Aims

• Describe the activation of the complement cascade via:– Classical pathway

– Alternative pathway

• Explain how activation of the complement cascade can impact other immunologic processes.

• Describe clinical implications of complement deficiencies.

• Readings: Abbas & Lichtman, Chapter 8

The Complement Activation Pathways

• There are three activation pathways – Classical - C1, C4, C2, C3– Alternate - properdin pathway– Mannose binding lectin or Lectin – uses MBL to

initiate the pathway

• All three activation pathways result in the formation of C3 & C5 convertases

• They converge at a single terminal pathway

Classical Pathway

RBC

bacteria

EC

antibody

Classical Pathway• C1 complex

– C1q has the antibody binding sites– C1r and C1s are serine proteases

C1-Inhibitor is released upon binding to Ab and this activates C1r & C1s.

Roitt’s Essential Immunology 2-2

C1C1sC1r

C1q

C1’C4a

C4b

C1’

C4b

C1’C2a

C2b

C4b

C1’

C4b2b

C3 Convertase

a b

C3

C1’

C4b2bC3a

C3b

Explosive amplification

C1’

C5 Convertase

C4b2b3bba

C5

C1’

C4b2b3bC5b

C5a

C1’

C4b2b3b C5b

C4b2b3b C5b

6 7

8

99 9 9

9999

K+Na+ and H2O

Membrane Attack Complex

Terminal Pathway

Activators of the Alternative Complement Pathway

• Anything that hydrolyzes C3– leukocyte proteases– plasmin– bacteria or bacteral products (LPS, bacterial cell

wall components)– aggregated IgA– cobra venom factor– Cellophane– Water “Ticking over”

Alternative Pathway

C3RBC

bacteria

EC

Alternative Pathway

C3aRBC

bacteria

EC

C3b

Alternative Pathway

RBC

bacteria

EC

C3bC3bC3b

Alternative Pathway

bacterium

C3bbaFactor B

Factor D

Alternative Pathway

bacterium

C3bBbBa

Alternative Pathway

bacterium

C3bBb

Properdin

C3b

C3a

C3 Convertase

Alternative Pathway

Roitt’s Essential Immunology 2-3

Alternative Pathway

bacterium

C3bBb

Properdin

C3b

C3a

C3 binding and cleavage is repeated over and over (explosive amplification)

Alternative Pathway

bacterium

Properdin

C3bnBb

C5 Convertase

Alternative Pathway

bacteriumProperdin C3bnBb

C5 Convertase

C5b

C5a

C5b

6 7

8

99 9 9

9999

K+Na+ and H2O

Membrane Attack Complex

C3bnBb

Terminal Pathway

Terminal Pathway• Formation of

the MAC is identical in classical and alternative pathway once C5 convertase is formed.

Abbas & Lichtman’s Basic Immunology 8-6

Lectin Pathway

RBC

bacteria

EC

MBL

Mannose Binding Lectin (MBL) binds terminal mannose residues of proteins and polysaccharides found on bacteria.

MBL

Terminal Mannose residues

Only real difference from the classical pathway is that MBL is substituted for C1 complex during initiation.

C1’

C4b2b3b C5b

Complement Pathway Regulation

• C3b by itself has a short half-life (s)

• C3b inactivator (Factor H, DAF, and Factor I)– Break apart stable structures and enzymatically cleave C3b

• C1 Inhibitor– Regulates classical pathway by dissociating C1r and C1s from C1q

– Can also regulate Lectin pathway by dissociating components of MBL

C5b6

7

8

9999

9999

C1’

C4b2b3b C5b

Complement Pathway Regulation

• C4 binding protein– Breaks apart C4b2b (classical C3 convertase)

• Anaphylatoxin inactivator or serum carboxypeptidase B – Removes terminal arginine residue from C3a,C4a, and C5a.

• Vitronectin (S protein)– Serum protein which can bind C567 preventing complete MAC formation

C5b6

7

8

9999

9999

Cells with Complement Receptors

ReceptorSpecificity Functions Cell typesCR1 C3b, C4b stimulates phagocytosis RBCs, M, PMN,

B cellsremoval of IC by RBCs

CR2 C3b, EBV B cell receptor complex B cellsEpstein-Barr virus receptor

CR3 C3b stimulates phagocytosis M, PMNs

CR4 C3b stimulates phagocytosis M, PMNs

C1q C1q binds IC to phagocytes B cells, M, platelets

endothelial cells

Complement Deficiencies

• Deficiency of early cascade members (C1, C4, C2, and C3)– Deficiency in opsonization

• Poor phagocytosis resulting in increased infection with encapsulated bacteria.

• Poor clearance of IC associated with autoimmune diseases.

Complement Deficiencies

Type I Hereditary angioedema – Stress and trauma provoked vasodilatation and

edema usually of the skin, extremities, or GI mucosa.

– Can be fatal if it involve larynx resulting in asphyxiation.

– Deficiency of C1INH• spontaneous generation of bradykinin• spontaneous activation of C1 C4a• production of C2a C2a kinin

Complement Deficiencies

• Deficiency of late cascade members (C5, C6, C7, C8 and C9)– Deficiency in the formation of MAC– C5, C6, C7 or C8 deficiency results in difficulty

killing gram negative bacteria (Neisseria meningitidis)

Summary

• Complement is a group of serum proteins – activated in an orderly fashion from inactive forms. This leads to “spin-off” peptides that have biological activity.

• Three main activation pathways and one terminal pathway that leads to the formation of the MAC.

• Complement activation is highly regulated.• Possession of complement component receptors lends

cells certain biological activities through interaction with complement.

• Deficiencies in complement components exist.

Next Lecture

• Antigen capture and presentation

• Exogenous and Endogenous antigens.

• Readings: Abbas & Lichtman, Chapter 3

Objectives

1. Describe the similarities and differences between the 3 complement cascade activation pathways.

1. Classical2. Alternative3. Lectin (Mannose Binding Lectin)

2. Describe complement regulation and deficiencies.