THE COMPLEMENT SYSTEM

The complement system The complement system is a set of plasma proteins that act in a cascade to attack and kill extracellular pathogens. Approximately 30 components: –activating molecules –complement receptors –regulator factors –membrane proteins wich inhibit the lysis of host cells Most of the complement proteins and glycoproteins are produced in the liver in an inactive form (zymogen). Activation is induced by proteolitic cleavage.

Amplification of the complement cascade inactive precursors limited proteolysis activating surface enzyme Activating surface needed!

Pathways of complement activation Cellular and Molecular Immunology, 7th ed., 2014 Elservier

INITIATION OF THE CLASSICAL PATHWAY

C1 is always present in serum but it can operate only on an activating surface Low affinity binding to the Fc region of antibody  conformational change  activation Multiple interaction with immune complexes Collagen „legs” Gobular „heads” The C1 complex

C-reactive protein also activates the classical pathway

At least two molecules of IgG bound to pathogens or soluble antigens are required to activate the complement cascade

Different isotypes of antibodies activate the complement system differently

Binding of IgM to antigen on a pathogen’s surface initiates the classical pathway of complement activation

INITIATION OF THE LECTIN PATHWAY

Mannose Eukaryotic cells Glucoseamine Mannose Galactose Neuraminic acid (sialic acid) Glycosylation of proteins is different in various species Prokaryotic cells

Mannose-binding lectin and ficolin bind mannose and N-acetylglucosamin, respectively Cellular and Molecular Immunology, 7th ed., 2014 Elservier

The activated MBL complex cleaves C4 and C2 to produce C4b and C2a, which associate to form the classical C3 convertase

INITIATION OF THE ALTERNATIVE PATHWAY

C3, the central component of the complement system ( molecules/ml) Strong covalent binding

C3b can derive from classical or the lectin pathway too Alternative pathway is instantly inactivated on eukariotic cell surfaces (in the presence of sialic acid molecules) Formation and action of the soluble C3 convertase that initiates the alternative pathway of complement activation

The early steps of complement activation by the alternative, classical, and lectin pathways Cellular and Molecular Immunology, 7th ed., 2014 Elservier

Complement receptors on phagocytes trigger the uptake and breakdown of C3b-coated pathogens

C3a and C5a contribute to local inflammatory responses

The membrane-attack complex (MAC) assembles to generate a pore in the lipid bilayer membrane

Membrane attack complex (MAC)

SUMMARY

Cellular and Molecular Immunology, 7th ed., 2014 Elservier Complement receptors

REGULATION OF THE COMPLEMENT SYSTEM

C1 inhibitor (C1INH) binds to C1r and C1s and dissociates them from C1q

C1 inhibitor (C1INH) permanently inhibits C1r and C1s

Formation and stability of the alternative C3 convertase on cell surfaces is determined by complement control proteins DAF: decay-accelerating factor MCP: membrane cofactor protein Factor H inhibits binding of only Bb to C3b and is thus a regulator of the alternative but not the classical pathway DAF and MCP also disrupt C3 convertase C4b2a

C4-binding protein (C4BP) can also serve as cofactor for factor I–mediated inhibition of C3 convertase

CD59 prevents assembly of the membrane attack complex on human cells

DAF C1Inh Properdin positive feedback Factor I CR1MCP C4BP Factor I F act -H CR1MCPDAF CD59 LECTIN PATHWAY Regulation of complement system membrane protein soluble molecule

Deficiencies of complement system – cascade molecules

Deficiencies of regulatory molecules, receptors