Complement system -main humoral mechanism of nonspecific immunity - > 40 glykoproteins - blood - blood - on the surface of immune cells - on the surface of immune cells - Complement components inter-react be precise and regulated manner to eliminate microbs, foreign cells or material. -Charles Bordet fresh serum of immunized animals agglutinate in vitro and lyse bacteria used for immunization - serum heated to 60 o C agglutinate bacteria, but do not lyse - serum heated to 60 o C agglutinate bacteria, but do not lyse - system responsible for lysis was named alexin

Complement components Classical pathaway C1q, C1r, C1s, C2, C3, C4 C1q, C1r, C1s, C2, C3, C4 Alternative pathway C3, faktor B, D, I, H, P C3, faktor B, D, I, H, P Lactin pathway C3, MBP, MASP C3, MBP, MASP Regulatory functions C1-inhibitor, C4-binding factor, I factor, H factor, S- protein, C1-inhibitor, C4-binding factor, I factor, H factor, S- protein, properdin, inactivator of anaphylaxis, DAF, MCP, MIRL properdin, inactivator of anaphylaxis, DAF, MCP, MIRL Receptors of C CR1- binds C3b, CR3 – binds iC3b,... CR1- binds C3b, CR3 – binds iC3b,... MAC C5, C6, C7, C8, C9 C5, C6, C7, C8, C9 Abnormálne proteíny C3 – nefritický faktor C3 – nefritický faktor

Biosynthesis of Complement 1. Hepatocytes 2. Mononuclear phagocytes – inflammatory site 3. Epithelial cells

Genetics of Complemet System 1.Isolated genes - C3 - chromosome 19 - C3 - chromosome 19 - I factor - chromosome 4 - I factor - chromosome 4 - C1-INH - chromosome 11 - C1-INH - chromosome 11 2.Genes in clusters chromosome 6 - C2, C4, B factor chromosome 6 - C2, C4, B factor chromosome 1 - C4 bp, H factor, CR1, CR2, DAF, MCP chromosome 1 - C4 bp, H factor, CR1, CR2, DAF, MCP

Activation of Immune System -Complemets of components are innactive in serum -3 pathways of activation 1.Classical pathway 2.Alternative pathway 3.Lectin pathway Cascade system of activation – active component serve as enzyme and activate (split) following component and activate (split) following component

Activation of Complement Classical pathway Activation signals: 1.Immune complexes complex Ag + Ab (IgM, IgG3, IgG1) complex Ag + Ab (IgM, IgG3, IgG1) 2.CRP – C-reactive protein During inflammation rise its During inflammation rise its concentration 100 times. concentration 100 times. CRP binds polysaccharides of bacteria, fungi, parasites and viruses. Its binding to Ag is non specific 3. Aggregated IgG 4. Polycationic and polyanionic compounds 5. RNA, DNA 6. LPS G- bacteria 7. Some viral proteins

Activation of Complement Classical pathway C1 – macromolecular complex - 3 subunitsC1q, C1r, C1s - 3 subunitsC1q, C1r, C1s Recognition function - C1q Effector functions - tetramolecular complex (C1r, C1s) 2 C1q - 3 types of chains (A, B,C) - triplet of chains A+B+C form subunit with binding site for - triplet of chains A+B+C form subunit with binding site for - C H 2 domain IgG - C H 4 domain IgM - C H 4 domain IgM Activation signal = binding of C1q to immunocomplex ( IgM, IgG + Ag) ( IgM, IgG + Ag)

Activation of Complement Classical pathway Binding of C1q to immune complex auto-catalytic splitting of proenzyme C1r for active enzyme C1r auto-catalytic splitting of proenzyme C1r for active enzyme C1r conversion of C1s for active serine protease C1s conversion of C1s for active serine protease C1s splitting of C2 na C2a a C2b splitting of C2 na C2a a C2b and C4 na C4a a C4b and C4 na C4a a C4b C4b2a = C3 convertase – split C3 for C3a a C3b C4b2a = C3 convertase – split C3 for C3a a C3b C4b2a3b = C5 convertase – split C5 C5a a C5b C4b2a3b = C5 convertase – split C5 C5a a C5b

Activation of Complement Alternative pathway Activation signals : 1. Aggregated IgG4, IgA1, IgA2, IgE 1. Aggregated IgG4, IgA1, IgA2, IgE 2. Polysaccharides 2. Polysaccharides 3. LPS of bacteria (low content of sialic acid) 3. LPS of bacteria (low content of sialic acid) 4. Various components of viruses, fungi, protozoa, 4. Various components of viruses, fungi, protozoa, cancer cells cancer cells Spontaneous conversion of C3 for C3b. C3b rapidly inactivated (H factor) binding to sialc (typical for cells MAO) Cells with low content of sialic acid (MIO) cause low affinity of H factor to C3b. C3b persist and binds B factor – further activation of C3 alternative pathway of activation

Activation of Complement Lectin pathway Resemble of classical pathway – 2 differences A) C1q is supplied by MBP ( mannose binding protein ) – strucrurally close to C1q B) MASP ( MBP asssociated serine protease ) – strucrurally close to C1r a C1s After binding of MBP to mannose or N-acetylglukoseamin – activation of MASP – splitting C4 a C2

Activation of Complement MAC

Biological funcions 1.Lysis 2.Opsonization – C3b, C3bi 3.Chemotaxis – C5a 4.Inflammation - anaphylatoxins: C3a, C4a, C5a 5.Modulation of immune complexes 6.Immunoregulation

Deficiences C3 – inherited >> susceptibility to bacterial infections C2 - immune complex diseases - autoimmune disseases Systemic lupus erythematosus (SLE) C1INH - hereditary angioneurotic oedem (HANE).