Complement System PDF

Definition of Terms: ▪ Complement Activation Alteration of a complement (protein) in such a way that it...

Definition of Terms: ▪ Complement Activation Alteration of a complement (protein) in such a way that it can proceed to interact with the next component in the pathway (cascade). ▪ Complement Fixation Utilization of complement components by the antigen- antibody complex. COMPLEMENT SYSTEM Definition of Terms: ▪ Hemolytic Units The dilution of a serum sample which can lyse a predetermined proportion of a sheep erythrocyte (srbc) suspension coated with anti-SRBC antibody. ▪ Complement Inactivation Denaturation (usually by heat) of one of the early components in –activation pathway resulting in the destruction of C- hemolytic activity. Complement System Complement ▪ Coined by Paul Ehrlich. ▪ Jules Bordet explain the nature of complement. Order of Discovery ▪ Characteristics: Soluble and cell bounded protein Heat labile proteins Order of Activation Predominantly inactive molecule All are produce on Liver Except: C1 Components (Intestinal Epithelial Cell) Factor D (Adipose Tissue) Other Source: Macrophage, Monocyte ▪ Designated by numbers, symbols and trivial names. General properties: Complement Thermolabile (56oC for 30 minutes): Inactivated by: o Acid and alkalis Regain activity at temperature 7-37oC o Proteolytic enzymes o Ether Activity lost in 3-4 days at refrigerator temperature o Chloroform Deteriorates w/in 1-2 days at room temperature o Alcohol o Bile salts o Soap Reacts best at pH 7.2-7.4; 30-37oC; with Calcium and Magnesium Bound to all antigen-antibody complexes Can be activated by non-serologic reactions Preserved BEST by lyophilization THREE PHASE FOR EACH OF PROTEINS OF COMPLEMENT SYSTEM THE MAIN PATHWAY CLASSICAL LECTIN ALTERNATIVE LYTIC PATHWAY PATHWAY PATHWAY PATHWAY 1.Initiation Activation Activation Activation 2.Amplification Proteins: Proteins: Proteins: C5, C6, C7, C1qrs, MBP C3 C8, C9 3.Membrane Attack Complex (MAC) C2, C3, C4 MASP Factors B and D MASP2 Properdin Control proteins: Protein S C1-INH, C4-BP Factors I* and H, DAF, CR1, etc. (Vitronectin) PATHWAYS OF COMPLEMENT CLASSICAL PATHWAY ACTIVATION ▪ Classical Pathway ▪ Alternative Pathway ▪ Lectin Pathway  ALTERNATIVE PATHWAY LECTIN PATHWAY  CLASSICAL ALTERNATIVE LECTIN CLASSICAL ALTERNATIVE LECTIN PATHWAY PATHWAY PATHWAY PATHWAY PATHWAY PATHWAY Antibody Yes (IgM, 2 IgG) No No Binds to Dependent mannose or Mannose and Initiation C1 (q,r,s) C3 related sugars in several other Unit Antigen-Antibody a calcium- sugars found Complexes, Lipopolysaccharide, dependent primarily on Stimulus Fungal Cell, Yeast, Activation C3 Convertase bacteria, some Binds to CRP, E. coli, Parasites Unit C5 Convertase yeasts, viruses, Mycoplasma, Protozoa MAC C5b6789 and several parasites Others BIOLOGICALLY ACTIVE PRODUCTS OF BIOLOGICALLY ACTIVE PRODUCTS OF COMPLEMENT ACTIVATION COMPLEMENT ACTIVATION Cause basophil/mast Component Biologic activity Effect Controls cells degranulation and C2b Accumulation Anaphylatoxin C4a, C3a, C5a Edema C1-INH (Prokinin) of body fluid smooth muscle contraction. Basophil and mast cell Chemotactic C3a, C4a Carboxypeptidase- C5a Promotes diapedesis. degranulation; Anaphylaxis Factor (Anaphylatoxin) B (C3a-INA) smooth muscle Opsonins C3b Promotes phagocytosis contraction  BIOLOGICALLY ACTIVE PRODUCTS OF BIOLOGICALLY ACTIVE PRODUCTS OF COMPLEMENT ACTIVATION COMPLEMENT ACTIVATION Component Biologic activity Effect Controls Component Biologic activity Effect Controls C3b and its Opsonization; Phagocytosis Factors H and I C5b67 Chemotaxis; Inflammatory Protein S products phagocyte activation attachment to lysis of by (MAC) other cell stander cells C5a Basophil and Anaphylaxis C3a-INA (anaphylatoxin; mast cell membrane chemotactic degranulation; factor) smooth muscle contraction Plasma Complement Regulators PLASMA COMPLEMENT REGULATORS Classical Pathway & Lectin Pathway C1 inhibitor Dissociates C1r and C1s from C1q Factor I Cleaves C3b and Cb Other Factor H Cofactor with I to inactivae C3B; prevents Action Source Comment binding of B to C3b Inhibits C4-binding protein / membrane cofactor Acts as a cofactor with I to inactivate C4b Liver protein / CD46 C1 Inhibitor MASP-2, Macrophage CR1 / CD35 Acts as a cofactor with I and binds C3b C1r, C1s Decay accelerating Factor / CD55 Accelerates dissociation of C3 convertase Act with DAF, Membrane inhibitor of reactive lysis MIRL Inhibits MAC through binding with CD8 to Factor I Inhibits C4b CR1, MCP / CD59 prevent insertion of CD9 S protein / vitronectin Prevents attachment of C5b67 complex to Complement Binds with Blood Cells CD35 cell membrane Receptor 1 C3b Plasma Complement Regulators Plasma Complement Regulators Classical Pathway & Lectin Pathway Classical Pathway & Lectin Pathway Other Other Action Source Action Source Comment Comment Cofactor to Membrane Prevent Membrane C4b, C3b, CD46 Inhibiting insertion of Blood Cell CD59 Cofactor Protein Factor B Reactive Lysis C9 Binds to Epithelial Cell Decay- C4b, C3b Endothelial accelerating and CD55 Cell Factor dissolves Fibroblasts C2a  Plasma Complement Regulators Plasma Complement Regulators Alternative Pathway Terminal Component Other Other Action Source Action Source Comment Comment Prevent the Prevent binding of 100x affinity from Factor H S Protein or Factor B to C3b binding to Vitronectin and C3b cell membrane DEFICIENCIES OF COMPLEMENT COMPONENTS DEFICIENT COMPONENT ASSOCIATED DISEASE C1 (1q,r,s) Lupuslike syndrome; recurrent infections Laboratory Detection of Complement Abnormalities C2 Lupuslike syndrome, recurrent infections, artherosclerosis Most common complement deficiency C3 Glomerulonephritis Nephelometry Most severe complement deficiency Most commonly measured Hemolytic Titration (CH50) Assay C4 Lupuslike syndrome ELISA C5-C8, Properdin C9 Neisseria infections No known disease association Complement Fixation Testing C1-INH Hereditary angioedema DAF, MIRLs Paroxysmal nocturnal hemoglobinuria Factor H or I Recurrent pyogenic infections MBL Pneumococcal diseases, sepsis, Neisseria infection MASP-2 Pneumococcal infections BIOLOGY OF IMMUNE RESPONSE