The complement system and innate immunity - part 1.pdf

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McGill University
Microbiology and Immun (Sci)
MIMM 314

Thecomplementsystem and innateimmunity February-05-11 12:08PM - Heat-labilecomponent of normal plasmathat augmentstheopsonization andkilling of bacteria byantibodies - Complementcan alsobe activated early in infection in theabsenceof antibodies - Complementfirst evolved as part ofthe innateimmunesystem, whereit hasan important rolein coating pathogensand facilitating their destruction 2-11: Complement is a systemof plasma proteins that is activated by thepresence of pathogens - Complementsystem is madeup of a largenumberof diff plasmaprot that interact with oneanother bothto opsonize pathogensandto inducea series of imfammatory responsesthat helpto fight infec. - Severalcomplement prot arepreateases thatbecome activated onlyafter cleavage, usuallybyanotherspecific protease.In theirinactive form --> called pro-enzymes or zymogens. EX: Pepsin, inactive: pepsinogen - Atsites of infec, theyarelocallyactivated by thepresence ofhe pathogenand triggera series of powerful inflammatory events.Thecomplement system becomes activated throughatriggered-enzyme cascadein which ac active complement proteasegeneratedby cleavageof its zymogen precursorthencleaves its substrate,anothercomplement zymogen to its activeform and so on. ○ In this way, theactivation of a smallnumber of complement proteins at thestartof thepathways highlyamplified by eachsuccessive enzymatic reaction, resultingin therapid generation oflargecomplement response. --> ANALOGOUS toblood coagulationsystem - Akey site for theactivation of the complement pathwayis thesurfaceof thepathogens ○ Thereare THREE distinct pathways thoughwhich omplement can beactivated: 1. CLASSICAL PATHWAY: triggeredby thebinding of comement component C1q to Ab complexed with Ag by the direct binding ofC1q t thepathogen surface, or by thebinding of C1qto C-reactiveprotein boundto the pathogensurface. 2. LECTIN PATHWAY: triggeredby mannose-binding lectin or theficolin proteins, normal serumconstituentsthat bindsome encapsulatedbacteria. 3. ALTERNATIVE PATHWAY: triggereddirectly on pathogensurfaces. ○ Allofthesepathways generatea crucial enzymatic activity that in turngenerates theeffector molecules of complement. - Waysin whichthe complement systemprotects against infec: 1. Generationsoflargenumbersof activated complement proteins that bind covalentlyto pathogens, opsonizingthem forengulfment by phagocytesbearing receptors for complement. 2. Smallfragmentsof some complement proteins act as chemoattractantstorecruit more phagocytes to thesiteof complementactivation and also to activatethesephagocytes 3. Thefinal componentsin thecomplement pathway damagecertain bacteria by creatingpores in thebacteria membrane - Importantrolein activating theadaptiveimmune system ○ Thisis a consequenceof opsonization, becauseAPC bear receptorsfor complement thatenhancethe uptakeof complement-coatedantigensand thepresentation oftheseantigens to theadaptiveIMM system. ○ Blymphocytes bear receptors for complement proteins thatact as co-stimulators,enhancing theresponseof thec cellto complement-coated Ag. - Dying cells can trigger complement activation. ○ Ascomplement-coated particles aremore efficiently taken up byphagocytes, complement is important in the efficient disposal of dead, damaged andapoptotic cellsand in doing so, protects againstthedev of autoimmunity. 2-12:Complement interacts with pathogensto mark them fordestruction by phagocytes - CLASSICAL PATHWAY: ○ C1q (first protein in thecomplement cascade) binds to thepathogensurface:  Threeways of binding to surface 1. DIRECTLY to surfacecomponents ofsome bacteria, including certain prteins of bacerial cell walls ad poluanionic surfacestructuressuchas lipoteichoic acid on Gram+ bacteria 2. Bindsto C-reactiveprotein, an acute-phaseprotein ofhuman plasmathat binds to phsphocholineresidues in bacteriapolysaccharides, such as pnewmococcal C polysaccharide 3. Linkbetween theeffector mechanisms of innateand adaptiveimmunity by binding to AB:AG complexes - LECTIN PATHWAY: Initiated by thebinding of carbohydrate-bindingproteins to arraysof