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Complement

Learn about the role of the complement system in immunity, activation pathways, biological significance, and regulatory mechanisms. Explore how mast cells are activated, their functions, and involvement in immune responses and allergies.

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Complement

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  1. Complement J. Ochotná

  2. Complement • humoralcomponentofnonspecificimmunity • helps remove microorganisms and own altered cells (apoptotic cells) • complementproteins are synthesized in the liver, less by tissuemacrophagesandfibroblasts

  3. Complement • systemofabout 30 serumandmembraneproteins • complementcomponents are present in serumin inactiveform • complementactivationiscascadecharacter

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

  5. Classical complement pathway • canbeinitiated by antibodiesIgG ( not by IgG4) andIgMor by pentraxins (CRP, SAP - acutephaseproteins) • afterbindingofantibodies to thebacteriasurface, Ab changesitsconformationandthancanbind C1 protein • https://www.youtube.com/watch?v=vbWYz9XDtLw

  6. Alternative complement pathway • C3 componentofcomplementrarelyspontaneouslybreaksinto C3b and C3a • C3bcancovalentlybind on thesurfaceof a particle (own cell, microorganism) orreactswithwater, therebyinactivates • https://www.youtube.com/watch?v=qga3Wn76d9w

  7. Lectin complement pathway • isinitiated by serummannosebindinglectin (MBL) • MBL binds to mannoseresidues on thesurfaceofsomemicrobes, afterthisbindingstartscleave C4 and C2 • thiswayissimilar to theclassicalpathway • https://www.youtube.com/watch?v=utQdPPeeTLQ

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

  9. Complement activation and efector functions

  10. Efector functions of complement

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

  12. Complement regulation • C1 inhibitor(C1-INH) – inhibits C1; ifmissing→ HAE • factor Iwithcofactors: MCP (membranecofactor protein), CR1,factor H – C3b, C4b cleavage • DAF (decay-accelerating protein)degradationof C3 and C5 convertase

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

  14. Complement receptors • Bindfragmentsofcomplementcomponents • CR1 - on variouscells - promotes C3b, C4b decay - stimulatephagocytosis - erythrocyte transport ofimmunecomplexes • CR2 - on B lymphocytesand FDC - activationof B cells

  15. Complement receptors • CR3, CR4 - on phagocytes - participation in opsonization, adhesion Anaphylatoxinreceptors • C3aR, C5aR – receptorsforanaphylatoxins - mast cell activation

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

  17. 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 parasitosis and allergy are not participating

  18. Mast cell functions • Defense againstparasiticinfections • In pathologicalcircumstances, responsiblefortheallergicreactions(immunopathologicalreaction type I) • Applyduringinflammation, in angiogenesis, in tissueremodeling

  19. Mast cell activation • cross-linkingofIgEreceptors(FcRI) • anafylatoxins (C3a, C4a, C5a) • TLR

  20. 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 → activation

  21. Mast cell activation • Mast cell degranulate (cytoplasmicgranulesmergerswiththesurfacemembraneandreleasetheircontents) • Activationofarachidonicacidmetabolism (leukotriene C4, prostaglandin D2) • Start ofcytokinesproduction (TNF, TGF, IL-4, 5,6 ...)

  22. Secretory products of mast cells • Cytoplasmaticgranules:hydrolyticenzymes, histamine, heparin, chondroitin sulphate, serotonin Histamine - vasodilation, ↑ vascular permeability(erythema, edema, itching), bronchoconstriction, ↑ intestinalperistalsis, ↑mucussecretion in therespiratorytractand GIT (helpseliminatethe parasite) • Arachidonicacidmetabolites(leukotriene C4, prostaglandin D2) • Cytokines (TNF, TGF , IL-4, 5,6 ...) • https://www.youtube.com/watch?v=MoM5JY_EeRo

  23. Basophils • Differentiatefrommyeloidprecursor • Receptor equipment, contentofgranules, themechanismsofstimulationandfunctions are verysimilar to mast cells • Play a role in parasiticinfectionsandallergies • Basophilactivationmarkers: CD 63, (CD 203)

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

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

  26. Causes of inflammation • Physicalinjury • Infection by pathogens • Damagecaused by chemicals • Cancer • Alergicdisease • Autoimmunedisease

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

  28. Inflammation • Thefirstsignalsforthedevelopmentofinflammatory response comefrommast cells, phagocytes, andthesubstancesreleasedfromdamagedcellsandcomponentsofextracellular matrix. • An antigen-specific mechanisms (T and B lymphocytes) are activated with longer duration of local inflammation.

