Cellular & Molecular Cellular & Molecular ImmunologyImmunology

20092009

ComplementComplement

Nicholas M. Ponzio, Ph.D.Nicholas M. Ponzio, Ph.D.Department of Pathology & Laboratory MedicineDepartment of Pathology & Laboratory Medicine

March 4, 2009March 4, 2009

Innate and adaptive immunity

FAMOUS BELGIANS

Jules Jean Baptiste Vincent BORDET(1870-1961)

Lysis of Vibrio cholera by immune serumExperiment #1

Since antibodies are heat stable, Bordet concluded that a heat labile substancewas needed in addition to antibodies to cause lysis

Fresh normal serum no lysisFresh immune serum lysisHeated immune serum no lysis

Lysis of Vibrio cholera by immune serumExperiment #2

Conclusion: A heat labile substance in normal serum “complements” the ability of antibodies in immune serum to lysetargets

Proof of Principle:Heated immune serum

+ fresh normal serum LYSIS

What is Complement ?• C is a complex series of proteins in the blood

• These proteins are sequentially activated (aka, fixed), and they non-specifically “complement” the action of antibodies

• In the process of being activated, the C proteins are cleaved into a major fragment and a minor fragment (aka, split product)

• These fragments are responsible for the observed biological functions of C

Biological Functions of C• Opsonization and Phagocytosis

Microbes coated with C componentsare ingested more efficiently

• Stimulation of InflammationC products can induce acute inflammation

• CytolysisC can cause lysis of microbes

• C activation involves the sequential proteolysis of proteins to generate enzymes with proteolytic activity

• C products attach to microbial surfaces or to antibodies that are bound to microbes

• C activation is inhibited by regulatory proteins present on host cells, but absent from microbes

To perform these functions:

Fig. 12-8 Pathways of Complement Activation

Structure of Complement Component C1

Classical pathway of complement activation

C2b

C2b

C4b2b

C4b2b

C5a

Structure of Complement Component C1

The C1 component of complement

Activation of complement by IgM and IgG antibodies

Fig. 12-8 Pathways of Complement Activation

Thioester bond of C3

Alternative pathway of complement activation

C5a

Late steps of complement activation:Formation of the membrane attack complex (MAC)

Electron micrographs of Membrane Attack Complex inserted into the cell membrane

MHC IMHC II

MHC I

MHC II

Table 14-6 Receptors for Fragments of C3

Co-receptor for B cell activation; Trapping of antigens in germinal centers; Receptor for EBV

B Cells, Follicular Dendritic Cells,

Type 2 (CR2, CD21)

Phagocytosis; Clearance of immune complexes; Promotes dissociation of C3 convertasesby acting as cofactor for cleavage of C3b, C4b

Mononuclear phagocytes, neutrophils, B and T cells, RBCs, FDCseosinophils,

Type 1 (CR1, CD35)

FunctionDistributionReceptor

Table 14-6 Receptors for Fragments of C3

Phagocytosis; Leukocyte adhesion

Mononuclear phagocytes, neutrophils, NK cells

Type 4 (CR4, CD11c/18)

Phagocytosis; Leukocyte adhesion to endothelium (via ICAM-1)

Mononuclear phagocytes, neutrophils, NK cells

Type 3 (CR3, CD11b/18)

FunctionDistributionReceptor

Regulation of complement activation by C1 inhibitor

Classical pathway of complement activation

Cleavage of C3b by Factor I

Inhibition of the membrane attack complex

Functions of the Complement

System

Functions of the Complement

System

Functions of the

Complement System

C3a & C5a = Anaphylatoxins

Functions of the Complement

System

Additional functions of the complement system:

• Trapping of IC in germinal centers – C receptors on Follicular Dendritic Cells bind IC and present antigen to B cells during humoral immune responses.

• B cell activation – C3d (cleavage product of C3b) binds to C receptors on B cells, providing a signal to initiate B cell activation during humoral immune responses.

9-5

• Classical Pathway:C1q, C1r, C4, C2, C3 (C2 most common)C2 & C4 -- autoimmune diseases

(e.g., SLE)C3 -- gram+ bacterial infections

• Alternative Pathway:Properdin & Factor D -- gram+ infections

• Membrane Attack Complex (MAC):C5 - 9 -- Neisseria bacterial infections

Complement Deficiencies