carbohydrateson thesurface ofpathogens. ○ Initiated by thebinding of carbohydrate-bindingproteins to arraysof carbohydrateson thesurface ofpathogens. Thesecarb-binding proteins includethelectin MBL, which binds to mannose-containingcarbs on bacteria r viruses, andtheficolins which bind to theN-acetylglucosaminepresenton thesurface ofsome pathogens. - ALTERNATIVE PATHWAY: ○ Initiated by thebinding of spontaneouslyactivatedcomplement component C3 in plasmato thesurfaceof a pathogen - In each pathway: seq of RX generates a proteasecalled C3CONVERTASE. ○ "earlyevents"consist of triggered-enzyme cascades in which complement zymogens aresuccessivelycleaved to yield twofragments, thelargerof which in an active serine protease. Theactive proteasestays on thesurfaceof the pathogentherebyensuringthat thenext activated proteasewill also be on thesurfaceof thepathogen.Thesmall peptidecan act as a solublemediator of inflammation ○ C3convertaseare covalentlyboundto thesurfaceof thepathogen:  Theycleave C3to C3band C3a. C3b is themain effector moleculeof thecomplement system and c3a is a potent peptidethatmediates inflammation. C3b acts as an opsonin, bond covalentlyto pathogenand thereby targetit fordestruction byphagocytes equipped for receptors for C3b  C3balsobinds to C3 convertaseand makes C5 CONVERTASE that producesthemost important and most potent inflammatorypeptide C5a and thelargeactive fragment C5b, thatinitates the"LATE" events □ Lateevents: seq of polymerization reactions in which a set of complement proteins knownas theterminal componentsinteractto form a membrane-attack complex, which creates a porein thecell membranes of certainpathogens--> maylead to death - Nomenclature ○ Allcomponentsof theclassical complement pathwayand themembrane-attack complex aredesignated by theletter Cfollowed bya number.The nativecomponentshavea simplenumber designation(ex. C1 or C3)and theproductsof cleavagesreactionsare designatedby added lower-caseletters; thelargercomponent (activeone) being designated byb and thesmallerfragment represented bya.  EXCEPTION: C2's largerfragment is denoted C2a andhas theenzymatic activity as well ○ Componentsofalternativepathwayare designatedby different capital letters; thecleavageproductsaredesignated byaddition of lower-caseletters b (largefrag) or a (smallfrag) ○ In lectin pathway, thefirst enzymes to be activated areknown as theMannose-binding-lectin-Assoicated-Serine- ProteasesorMASP 1 and MASP 2; therest of thepathwayis sameas classical - C3formation ○ Classicalandlectin pathways:the c3 convertaseis formed from membrane-boundc4b complexed with c2a, designatedc42a. ○ In thealternativepathway, a homologousc3 convertaseis formed from membrane-boundc3b complexed with Bb, C3bBb.  Alternativepathwaycan act as an amplification loop for allthreepathways, becauseit is initiate by thebinding ofc3b - Regulation ○ Key activated complement componentsare rapidlyinactivated unlessthey bind to thepathogensurfaceon which theiractivation was initiated ○ Severalpoints in thepathway at which regulatoryproteinsact on complement componentsto prevent the inadvertentactivationof complement on host-cell surfaces; therebyprotecting them from accidental damage 2-13:The classicalpathwayis initiated by activation of theC1 complex 2-13:The classical pathwayis initiated by activation of theC1 complex - C1q linkstheadaptivehumoralimmune responseto thecomplement system by binding to AB:AG complexes. - Canalsobe activated duringinnateimmune response: ○ NATURALANTIBODIES areproduced by theimmunesystem in theabsenceof any infection. They havebroad specificity for self andmicrobial AG; can react with manypathogensand as in adaptiveimmunity, can activate complementthroughthebinding of C1q. ○ Mostnaturalantibodythat is produced is ofthe classIgM and that is theclass thatsis most efficient at binding C1q --> naturalABprovidean effective means by which complement activation can bedirected on pathogensurface immediatelyupon infec ○ C1qcan bind directly to surfaceof some pathogensandtrigger complement activation in theabsenceof Ab. - Classicalpathway: ○ C1COMPLEX: consists of a singleC1q moleculeboundto two melecules each of thezymogens
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