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Complement

Complement. J . Ochotná. Complement. humoral component of nonspecific immunity helps remove microorganisms and own altered cells (apoptotic cells) complement proteins are synthesized in the liver, less by tissue macrophages and fibroblasts. Complement.

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Complement

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  1. Complement J. Ochotná

  2. Complement • humoral component of nonspecific immunity • helps remove microorganisms and own altered cells (apoptotic cells) • complement proteins are synthesized in the liver, less by tissue macrophages and fibroblasts

  3. Complement • system of about 30 serum and membrane proteins • complement components are present in serum in inactive form • complement activation has cascade character

  4. Complement • themaincomplementcomponents: C1-C9 (C3 isthecentralcomponent) • othercomplementcomponents: factor B, factor D, factor P • regulatoryproteins: C1 - inhibitor, factor I, factor H, C4bp, DAF, MCP, CR1, factor S (vitronectin), CD59 (protektin), anaphylatoxininactivator

  5. Biological significance • Opsonization (C3b, C4b) • Chemotaxis (C3a, C5a) • Osmotic lysis (MAC C5b-C9) • Anaphylatoxins (C3a, C4a, C5a)

  6. Pathways of complement activation • Classical pathway • Alternative pathway • Lectin pathway Riedemann N.C.

  7. Classical and alternative pathway

  8. Alternative complement pathway • C3 componentofcomplementrarelyspontaneouslybreaksinto C3b and C3a • C3bcancovalentlybind on thesurfaceof a particle (own cell, microorganism) orreactswithwater, therebyinactivates

  9. Alternative complement pathway • to bound C3b joins a factor B, which is cleaved by factor D to Ba and Bb, resulting complex C3bBb is stabilized by factor P (properdin) and functions as an alternative C3 convertase

  10. Alternative complement pathway • C3 convertasecleaves C3 to C3a (chemotaxis) and C3b, whichbinds to thesurfaceoftheparticles (opsonization), orgivesrise to other C3 convertases

  11. Alternative complement pathway • some C3 convertases form C3bBbC3b that act as an alternative C5 convertase, which cleaves C5 to C5a (chemotaxis) and C5b (starts terminal lytic phase)

  12. Alternative complement pathway • C5b starts terminal lytic phase

  13. Classical complement pathway • can be initiated by antibodies IgG ( not by IgG4) and IgM or by pentraxins (CRP, SAP - acute phase proteins) • after binding of antibodies to the bacteria surface, Ab changes its conformation and than can bind C1 protein

  14. Classical complement pathway • C1 changes its conformation and acquires proteolytic activity, than cleaves C4 and C2 proteins

  15. Classical complement pathway • fragments C4b and C2a bind to the surface of microorganism and create the classic C3 convertase (C4bC2a), which cleaves C3 to C3a and C3b Descriptionof C3 convertase has beenmodified to C4bC2a

  16. Classical complement pathway • then creates a classic C5 convertase (C4bC2aC3b) that cleaves C5 to C5a and C5b

  17. Lectin complement pathway • is initiated by serum mannose binding lectin (MBL) • MBL binds to mannose residues on the surface of some microbes, after this binding starts cleave C4 and C2 • this way is similar to the classical pathway

  18. Lectin complement pathway

  19. Terminal (lytic) phase of the complement cascade • C5b fragments creates a complex with C6, C7 and C8, the complex dive into the lipid membrane of the cell and attache into a circle 13-18 molecules of C9 => MAC (membrane attack complex), forms a transmembrane channel, which causes osmotic lysis of the target cell(G-bacteria, protozoans, some viruses). • Most microorganisms are resistant to this lytic effect of complement (protection by cell wall).

  20. Terminal phase of the complement cascade

  21. Complement activation and efector functions

  22. Complement regulation and protection of own cells • Activation of complement cascade is controlled by the plasma and membrane inhibitors. Anaphylatoxin inactivator DAF Protectin MCP

  23. Complement regulation • C1 inhibitor(C1-INH) – inhibits C1; if missing→ HAE • factor Iwith cofactors: MCP (membrane cofactor protein), CR1,factor H – C3b, C4b cleavage • DAF (decay-accelerating protein)-degradation of C3 and C5 convertase

  24. Complement regulation • factor S (vitronectin) – inhibitscomplex C5bC6 • CD 59(protectin) - preventsthepolymerizationof C9 • anaphylatoxininactivator(CPN)- inactivatesanafylatoxins (C3a, C4a, C5a)

  25. Complement receptors • Bind fragments of complement components • CR1 - on various cells - promotes C3b, C4b decay - stimulate phagocytosis - erythrocyte transport of immunecomplexes • CR2 - on B lymphocytes and FDC - activation of B cells

  26. Complement receptors • CR3, CR4 - on phagocytes - participation in opsonization, adhesion • C3aR, C5aR – receptors for anaphylatoxins - mast cell activation

  27. 4 basic complement functions • Opsonization (C3b, C4b) • Chemotaxis (C3a, C5a) • Osmotic lysis (MAC C5b-C9) • Anafylatoxins (C3a, C4a, C5a)

