Complement system main humoral mechanism of nonspecific immunity

Complement system -main humoral mechanism of nonspecific immunity - > 40 glykoproteins - blood - on the surface of immune cells - Complement components inter-react be precise and regulated manner to eliminate microbs, foreign cells or material. -Charles Bordet 1896 - 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 - system responsible for lysis was named alexin

Complement components Classical pathaway C 1 q, C 1 r, C 1 s, C 2, C 3, C 4 Alternative pathway C 3, faktor B, D, I, H, P Lactin pathway C 3, MBP, MASP MAC C 5, C 6, C 7, C 8, C 9 Abnormálne proteíny C 3 – nefritický faktor Regulatory functions C 1 -inhibitor, C 4 -binding factor, I factor, H factor, S- protein, properdin, inactivator of anaphylaxis, DAF, MCP, MIRL Receptors of C CR 1 - binds C 3 b, CR 3 – binds i. C 3 b, . . .

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

Genetics of Complemet System 1. Isolated genes - C 3 - chromosome 19 - I factor - chromosome 4 - C 1 -INH - chromosome 11 2. Genes in clusters chromosome 6 - C 2, C 4, B factor chromosome 1 - C 4 bp, H factor, CR 1, CR 2, 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

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

Activation of Complement Classical pathway C 1 – macromolecular complex - 3 subunits. C 1 q, C 1 r, C 1 s Recognition function Effector functions - C 1 q - tetramolecular complex (C 1 r, C 1 s)2 C 1 q - 3 types of chains (A, B, C) - triplet of chains A+B+C form subunit with binding site for - CH 2 domain Ig. G - CH 4 domain Ig. M Activation signal = binding of C 1 q to immunocomplex ( Ig. M, Ig. G + Ag)

Activation of Complement Classical pathway Binding of C 1 q to immune complex auto-catalytic splitting of proenzyme C 1 r for active enzyme C 1 r conversion of C 1 s for active serine protease C 1 s splitting of C 2 na C 2 a a C 2 b and C 4 na C 4 a a C 4 b 2 a = C 3 convertase – split C 3 for C 3 a a C 3 b C 4 b 2 a 3 b = C 5 convertase – split C 5 a a C 5 b

Activation of Complement Alternative pathway Activation signals : 1. Aggregated Ig. G 4, Ig. A 1, Ig. A 2, Ig. E 2. Polysaccharides 3. LPS of bacteria (low content of sialic acid) 4. Various components of viruses, fungi, protozoa, cancer cells Spontaneous conversion of C 3 for C 3 b 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 C 3 b persist and binds B factor – further activation of C 3 alternative pathway of activation

Activation of Complement Lectin pathway Resemble of classical pathway – 2 differences A) C 1 q is supplied by MBP (mannose binding protein) – strucrurally close to C 1 q B) MASP (MBP asssociated serine protease) – strucrurally close to C 1 r a C 1 s After binding of MBP to mannose or N-acetylglukoseamin – activation of MASP – splitting C 4 a C 2

Activation of Complement MAC

Biological funcions 1. 2. 3. 4. 5. 6. Lysis Opsonization – C 3 b, C 3 bi Chemotaxis – C 5 a Inflammation - anaphylatoxins: C 3 a, C 4 a, C 5 a Modulation of immune complexes Immunoregulation

Deficiences C 3 – inherited >> susceptibility to bacterial infections C 2 - immune complex diseases - autoimmune disseases Systemic lupus erythematosus (SLE) C 1 INH - hereditary angioneurotic oedem (HANE).