology

  • Nephrology

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    Homeostasis of AP C3 activation in vivo

    C3b

    C3

    C3bBb P

    iC3b

    H

    I

  • Nephrology

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    Stabilisation of C3bBb by C3 -Nephritic factor

    C3b

    C3

    C3bBb

    iC3b

    H

    I

    C3Nef

    X

    MPGN and PLD

  • Nephrology

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    Prolonged C3bBb function by reduced or inhibited function of I and H

    C3b

    C3

    C3bBb

    iC3b

    H

    I

    X

  • Nephrology

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    Increased C3bBb function by gain of function C3 and B mutations

    C3b

    C3

    C3bBb P iC3b

    H

    I

    X

  • Nephrology

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    Ratio of C3/3d is a good diagnostic measure of hypercatabolism of C3

    C3b C3

    H

    I

    C3a + convertases

    iC3b

    C3c C3d

  • Nephrology

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    Uncontrolled Complement Activation

    -Systemic Thrombotic Microangiopathies -Atypical HUS -STEC HUS -Paroxysmal Nocturnal Hemoglobunuria

  • Nephrology

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    Chronic Uncontrolled Complement Activation Leads to Vasoconstriction and Thrombosis

    Adapted from Zipfel PF et al. Current Opinions in Nephrology and Hypertension 2009, 19:372-378, Gladwin MT et al. Free Rad Biol & Med. 2004;36(6):707-717; Rother RP et al. JAMA. 2005;293:1653-1662.

    CLOT Platelet Activation

    Leukocyte Activation

    Chronic Uncontrolled Complement

    Activation

    C5a

    C5b-9

    C5b-9

    [NO]ò • Impaired regulation of smooth muscles • Local vasoconstriction • Pro-inflammatory effect on endothelial cells

    Inflammation Platelet Aggregation

    Chronic Hemolysis

    Chronic hemolysis Local vasoconstriction

    Inflammation Systemic thrombosis

  • Nephrology

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    PNH: Chronic Uncontrolled Complement Activation Leads to Vasoconstriction and Thrombosis – Systemic Manifestations

    • Chronic uncontrolled complement activation results in • Chronic Hemolysis, Platelet Activation, Systemic Thrombosis,

    Renal Impairment, Pulmonary Hypertension

    Chronic Kidney Disease § Renal insufficiency § Dialysis § Hypertension

    End-Organ Damage § Brain § Liver § Gastrointestinal (GI)

    Anemia § Transfusions § Hemosiderosis

    Fatigue / Impaired Quality of Life

    § Abdominal pain § Dysphagia § Poor physical functioning § Erectile dysfunction

    Pulmonary Hypertension § Dyspnea § Cardiac Dysfunction

    Thrombosis Venous § PE/DVT § Cerebral § Dermal § Hepatic/Portal § Abdominal ischemia

    Arterial § Stroke/TIA § MI

    1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R. Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz;S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; p. 419-427. 3. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 4. Rosse W et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62. 5. Rother R et al. JAMA. 2005;293:1653-1662. 6. Socie G et al. Lancet. 1996;348:573-577. 7. Hill A et al. Br J Haematol. 2007;137:181-92. 8. Lee JW et al. Hematologica 2010. 95 (s2): Abstract #505 and 506. 9. Hill A et al. Br J Haematol. 2010; May;149(3):414-25. 10. Hillmen P et al. Am. J. Hematol. 2010; 85:553–559.

  • Nephrology

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    Causes of Systemic Thrombotic Microangiopathy

    SYSTEMIC THROMBOTIC MICROANGIOPATHY: Multiple thromboses and inflammation throughout the body

    Cell surface and fluid phase complement inhibitors

    aHUS STEC-HUS TTP Genetic defect in complement regulation Shiga toxin Severe deficiency of ADAMTS13 activity

    §  Direct complement activation §  Interferes with Complement regulation §  Endothelial damage

    Uncleaved Long VWF Multimeric Strings

    Chronic uncontrolled complement activation

    Platelet, white blood cell and endothelial cell activation

    Platelets

    Uncleaved long VWF multimeric strings

    Adapted from Zipfel PF et al. Current Opinions in Nephrology and Hypertension 2009, 19:372-378

    Complement activation potentially by: -  platelet aggregates -  platelet microparticles -  P-selectin -  thrombi - injured endothelium

  • Nephrology

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    Shiga Toxin Directly Activates Compleme