Complement system The Complement C system in immunology
- Slides: 22
Complement system
�The Complement (C) system in immunology refers to a system consisting of some (approximately 20) non-specific proteins present in normal human and animal serum �Term “complement” refers to the ability of these proteins to complement i. e. augment the effects of other components of the immune system �Complement is an important component of our innate host defenses
�Term complement was coined by Paul Ehrlich because it augmented the action of antibody �Constitutes 10 -15 % of total human serum globulins �They are heat-labile, inactivated at 560 C for 30 minutes �Synthesized mainly by the liver �Also produced by blood monocytes, tissue macrophages, epithelial cells of GIT and genitourinary tracts
�C ordinarily does not combine with free antigen or antibody, but only with antigen-antibody complex �Among Igs, only Ig. M, Ig. G 3, Ig. G 1 and Ig. G 2 in that order fix complement �This property is due to the presence of C binding site on the Fc portion of these immunoglobulins
�Complement system consists of about 20 proteins which include the complement components, the properdin system and the control proteins �The action of complements act as a cascade (one event must occur before another takes place)
• C 1(q, r, s), C 2, C 3, C 4, C 5, C 6, C 7, C 8, C 9 • factors B, D, H and I, properdin (P) • mannose binding lectin (MBL), MBL associated serine proteases (MASP-1 MASP-2) • C 1 inhibitor (C 1 -INH, serpin), C 4 -binding protein (C 4 -BP), decay accelerating factor (DAF), Complement receptor 1 (CR 1), protein-S (vitronectin)
�Activation of Complement : �Initiated either by antigen-antibody complexes or by a variety of non-immunologic molecule like bacterial endotoxin, lipopolysaccharides, zymosan (yeast cell wall) �Sequential activation of complement components occurs via one of the 3 pathways � 1) Classical pathway � 2) Alternate pathway � 3) Lectin pathway
�In the classical pathway, antigen-antibody complexes activate the pathway �In the alternative pathway, many cell surface substances initiate the process - bacterial lipopolysaccharidess (endotoxin), fungal cell wall, viral envelopes etc �In the lectin pathway, mannan-binding lectin (MBL) binds to the surface of microbes bearing mannan ( a polymer of mannose) and this activates the process
�Action of membrane attack complex (MAC): �Insertion of MAC to the target cells leads to disruption of the membrane and entry of water and loss of electrolytes from the cell, thus resulting in cytolysis
�Regulation of complement system: �Destruction of tissues by excessive activity of complement is prevented by regulation �Control of the complement cascade in normal serum is exerted by: �Inhibitors – halt the complement cascade �Inactivators – destroy the complement proteins
�Regulation of the complement system: � 1) the complement binding site on the H chain of Ig. M and Ig. G is available to the C 1 component only if antigen is bound to the antibody � 2) C 1 inhibitor inactivates the protease activity of C 1, thus to activate the classical pathway the process should proceed past this point by generating sufficient C 1 to overwhelm the inhibitor
� 3. Regulation of the alternative pathway is mediated by the binding of factor H to C 3 b and cleavage of this complex by factor I, a protease. �The pathway can proceed beyond this regulatory point only if sufficient C 3 b attaches to cell membranes which protects it from degradation by factor H and I
� 4. Properdin protects the C 3 b and enhances activation of alternate pathway � 5. Decay accelerating factor ( DAF, CD 55) – a glycoprotein located on the surface of human cells provides protection of cells from lysis � It acts by binding to C 3 b and C 4 b and limits the formation of C 3 convertase and C 5 convertase, this prevents the formation of membrane attack complex
�Biological effects of complement : � 1) Bacteriolysis and cytolysis: � insertion of membrane attack complex to cells lysis of bacteria, erythrocytes, tumor cells etc � 2) Amplification of inflammatory response: �C 3 a, C 4 a, C 5 a are anaphylatoxic by degranulation of mast cells to release histamine and other mediators �They cause increased vascular permeability, smooth muscle contraction �C 567 is chemotactic
� 3) Hypersensitivity reactions: �Complement participates in type II (cytotoxic) and type III (immune complex) hypersensitivity reactions � 4) Opsonization: �Facilitates the destruction of pathogens by phagocytic cells by binding of C 3 b to the receptors on phagocytes
� 5) Immune adherence: �C 3 and C 4 bound antigen-antibody complexes adhere to RBCs, platelets and are thus rapidly recognised by phagocytes � 6) Endotoxic shock: �Endotoxin activated complement cascade leads to excessive C 3 activation and platelet adherence �Platelet lysis releases large amount of platelet factors leading to disseminated intravascular coagulation (DIC)
� 7)Autoimmune diseases: �Serum complement levels are decreased in diseases like systemic lupus erythematosus and rheumatoid arthritis thus may be involved in pathogenesis of them
�Clinical aspects: �Deficiencies of complement: �Leads to poor host resistance against infections and results in recurrent bacterial and fungal infections and collagen disorders
Deficiency Disease C 1 inhibitor Hereditary angioneurotic oedema C 1, C 2, C 4 components Systemic lupus erythematosus, other collagen vascular diseases C 3 and its regulatory protein C 3 b inactivator Recurrent pyogenic infections C 5, C 6, C 7, C 8, C 9 components Bacteremia, mainly by Gram negative diplococci, toxoplasmosis
�Quantitation of complement: �Complement activity in serum is measured by estimating the highest dilution of the serum that lyses sheep RBCs sensitized by anti-erythrocytic antibody �Complement components can be measured by radial immunodiffusion method ( does not differentiate active and inactive fractions)
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