Biological Consequences of Complement Activation PDF

Biological consequences of complement activation Learning Objectives On completion of this session you should be able to 1) Understand the role of the complement system in the innate immune response. 2) Explain the mechanisms by which complement activation leads to pathogen elimination. B...

Biological consequences of complement activation Learning Objectives On completion of this session you should be able to 1) Understand the role of the complement system in the innate immune response. 2) Explain the mechanisms by which complement activation leads to pathogen elimination. Biological Consequences of Complement Activation 1) Amplifies humoral response and causes it to be an effector response 2) Lyse cells 3) Participate in inflammatory response 4) Opsonisation of antigen 5) Clearance of immune complexes Cell Lysis 1) MAC and lyse broad spectrum of cells 2) Gram+ bacteria generally more resistant because of thick peptidoglycan 3) Some have developed ways to evade MAC Mediating Inflammation 1) Action of anaphylatoxins e.g. Ca5, C3a, C4a 2) Cleavage products of complement components mediate inflammation 3) Induce smooth muscle contraction and increase vascular permeability -> local accumulation of fluid (oedema) 4) Anaphylatoxins are also chemotactic for neutrophils 5) Smaller fragments bind to basophils and mast cells -> release of inflammatory mediators e.g. histamine Opsonisation 1) C3b and C4b have opsonising activity – cause phagocytosis Viral neutralisation 1) C1 binding to and become activated by viruses 2) MBL of the lectin pathway binds to and is activated by mannose residues on the surfaces 3) Antibodies generated mediate further binding and activation of the classical pathway on the surface of the virus 4) Repeating subunits on the viral capsid or membrane surfaces activate the alternative pathway 5) Binding of complement proteins leads to opsonization and lysis of the virus by phagocytic cells 6) Complement binding also interferes with the ability of the virus to interact with the membrane of its target cells and thus blocks viral entry into the cell Clearing of Immune Complexes 1) Tissue damage can result from build up of immune complexes 2) C3b coats immune complexes 3) RBC have capability of binding C3b coated complexes and carrying them to liver and spleen to be cleared 4) Deficiencies with any of complement may result in improper binding of C3b and loss of clearing may occur Complement Receptors 1) With the exception of the MAC, complement effector mechanisms are mediated through binding to complement receptors (CRs) 2) Range of receptors e.g. 1. CR1 – binds C3b and iC3b and C3d 2. CR2 – binds iC3b and C3d 3. CR3 – binds iC3b -> phagocytosis 4. CR4 – binds iC3b -> phagocytosis 5. C3aR and C5aR – binds C3a and C5a and mediate inflammatory effects 6. C1qR – group of receptors binding C1q and MBL and related collectins Summary 1. Once activated, the complement system performs several critical functions to enhance the immune response. 2. The formation of the membrane attack complex (MAC) can directly lyse pathogen cell membranes, leading to cell death. 3. The complement system induce inflammation, recruiting immune cells to the infection site and promoting a robust immune response. 4. These actions collectively improve the efficiency of the immune system in eliminating pathogens and maintaining homeostasis.