Complement System Regulation

Complement System Regulation

• C1-INH removes activated C1qrs complexes from surfaces and blocks further activation.
• Clusterin and S protein are regulators of the terminal activation cascade of complement, binding to C5b-7 complex and preventing the insertion of C8 and C9, leading to the inhibition of MAC formation.

Membrane Bound Regulators

• Complement receptor 1 (CR1) is expressed by many cells, including erythrocytes and lymphocytes, and has a decay accelerating activity towards C3 and C5 convertases.
• CR1 serves as a cofactor for factor I, which degrades C3b and C4b.
• Membrane cofactor protein (MCP) binds to C3b and acts as a cofactor for factor I, facilitating the inactivation of C3b.
• CD59 is a regulator of the MAC that binds to C8 and C9, and subsequently inhibits binding to C5b-7 and formation of MAC.
• Decay accelerating factor (DAF) is attached to cell membranes and dissociates C3 and C5 convertases.

Phagocytosis and Opsonization

• Phagocytosis is the engulfing and ingestion of bacteria or other foreign bodies by phagocytes.
• Opsonization is the process by which bacteria are labeled in such a manner that they become more efficiently engulfed by phagocytes.

Role of Complement System

• The complement system plays a crucial role in the immune response.

Complement Regulation

• Fluid phase regulators:
  • Complement C1 inhibitor (C1-INH)
  • C4 binding protein (C4bp)
  • Factor H
  • Clusterin and S protein
• Membrane bound regulators:
  • Complement receptor 1 (CR1)
  • Protectin (CD59)
  • Membrane cofactor protein (MCP)
  • Decay accelerating factor (DAF)
  • Complement factor I

Complement Factor I

• Soluble glycosylated serine protease found in plasma
• Protects host cells from complement-mediated attack
• Cleaves C3b and C4b, generating iC3b and iC4b, and prevents complement convertases formation

Factor H

• Main fluid phase regulator of the alternative pathway
• Accelerates the decay of the alternative pathway C3 convertase (C3bBb) by binding to C3b and removing it from the complex
• Acts as a cofactor in the factor I-mediated conversion of C3b to iC3b, C3c, and C3dg

C4 Binding Protein (C4bp)

• Major regulator of the complement system
• Binds with C4b and inhibits its binding with C2, preventing the formation of C3 convertase
• Acts as a cofactor in the factor I-mediated conversion of C4b to iC4b, C4e, and C4d

Complement C1 Inhibitor (C1-INH)

• Serine protease inhibitor that binds to C1 complex and prevents spontaneous activation of the proenzymes C1r and C1s
• Forms a complex with active enzymes to trap and inactivate them

Lectin Pathway of Complement Activation

• Homologous to the classical pathway, differing only in the complement initiator molecular complexes
• Ag-Ab independent
• Initiated by mannan-binding lectin (MBL), ficolins, or collectins complexes that encounter microbial carbohydrates or N-acetyl groups decorating the surface of a pathogen (PAMP)
• This binding leads to the activation of the MBL-associated serine proteases (MASPs), of which MASP-2 acts on C4 and C2 in a similar manner to C1s in the classical pathway, resulting in the formation of the C3-convertase

Lectin Pathway Recognition Molecules

• Mannan binding lectin (MBL) binds to carbohydrates on the surface of cells
• Ficolins:
  • L-ficolin (serum protein)
  • H-ficolin (serum protein)
  • M-ficolin (found in monocytes and neutrophils)
• Collectins:
  • Collectin liver 1 (CL-10)
  • Collectin kidney 1 (CL-11)
  • Collectin placenta 1 (CL-12)