Complement System Lecture Notes PDF

# Complement System ## Introduction - The complement system supports antibodies and phagocytic cells to remove pathogens from the body. - It consists of a number of heat-labile serum proteins, normally circulating as inactive precursors (proenzymes or zymogens). - It is a biochemical cascade. - It...

# Complement System ## Introduction - The complement system supports antibodies and phagocytic cells to remove pathogens from the body. - It consists of a number of heat-labile serum proteins, normally circulating as inactive precursors (proenzymes or zymogens). - It is a biochemical cascade. - It can be considered a link between innate and adaptive systems because it functions in both arms. ## Synthesis of Complement - The complement proteins are synthesized by: - Liver hepatocytes - Tissue macrophages - Blood monocytes - Epithelial cells of the genitourinal tract and GIT ## Components of Complement - The main components of the complement pathways are proteins called C1-C9 and others. - Peptide fragments formed by activation of complement (C2, C3, C4, C5, B) are denoted by small letters 'a & b', with the smaller fragment being 'a' and the larger fragment being 'b'. - The larger fragment (b) binds to the target near the site of activation and the smaller one (a) diffuses to produce other functions. ## Complement Activation - Complement activation occurs by three pathways: - Classical pathway - Alternative pathway - Lectin pathway - All three pathways have a common final pathway that leads to the formation of the membrane attack complex (MAC). - During complement activation, the released small fragments have different biological activities. ## The Classical Pathway - **C1** is formed of: - C1q - C1r2 - C1s2 - It is stabilized by Ca. ### Initiation - **C1q activation:** - C1q binds to (recognizes) the Fc region of IgM or IgG that is bound to antigens. - This binding leads to conformational changes in the C1q molecule, leading to the activation of two C1r molecules. - They then cleave two C1s. ### Pathway - C1qr2S2 splits C4 and C2, producing C4a, C4b, C2a and C2b. - C4b and C2b bind to form C4b2b (C3-convertase of the classical pathway). - C3-convertase (C4b2b) cleaves C3 into C3a and C3b. - C3b joins with C4b2b to make C4b2b3b (C5 convertase). ## Common Pathway - It starts with the production of the C5 convertase, which cleaves C5 into C5a and C5b. - C5b will bind to the surface of the target cell. - C5b binds to C6 (C5b6) unless it will be rapidly inactivated. - The reaction takes place on the hydrophilic surface of the cell membrane. - C7 binds to the C5b6, exposing the hydrophobic region. - C8 will bind to C5b67, again exposing the hydrophobic region. - C5b678 create a small pore that can lyse RBC but not nucleated cells. - The final step is binding of 10-14 molecules of C9 to the C5b678 complex to form the membrane attack complex (MAC), which is inserted into the cell membrane, punctures a hole, and initiates cell lysis by influx of water and loss of electrolytes (osmotic lysis). ## Alternative Pathway - It does not need an antibody for its activation, so it is a component of innate immune system. - It can be activated by one of the following factors: - LPS from Gm-ve bacteria - Teichoic acid from Gm+ve bacteria - Zymocan from fungal & yeast cell wall - Some viruses & virus infected cells - Many non-pathogenic antigens: Heterologous RBCs, Dextran sulfate, pure CHO (agarose, inuline) & copra venom factor. ### Pathway - Factor D cleaves factor B into Ba and Bb. - Bb will bind to C3b to the form C3bBb (C3-convertase). - This C3bBb is stabilized by properdin. - C3bBb will hydrolyse C3 in the blood into C3a and C3b (amplification). - Another C3b complex binds to the initial C3bBB to form the C5 convertase of the alternative pathway, C3bBbC3b. - After production of the C5 convertase, the common pathway will start and complete like previous. ## Activation of the Alternative Pathway - The alternative pathway is triggered when C3 directly recognizes certain microbial surface structures. - C3 is also spontaneously activated in solution at a low level and binds to cell surfaces but it is then inhibited by regulatory molecules present in mammalian cells. - Because microbes lack these regulatory proteins, the spontaneous activation can be amplified on microbial surfaces. ## Lectin (MPL) Pathway - Lectins are proteins that recognize and bind to specific CHO targets. - The lectin pathway is initiated by the binding of mannose-binding lectin (MBL) and ficolins to mannose residue on glycoproteins or CHO on the surface of microorganisms (e.g., Salmonella, Listeria, Neisseria, Candida, Cryptococcus and some viruses e.g., HIV 1). - MBL is a member of the collectin family and is a acute phase protein. Its function is similar to C1q of the classical pathway. ### Pathway - Binding of MBL to mannose residues on the pathogen surface activates the MBL-associated serine proteases, MASP-1 and MASP-2 (with enzymatic activity). - This active complex can cleave and activate C4 into C4a and C4b and C2 into C2a and C2b, forming C4b2b (C3-convertase), as in the classical pathway. ## Biological Effects of Complement Factors ### 1. Inflammatory Effect - Anaphylatoxins cause: - Contraction of smooth muscles - Increased permeability of blood vessels - Degranulation of basophils - Chemotaxis, release of O2-radicals, and lysosomal enzymes - **C3a, C4a, C5a** are all anaphylatoxins with different strengths of activity, with C5a being the strongest. ### 2. MAC Mediates Cell Lysis - The MAC is the terminal complex of the complement system and damages the membrane of cells. - This causes lysis of a variety of cells including: - Gram-negative bacteria - Parasites - Viruses - RBCs - Nucleated cells ### 3. Immune Clearance - The immune system recognizes antibody-antigen complexes as foreign agents and targets them for clearance. - Complement proteins help to remove immune complexes by depositing them in the spleen and liver to be removed by phagocytosis. ### 4. Opsonization (C3b & C4b) - C3b and C4b bind to bacteria, facilitating their phagocytosis by phagocytic cells. - Phagocytic cells have complement receptors (CR) for C3b and C4b, which promotes their phagocytosis ability. ### 5. Viral Neutralization - C3b mediates viral neutralization by coating it, preventing its binding to the host cell. - Complement is also effective in lysing most enveloped viruses. ### 6. Enhancement of Antibody Production - The binding of C3b to its receptors (CR1) on the surface of activated B cells greatly enhances antibody production compared to that by B cells that are activated by antigen alone. - Patients deficient in C3b often have less antibody than those with normal amounts of C3b. - Low concentrations of both antibody and C3b can lead to impairment of host defences and multiple, severe pyogenic infections. ## Comparison Between Classical and Alternative Pathways | Feature | Classical Pathway | Alternative Pathway | |---|---|---| | Specificity | Specific acquired immunity | Non-specific innate immunity | | Trigger | Initiated by antibody | Bacterial endotoxin, capsule, ... | | Components | Interaction of all components | C1, C4, C2 are bypassed | | Properdin | Properdin system not involved | Properdin system is involved |