The Complement System PDF

The Complement System Objectives What is the complement system? Understand and explain the three pathways of complement activation Biological effects or consequences of complement activation Regulation of the complement system Know some examples of complement disorders ...

The Complement System Objectives What is the complement system? Understand and explain the three pathways of complement activation Biological effects or consequences of complement activation Regulation of the complement system Know some examples of complement disorders  The Complement System Jules Bordet (1890s) – sheep antiserum causes lysis to Vibrio cholerae Substances named alexins??? Paul Ehrlich coined the term complement – activity of blood serum that completes the action of Abs Heat - labile component of serum that complemented or augment Abs in killing bacteria Later researches – action of complements due to interactions of large and complex group of proteins  The Complement System About 30 proteins (20 serum proteins and 10 regulated receptors) on cell surfaces Provide immune protection (defense against pathogens and tissue damage) Plays major role in both innate and adaptive immunity Synthesized mainly by liver hepatocytes and also monocytes, macrophages, epithelial cells of GIT or genitourinary tracts  The Complement System Designated by numbers (C1 – C9), letters (Factor D, H) or trivial names (homologous restriction factor, HRF) Complement are synthesized as proenzymes – activation by cleavage The peptide fragments are designated by small letters Smaller fragments are designated ‘a’ – diffusion and larger ones ‘b’ – remain bound to microbe Exception: C2 a – larger and b – smaller Activated complements become inactive if they do not react with next component  General Properties Present in serum of all animals Soluble proteins or glycoproteins Heat-labile Binds to Fc portion of Igs (effector functions) Consists about 5% of normal serum proteins  Complement Activation Pathways Activation is by sequential means involving many components Classical pathway – is Ab dependent triggered by Ag-Ab complex only IgM and IgG can activate complement Alternative pathway – Ab independent activated by antigen directly eg bacterial cell surface components (LPS) or viral proteins on cell surfaces Mannose – binding lectin pathway – Ab independent activated by sugars of high mannose content  Complement Activation Pathways Which is more important in innate immunity? All three pathways lead to production of C3b (central molecule of complement cascade) Presence of C3b on microbe marks it as foreign and target it for destruction (opsonization) Phagocytes have receptors for C3b on their surfaces C3b combines with other components to generate C5 convertase (leads to production of membrane attack complex (MAC)  Stages of Complement Activation Formation of C3 convertase Formation of C5 convertase Formation of MAC Activation, Amplification and Attack (the three AAA) The Complement System  Biological Consequences of Complement Activation Opsonization – C3b and C1q enhance phagocytosis Chemotaxis – C5a and C5,6, 7 complex attract neutrophils C5a enhances adhesiveness of neutrophils to the endothelium Lysis (MAC) – creates pores in the membrane and disrupts its integrity. May have little effect on gram +ve organisms Enhancement of Ab production – binding of C3b to its receptor on surface of B cells enhance Ab production Clearance of immune complexes from circulation and deposit them in liver and spleen  Biological Consequences of Complement Activation Hypersensitivity reactions or anaphylatoxins C3a, C4a and C5a – degranulation of mast cells with release of mediators (histamine) C3a binds to receptors on basophils and mast cells to release histamine Histamine into tissue cause increased capillary permeability and smooth muscle contraction Fluid is released into tissues calling oedema or swelling.  Regulation of the Complement system C1 inhibitor – serpin (serine protease inhibitor): it irreversibly binds to and inactivates C1r and C1s as well as MASP Properdin – protects C3b and stabilizes C3 convertase Decay accelerating factor (DAF) – prevents assembly of C3bBb (no formation of MAC) Factor I –cleaves cell-bound C3b and C4b making them inactivate Factor H – reduce amount of C5 convertase by increasing decay acceleration activity against C3bBb (C3 convertase)  Regulation of the Complement system Complement receptor 1 (CR-1 or CD 35) cofactor for factor I Protectin (CD 59 – MACI) and Vitronectin (S – protein) – inhibits formation MAC by binding to C5b678 NB: present on self cell to prevent complement from damaging them C4b-binding proteins (C4BP) – inhibits action of C4b mainly in classical pathway. Splits C4 convertase and is cofactor of factor 1  Disorders of the Complement system Autoimmune diseases – lupus erythematosus (inflammation and tissue damage in the affected organs) Hereditary angioedema – due capillary permeability edema in several organs Asthma Schizophrenia Alzheimer Disease Multiple sclerosis – condition that affects brain and spinal cord that may cause bad vision