  29. Inflammation

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

  31. 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, TNF, IL-1) CRP, SAP - opsonization and complement activation

  32. Inflammation - systemic reaction • Septicshock- themassivepenetrationofmicroorganismsintothebloodstream (TNF) • Anaphylacticshock- basophiland mast cellsactivationwithallergen (histamine)

  33. Tissue repair • eliminationofdamagedcellswithphagocytes • activationoffibroplasticmechanisms • activationofangiogenesis • regenerationandtissueremodeling • TGF 

  34. Antigens

  35. 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)

  36. Hapten • smallmolecules, that are able to inducespecificimmune response onlyaftertheattachmentto themacromolecularcarrier • separatehaptens are not immunogenic • typicallydrugs (eg penicillinantibiotics, hydralazin)

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

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

  39. Antigen • endogenousantigens- autoantigens (selfAg) • exogenousantigens- foreignsubstancesfromtheenvironment • allergenisexoantigenthat in thesusceptibleindividualscan cause pathological (allergic) immune response

  40. Properties of antigen • immunogenicity proteins> carbohydrates> macromoleculecomplexes (glycoproteins, nucleoproteins, andglycolipids)> lipids • specificity

  41. Factors affecting immunogenicity • Physical:solubility - insoluble Ag more immunogenicmolecular weight - ideal 5-40 kDa • Chemical:structure - the number of determinantsdegradability - "ease" of uncovering the determinants in antigen presenting cells (APC cell) • Biological:biological heterogeneitygenetic and physiological disposition of the body

  42. Degree of foreignness • Autogeneic- antigensofthesameindividual • Syngeneic- antigensofgeneticallyidenticalindividuals (eg twins) • Allogeneic (alloantigens) - antigensgeneticallydifferentindividualsofthesame species • Xenogeneic (heterologous) - antigensderivedfromindividualsofdifferent species (eg monkeykidneytransplant man)

  43. Typesofantigensaccordingto antigen presentation • T- dependentantigens • T- independent antigens

  44. Thymus dependent antigens • more frequently, mostlyprotein Ag • forspecifichumoralimmune response to antigen isnecessaryassistanceof THlymphocytes(or response isn´t enougheffective) • assistanceisimplemented in theformofcytokinesproduced by THlymphocytes

  45. T-independent pathway T- independent antigens • can stimulate B cells directly • mainly bacterial polysaccharides, lipopolysaccharides and polymeric forms of proteins (e.g. Haemophilus, Str.pneumoniae)

  46. Superantigens • stimulate T cellspolyclonalyandmassively (massivecytokinerelease) • massiveactivationof T cellscan cause shock • e.g. bacterialtoxins (Staph.aureus, Str.pyogenes, Pseud.aeruginosa)

  47. Superantigens • Superantigens are proteins with 2 binding sites, one interacts with the epitope presented on all MHCgpII, second interacts with structures presented in many different TCR molecules

  48. Sequestered antigens • autoantigens, that are normally hidden to immune system and therefore unknow (e.g. brain, the lens of the eye , testes) • if they are "uncovered" by demage, exposed to the immune system, are recognized as foreign (one of the theories of autoimmune processes)

  49. Immunologically privileged sites • brain, eye, gonads • are protectedfrompotentiallydamaginginflammatoryimmuneresponses • thistissues are far lessrejected in allogeneictransplant (cornea) • thisprivilegedpositionis not absolute

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