  28. Basophils and mast cells and their importance in immune responses

  29. Mast cells • Mucosal mast cells- in the mucous membranes of respiratory and gastrointestinal tract, produce histamine, serotonin, heparin, tryptase, leukotriene C4 ..., participate in parasitosis and allergy • Connective tissue mast cells– in the connective tissue, producing tryptase, chymase, prostaglandinD2 ..., are multiplicated in fibrosis, in parasitosis and allergy are not participating

  30. Mast cell functions • Defense against parasitic infections • In pathological circumstances, responsible for the early type of hypersensitivity (immunopathological reaction type I) • Apply during inflammation, in angiogenesis, in tissue remodeling

  31. Mast cell activation Mast cellscanbestimulated to degranulate by: • cross-linkingofIgEreceptors(FcRI) • anafylatoxins (C3a, C4a, C5a) • TLR

  32. Mast cell activation by cross-linking of IgE Fc receptors • BindingofIgE to highaffinnityFc receptor forIgE (FcRI) • Bindingof multivalent antigen (multicellular parasite) to IgE • AggregationofseveralmoleculesofFcRI

  33. Mast cell activation • Mast cell degranulate (cytoplasmic granules mergers with the surface membrane and release their contents) • Activation of arachidonic acid metabolism (leukotriene C4, prostaglandin D2) • Start of production of cytokines (TNF, TGF, IL-4, 5,6 ...)

  34. Secretory products of mast cells • Cytoplasmatic granules: hydrolytic enzymes, histamine, heparin, chondroitin sulphate, serotonin Histamine - vasodilation, ↑ vascular permeability(erythema, edema, itching), bronchoconstriction, ↑ intestinal peristalsis, ↑mucus secretion in the respiratory tract and GIT (helps eliminate the parasite) • Arachidonic acid metabolites (leukotriene C4, prostaglandin D2) • Cytokines (TNF, TGF , IL-4, 5,6 ...)

  35. Basophils • Differentiate from myeloid precursor • Receptor equipment, content of granules, the mechanisms of stimulation and functions are very similar to mast cells • Play a role in parasitic infections and allergies • Basophil activation markers: CD 63, (CD 203)

  36. Immune mechanisms of inflammation (Local and systemic reactions)

  37. Inflammation Is a protectivephysiological response leading to protectionagainstinfection in damagedsites, localizationofdamage, eliminationofnecroticcellsandtissuerepair.

  38. Local body's response to inflammationClassical signs- pain (dolor), fever (calor), redness (rubor), swelling (tumor)

  39. Inflammation • The first signals for the development of inflammatory response come from mast cells, phagocytes, and the substances released from damaged cells and components of extracellular matrix. • With longer duration of local inflammation are activated an antigen-specific mechanisms (T and B lymphocytes).

  40. Inflammation

  41. Inflammation – local reaction • vasodilation, ↑ vascular permeability (histamine, serotonin, bradykinin, complementcomponents C3a, C5a, leukotrienes , prostaglandins, …) → rednes, swelling • ↑expressionofadhesionmoleculeson endothelia(TNFa, IL-1) →leukocyte adhesion to the endothelium • influence oflocal nerve endings via prostaglandins → pain • Increasedlocaltemperature(IL-1, IL-6, TNF, prostaglandins)

  42. Inflammation - systemic reaction • Leukocytosis • Fever (TNF, IL-1, IL-6, IFN ) ↑ tissue metabolism↑ mobility of leukocytes↑ formation of IFN, cytokines, Ig↑ expression of Hsp • Acute phase proteins (IL-6, TNFa, IL-1) CRP, SAP - opsonization and complement activation

  43. Inflammation - systemic reaction • Septic shock- the massive penetration of microorganisms into the bloodstream (TNF) • Anaphylactic shock- basophil and mast cells activation with allergen (histamine)

  44. Tissue repair • elimination of damaged cells with phagocytes • activation of fibroplastic mechanisms • activation of angiogenesis • regeneration and tissue remodeling

  45. Antigens

  46. Antigen (immunogen) • substance which provokes specific immune response • usually proteins or polysaccharides (lipids and nucleic acids only in the combination with proteins or polysaccharides) • molecules > 5 kDa (optimal size of the antigen molecules is about 40 kDa)

  47. Hapten • small molecules, that are able to induce specific immune response only after the attachment to the macromolecular carrier • separate haptens are not immunogenic • typically drugs (eg penicillin antibiotics, hydralazin)

  48. Epitope (antigenic determinant) • part of the antigen which is recognized by immune system (lymphocytes- BCR, TCR, Ig) • cross-reactive antigens - shares one or more identical or similar epitopes

  49. Interaction antigen – antibody • Binding site of antibody (paratop) form non-covalent complexes with the corresponding part on antigen molecule (epitope) • participation: the hydrogen bonds, electrostatic and hydrophobic interactions, van der Waals forces • antigen-antibody complex is reversible

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