Complement System: Pathways, Regulations and biological effects.pptx
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The complement system is a group of serum proteins that enhance immune responses through activation and form a crucial part of both innate and adaptive immunity. It consists of nine components (C1 to C9) and operates through classical, alternative, and lectin pathways, each having distinct starting points but sharing a common ending mechanism leading to cell lysis. Regulatory proteins ensure that complement activity is restricted to designated target cells to prevent damage to host cells.
Complement System: Pathways, Regulations and biological effects.pptx
- 1. COMPLEMENT SYSTEM SACHIN K SHARMA PHD SCHOLAR DEPT. OF MICROBIOLOGY SMIMS
- 2. DEFINITION • The term ‘complement’ (C) represents a group of proteins normally found in serum in inactive form, but when activated they augment the immune responses. • They constitute about 5% of normal serum proteins and their level does not increase following either infection or vaccination.
- 3. PROPERTIES • Bind to fc region of antibody: the effector function of complement is mediated by binding with fc portion of antibody. It disappears from serum following binding) • Role of antigen: the classical pathway of complements do not bind to free antibodies but they can only fix to those antibodies which are bound with antigens. However fixation of complement is not influenced by the nature of antigens, but only by the class of antibody
- 4. PROPERTIES (CONTD.) • Species nonspecific: Complements are present in the sera of all mammals, birds, amphibians and fish. Complements from one species can react with antibodies from other species, though the efficiency decreases with increase in taxonomic distance • Heat labile: complements get denatured by heating the serum at 56°C for 30 minutes. Such serum with lost complement activity is called inactivated serum.
- 5. Complement Components The complement system comprises of about 30 serum proteins grouped into complement components, the properdin system and the regulatory proteins. • The complement components are named by numerals. There are nine components; C1 to C9. C1 has three subunits—c1q, c1r and c1s. • The properdin system and the regulatory proteins are named by letter symbols, e.g. Factor-B.
- 6. SYNTHESIS • Liver is the major site for synthesis of complement proteins. • Other minor sites include blood monocytes, tissue macrophages, and epithelial cells of GIT and genitourinary tract.
- 7. Complement Activation All the complement proteins are synthesized in inactive form (e.g. Zymogens) and are activated by proteolysis. • Complements have two unequal fragments (large and small fragment) • The larger fragments are usually designated as ‘b’ (e.g. C3b) and the smaller fragments are designated as ‘a’ (e.g. C3a). An exception is C2a which is larger fragment. • During proteolysis, the smaller fragment is removed exposing the active site of the larger fragment. The larger fragment participates in the cascade reaction of complement pathway and the smaller fragment diffuses away to mediate other functions.
- 8. Cascade Reaction • The fragments of complements interact in a definite sequential manner with a cascade like effect, which leads to formation of complex. Such complex having enzymatic activity is designated by putting a bar over the number or symbol (e.g. CbBb).
- 9. STAGES OF COMPLEMENT ACTIVATION 1. Initiation of the pathway 2. Formation of C3 convertase 3. Formation of C5 convertase 4. Formation of membrane attack complex (MAC). All the pathways differ from each other in their initiation till formation of c3 convertase. Then, the remaining stages are identical in all the pathways.
- 10. Compliment Pathways 1. Classical pathway: This is an antibody dependent pathway. Pathway is triggered by the antigen–antibody complex formation 2. Alternative pathway: This is an antibody independent pathway, triggered by the antigen directly 3. Lectin pathway: This is a recently described pathway. It resembles classical pathway, but it is antibody independent.
- 12. Classical Pathway Classical pathway is antibody dependent. However, not all antibodies can bind to complements of classical pathway. • Decreasing order of ability of antibodies to fix complement is—IgM (most potent) > IgG3 > IgG1 > IgG2. • The other classes of antibodies do not fix complements. CH2 domain on IgG, CH4 on IgM participate in complement binding. The classical pathway begins with activation of C1 and binding to antigen– antibody complex.
- 13. 1. Initiation The first step is the binding of C1 to the antigen–antibody complex. • The first binding portion of C1 is C1q, which reacts with the fc portion of IgM or IgG bound to antigen. • C1q is a hexamer having six globular heads each acting as a combining site. • Effective activation of classical pathway begins only when c1q is attached to the fc portion of antibody by at least two of its globular binding sites • C1q binds in presence of calcium ions, which in turn activates sequentially c1r followed by C1s.
