Download - Role of Complement in TMA-mediated diseases …...Nephrology De afbeelding kan niet worden weergegev en. Mogelijk is er Alexion Antwerp 2012 Role of Complement in TMA-mediated diseases

Nephrology

De afbeelding kan niet worden weergegeven. Mogelijk is er

Alexion Antwerp 2012

Role of Complement in TMA-mediated diseases Mohamed R Daha [email protected]

Nephrology


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


What is Complement?

Nephrology


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


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


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


Covalent C3 deposition

C3b

C3b

Amplification

C3b

iC3b

C3dg

Terminal activation

Cellular interactions

Nephrology


The complement system

C3 Classical pathway

Lectin pathway

Alternative pathway C3b

C3a C5b-9

Terminal pathway

Nephrology


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


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


Membrane-bound regulators of complement

From: Kim et al,

Clinical Immunology

Nephrology


Homeostasis of AP C3 activation in vivo

C3b

C3

C3bBb P

iC3b

H

I

Nephrology


Stabilisation of C3bBb by C3 -Nephritic factor

C3b

C3

C3bBb

iC3b

H

I

C3Nef

X

MPGN and PLD

Nephrology


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

C3b

C3

C3bBb

iC3b

H

I

X

Nephrology


Increased C3bBb function by gain of function C3 and B mutations

C3b

C3

C3bBb P iC3b

H

I

X

Nephrology


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

C3b C3

H

I

C3a + convertases

iC3b

C3c C3d

Nephrology


Uncontrolled Complement Activation

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

Nephrology


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


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


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


Shiga Toxin Directly Activates Complement - Causing Systemic Multiple Thromboses, Inflammation and Occlusion of Small Vessels

Adapted from Zipfel PF et al. Current Opinions in Nephrology and Hypertension 2009, 19:372-378; Desch et al JASN. 2007; 18:2457-60. Licht C et al Blood 2009 114:4538-4545; Noris et al NEJM. 2009; 361: 1676-87; Stahl et al Blood 2008; 111(11)5307-15; Morigi et al J Immunol 2011 ePub 3 June

Endothelial Activation

Platelet

Platelet Activation Leukocyte

Activation

Uncontrolled Complement

Activation

Endothelial swelling and disruption Platelet consumption

Mechanical hemolysis

Blood clot formation Vessel occlusion Inflammation

Ischemia Hypoxia

Platelet aggregation

Inhibition of Factor H

Shiga toxin

Nephrology


Treatment of diseases with uncontrolled activation of complement

-Several complement inhibitors - Eculizumab

Nephrology


Eculizumab Blocks Terminal Complement

Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395. Walport MJ. N Engl J Med. 2001;344(14):1058-66. Soliris® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2011. Rother RP et al. Nature Biotech. 2007;25(11):1256-64.

§  Proximal functions of complement remain intact •  Weak anaphylatoxin •  Immune complex clearance •  Microbial opsonization

§  Terminal complement - C5a and C5b-9 activity blocked

§  Eculizumab binds with high affinity to C5

CH

2 C

H3

Eculizumab

Nephrology

De afbeelding kan niet worden weergegeven. Mogelijk is er Rother et al. Nat Biotech. 2007;25:1256-1264.

Sustained Inhibition of Complement-Mediated Hemolysis as Measured by LDH in PNH Patients Treated with Eculizumab

Eculizumab

Nephrology


The Complement Balance

Risk Activation

Lack of Inhibition

Inflammation Lysis Cell Damage

Inhibition Activation

Zipfel PF Immunol Lettr. 2009 126:1-7

Health