300 likes | 592 Views
Complement. Objectives. Discuss the role of complement in the immune system. Discuss complement regarding its: Components Activation pathways Biological activities. Complement. System comprised of more than 25 glycoproteins Make up about 10% of total serum proteins
E N D
Objectives • Discuss the role of complement in the immune system. • Discuss complement regarding its: • Components • Activation pathways • Biological activities
Complement • System comprised of more than 25 glycoproteins • Make up about 10% of total serum proteins • Components formed mainly in the liver • C1 forms in intestinal epithelial cells • Factor D forms in adipose tissues • Components form a cascade, with each step triggering (and often amplifying) the next step
Complement • In plasma – the components are in inactive form • Once activated, each component splits • The smaller “a” fragment serves to stimulate the immune system • The larger “b” fragment further activates the cascade • The exception to this is C2… C2a is the larger molecule that promotes the cascade • Activated components are written with a line over the letter or number. For example: ____ • C4b2a
3 Functions • Cell lysis – Cell swells and bursts • Opsonization - Neutrophils and macrophages have receptors for C4b or C3b, which promotes phagocytosis
3 Functions 3. Regulate immune and inflammatory response • Immune adherence – enhanced response to an antigen. Receptors for complement found on Red Blood Cells (RBCs), platelets, B lymphocytes, endothelial and epithelial cells • Anaphylatoxins - chemicals that increase vascular permeability, contract smooth muscle, and cause the release of histamine from basophils and mast cells • C3a, C4a, and C5a are anaphylatoxins • Chemotaxins – signal leukocytes to migrate to an affected area • C5a is also a chemotaxin • C5b67 promotes monocyte and neutrophil adherence to blood vessel endothelium, and extravasation
3 Activation Pathways • Classical • Alternative • Lectin
Classical Pathway • Begins with antibody sensitization of antigen on cell • 2 Fc pieces in close proximity • IgM better than IgG (1 IgM vs. 800 IgG) • IgG1 & IgG3 better at activation than IgG2 or IgG4 • C1 = Recognition unit • C1q • C1r • C1s Y C1 Y
Recognition Unit Y • C1q combines with the Fc piece • 6 globular heads attached to collagen-like tails. • C1r that acts as a protease on C1s • C1r and C1s intertwine with the tails. • 2 C1q heads must interact with Fc pieces for complement to be activated. Y
Classical - Activation Unit C4a C4 C2 C4b2a Y C1 C1s Y C2b • C4, C2, and C3 components participate • Amplification of cascade • 1 molecule of C1s activates approximately 30 C4 molecules.
Activation Unit • C2 is active only if it binds to C4b before being cleaved by C1s • This reaction is enhanced if C4b binds to the antigen rather than being free in serum • Once C4b2a is formed, antibody is no longer necessary to ensure cell lysis
Activation Unit C4a C3a C4 C2 C4b2a C3 Y C1 C1s Y C3b C4b2a3b C2b • C4b2a = C3 convertase • One C4b2a complex converts about 200 C3 molecules • Requires Mg+
Activation Unit • C3 most abundant complement component • C3 common to all pathways • C3b on a cell enhances opsonization • C3b combines with C4b2a to form C4b2a3b = C5 convertase
Classical – MAC C4a C3a C5a C4 C2 C9 C8 C7 C6 C4b2a C3 C1s Y C5 C1 C3b C4b2a3b Y C2b C5b • Membrane Attack Complex = C5, C6, C7, C8, C9
MAC • C5b binds to C6 and C7 in serum • This complex will bind to any nearby cell membrane, not just the cell that originally triggered the cascade. (The “innocent by-stander” effect) • May also form a micelle – free floating sphere- which has antiviral properties • C5b678 form a surface on the cell membrane for polymerization of C9 • A pore forms in the cell, allowing an influx of water • The cell swells and lyses
Hemolysin • An antibody that can activate complement, resulting in lysis of an RBC is termed a hemolysin. C1 Y Y
Alternative (Properdin) Pathway Properdin C5a C5 C3b C3bBb C3bBbP C9 C8 C7 C6 Factor B Factor D C5b • Activated by bacteria, fungus, yeast, viruses, parasites, and tumor cells • Oldest pathway • Relies on the natural splitting of C3 into C3a and C3b (exact process unclear)
Alternative • C3b and Factor B need Mg+ to combine • Factor D splits Factor B that has been bound to C3b • Properdin stabilizes the C3bBb complex • C3bBbP is a C5 convertase • Once C5b formed, cascade continues as in the classical pathway
Lectin Pathway • Mannose is a sugar commonly found in bacterial cell walls • This pathway can be activated by bacteria, yeast, viruses and protozoa C4a C3a C4 C2 MBL C4b2a C3 C5a C2b C9 C8 C7 C6 C3b C4b2a3b C5 C5b
Lectin Pathway • MBL= Mannose Binding Lectin equivalent to C1q of classical pathway • MBL also increases opsonization • MASP-1 and MASP-2 function similarly to C1r and C1s respectively • MASP = Mannose Associated Serine Proteases • Once MBL activates the cascade, the cascade continues as in the classical pathway
Inhibitors of Complement • Activated enzymes decay quickly. • Half life of activated components ranges from a fraction of a second to approximately 30 minutes. • If Ca+ and Mg+ are not present, the cascade can NOT be activated. • Carboxypeptidase N inactivates anaphylatoxins. • Heating serum at 56oC for 30 minutes destroys complement components.
Specific Inhibitors • C1-INH irreversibly binds to the active sites of C1r and C1s. • Factor I degrades C4b and C3b • Membrane cofactor protein –cofactor for Factor I • C4-binding protein – prevents C4 and C2 from joining (cofactor for Factor I)
Specific Inhibitors • Complement Receptor 1 (CR1) • Found as a surface protein on most WBCs and follicular dendritic cells • Binds C3b allowing degradation by Factor I • Increases clearance of C3b coated cells via macrophages of liver and spleen • Also increases the length of time antigen remains near germinal centers of lymph nodes (May assist with B cell differentiation)
Specific Inhibitors • Sialic acid of cell membrane inactivates C3b bound to cells • Decay Accelerating Factor (DAF) – dissociates C2 from C3 • S protein – prevents C5b67 complex from binding to cell • MIRL – Binds to C8 • MIRL = Membrane Inhibitor of Reactive Lysis • Protectin – Prevents binding of C5b678 to cell, so no polymerization of C9 is allowed
Inhibitors - Alternative Properdin C5a C5 C3b C3bBb C3bBbP C9 C8 C7 C6 Factor B C5b • DAF & Factor H – compete with Factor B for binding with C3b
Complement Deficiencies • Complement deficiencies rare • C2 deficiency most common (1 in 10,000) • C3 deficiency most problematic as it participates in all pathways • Deficiencies in complement components can lead to: • Increased susceptibility to infection • Accumulation of immune complexes • Autoimmune disease
Pathologic Conditions • Complement is harmful if: • Activated systemically • Activated by tissue necrosis • Allows build up of immune complexes • Immune complexes play a role in Goodpasture’s syndrome, SLE, MS, Guillain-Barre’ syndrome and other autoimmune diseases
Pathologic Conditions • Paroxysmal Nocturnal Hemoglobinuria (PNH) • Abnormal DAF on RBCs • Cells more susceptible to lysis • C1-INH deficiency – Hereditary angioedema • C2b accumulates, but does not participate in the complement cascade • Increases vascular permeability
The End Can you list the complement components in order of activation?