Complement Activation Pathways: Key Mechanisms in Immune Defense

The complement system is a key part of the immune response, made up of proteins that eliminate pathogens. It is activated through three main pathways:

Classical Pathway: Triggered by antibodies bound to antigens on a pathogen's surface.
Lectin Pathway: Initiated by mannose-binding lectin binding to sugars on pathogens.
Alternative Pathway: Activated spontaneously on pathogen surfaces without antibodies.
All pathways converge to form C3 convertase, leading to the destruction of pathogens by marking them for immune attack and creating pores in their membranes. This process enhances the body's ability to fight infections quickly and effectively.

1. Elective Seminar Topic - Complement Activation Pathways Presented by- Deepanshi M.Sc. Microbiology(2nd Sem)

2. Complement A group of proteins which are present in blood in inactive state. These groups of proteins are mainly synthesized by hepatocytes and some by blood monocytes, macrophages and epithelial cells of GI tract and genitourinary tract. They are designated as - Numerals - C1, C2, C3, C4, -------C9 letter Symbols - factor D trivial name - homologous restriction factor

3. Complement Activation Complement Activation pathway involve the activation of one component that triggers the activation of the next component in the sequence. Upon activation, individual components are split into two fragments - designated by lower case letters. Smaller cleaved fragment is designated with ‘a’ while large fragment with ‘b’. Exception in case of C2. The larger fragment bind to target near activation site while small fragment diffuse from site and initiate localized inflammatory responses.

4. Three Pathways of Complement Activation Classical Pathway Alternative or Properdin Pathway Lectin Pathway

5. It initiates with the formation of Ag-Ab complex induces conformational changes on Fc of Ab to which C1 binds. C1q of C1 binds to the Fc region of Ab. This activates C1r that activate the another C1r, and both activate C1s. C1s cleaves C4 and C2. First, cleaving C4 exposes the binding site for C2. C4b binds to C1 and the C2 proenzyme then attaches to exposed binding site on C4b, here the C2 is then cleaved by neighbouring C1s, the smaller fragment diffuses away. Classical Pathway It commonly begins with the formation of Ag-Ab complex. Thus, this pathway is a major effector pathway of humoral adaptive immune response. Steps of Classical Pathway

6. The resulting C4b2a complex is called C3 Convertase. C3 Convertase converting C3 into an active form C3b. C3b binds to C4b2a to form a trimolecular complex C4b2a3b called C5 Convertase. C3b component of C5 convertase binds to C5 and alter its confirmation, then C4b2a component cleaves C5 into C5a and C5b. The terminal sequence of complement activation pathway involves C5b, C6, C7, C8, C9, which interact sequentially to form a macromolecular structure called Membrane Attack Complex (MAC). Steps of Classical Pathway

7. This pathway is Ab independent. This pathway is generally trigerred by LPS from outer membrane of gram negative bacteria, cell wall of some yeasts, tumor antigen and a protein present in cobra venom, known as cobra venom factor. This pathway is an effector arm of innate immune defenses. The major pathway of complement activation involves four serum proteins - C3, factor B, factor D and Properdin (Factor P). Alternate/Properdin Pathway

8. Serum C3 is subjected to spontaneous hydrolysis to yield C3a and C3b. The C3b component can bind to foreign surface Ags or host‘s own cell. The C3b present on surface of foreign cells can bind another serum protein called factor B to form a complex stabilized by Mg2+. Binding of factor B to C3b serves as the substrate for an enzymatically active serum protein called factor D. factor D cleaves the C3b bound factor B, releasing a small fragment (Ba) that diffuses away and generating C3bBb (C3 Convertase). Properdin binds with C3 convertase and stabilize it. C3 Converatse convert the C3 into its active form. C3b binds to C3 Convertase to form C5 Convertase(C3bBb(3b)n). C5 Convertase convert the C5 into C5a and 5b The terminal sequence of complement activation pathway involveC5b, C6, C7, C8, C9, which interact sequentially to form a Macromolecular structure called Membrane Attack Complex (MAC). Alternate/Properdin Pathway

9. Lectin is a protein that recognize and bind to specific carbohydrate target. The lectin pathway is activated by terminal mannose residues of glycoprotein or polysaccharide found on the surface of Bacteria. Mannose Binding Lectin (MBL) binds to the mannose residues to initiate the lectin pathway. Lectin Pathway

10. Steps of Lectin Pathway

11. Thankyou