- 14. Formation of C3 convertase • Activated C1s acts as an esterase (C1s esterase), which can cleave C4 to produce C4a (an anaphylatoxin), and C4b which binds to C1 and participates further in complement cascade. • C14b in the presence of magnesium ions cleaves C2 into C2a, which remains linked to complement complex, and C2b (has kinin like activity), which is released outside. • C14b2a is referred to as C3 convertase of the classical pathway
- 15. Formation of C5 convertase • C3 convertase hydrolyses many C3 molecules into two fragments: C3a (an anaphylatoxin) and C3b which remains attached to C14b2a to form C14b2a3b complex, which acts as C5 convertase of classical pathway.
- 16. Formation of Membrane Attack Complex • This phase begins with C5 convertase cleaving C5 into C5a and c5b, which continues with the cascade. • C5b is extremely labile, gets stabilized by binding soon with C6 and C7 to form C5b67 followed by addition of C8 the hydrophobic regions on C7 and C8 help in penetration into the target cell membrane. • This inserted membrane complex (C5b678) has a catalytic property to bind to C9 molecule and then it polymerizes the C9 into a tubular channel of 10 nm diameter penetration of C9 causes formation of channels or pores on the target cell membrane each tubular channel behaves hydrophobic outside, but hydrophilic inside; thus allowing free passage of ions and water into the cell leading to cellular swelling and lysis. • Because C5b6789 destroys the target cell by attacking the cell membrane; it is called membrane attack complex (MAC) and the process of cytolysis is referred to as complement-mediated cytotoxicity.
- 18. Alternative Pathway • Alternative pathway is independent of antibody; hence is considered as a part of innate immunity. • It also goes through the four stages; but differs from the classical pathway in first two stages. • Unlike the classical pathway which involves all complement components from C1 to C9; in alternative pathway three complement components C1, C4 and C2 are not involved. Instead, it requires three other complement proteins present in serum named factor B, factor D and properdin.
- 19. Initiation • The alternative complement cascade is initiated by various cell surface constituents that are foreign to the host, e.g. Bacterial endotoxin. • The first complement component to be involved in alternative pathway is free C3 in the serum. C3 hydrolyzes spontaneously, to generate: • C3a which diffuses out and • C3b fragment which attaches to foreign cell surface antigen.
- 20. Formation of C3 convertase • In the next step, factor B binds to c3b coated foreign cells. • Factor D, another alternative pathway complement factor, acts on factor B, and cleaves it into Ba (diffuses out) and Bb (remains attached). • C3bBb is also called C3 convertase of alternative pathway. • C3bBb has a very short half-life of 5 minutes. If it is stabilized by another complement protein called properdin its half-life is increased to 30 minutes. • Remaining stages are same as in classical pathway.
- 22. REGULATION OF COMPLEMENT PATHWAYS • Complement system are antigen non-specific; capable of attacking microorganisms as well as host cells. Hence, several regulatory mechanisms have evolved to restrict complement activity only to the designated target cells. • There are a series of regulatory proteins, which inactivate various complement components at different stages.
- 23. REGULATION OF COMPLEMENT PATHWAYS For example: 1. C1 inhibitor (or C1 esterase inhibitor): it is a soluble glycoprotein, inhibits the action of c1q by splitting c1qrs into c1rs and c1q. Thus, the whole classical pathway is inhibited. 2. DAF (decay accelerating factor): it is CD55 molecule present on cell membrane, accelerates dissociation of C3 convertase; thus inhibiting all three pathways.
- 24. Effector functions of Complement 1. Target cell lysis by MAC complex MAC makes pores or channels in the target cell membrane; thereby allows the free passage of various ions and water into the cell leading to cell swelling, lysis and death. 2. Inflammatory response 3. Opsonization: : C3b and C4b act as major opsonins that coat the immune complexes and particulate antigens. 4. Removing the immune complexes from blood
- 25. Effector functions of Complement (Contd.) 5. Viral neutralization: complements play a crucial role in neutralization of the viruses; which occurs by many ways— • Complements coated on virus surfaces neutralize the viral infectivity by blocking their attachment sites. • C3b mediated opsonization of viral particles • Lysis of the enveloped viruses either by activation of classical pathway (most viruses) or some time by alternative or lectin pathways (by some viruses like Epstein–Barr virus, rubella virus, etc.).