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Slide 1

Sorveto, Dayle Daniel G.Complement SystemOverview

Biological Activities of Complement ComponentsCleavage of the C3 and C5 components produces important factors that enhance clearance of the infectious agent by promoting access to the infection site and by attracting the cells that mediate protective inflammatory reactions. C3b is an opsonin that promotes clearance of bacteria by binding directly to the cell membrane to make the cell more attractive to phagocytic cells such as neutrophils and macrophages, which have receptors for C3b. C3b can be cleaved further to generate C3d, which is an activator of B lymphocytes. Complement fragments C3a and C5a serve as powerful anaphylatoxins that stimulate mast cells to release histamine, which enhances vascular permeability and smooth muscle contraction. C3a and C5a also act as attractants (chemotactic factors) for neutrophils and macrophages. These cells also express receptors for C3b, are phagocytic, and promote inflammatory reactions. Role in InflammationOpsonization:- C3b is important!Chemotaxis:- complement fragments diffuse from target stimulating cellular movement and activation.Target cell lysis:-membrane attack complex hydrophobic plug inserted into lipid membrane bilayer

Membrane Attack ComplexThe terminal stage of the classical pathway involves creation of the membrane attack complex, which is also called the lytic unit.The five terminal complement proteins (C5 through C9) associate into a membrane attack complex on target cell membranes to mediate injury.Initiation of membrane attack complex assembly begins with C5 cleavage into C5a and C5b fragments. A (C5b,6,7,8)1(C9)n complex forms and drills a hole in the membrane, leading to the hypotonic lysis of cells. The C9 component is similar to perforin, which is produced by cytolytic T cells and natural killer cells. Regulation of Complement ActivationHumans have several mechanisms for preventing generation of the C3 convertase to protect against inappropriate complement activation. These include C1 inhibitor, C4 binding protein, Factor H, Factor I, and the cell surface proteins, which are decay-accelerating factor (DAF) and membrane cofactor protein.In addition, CD59 (protectin) prevents formation of the membrane attack complex.Most infectious agents lack these protective mechanisms and remain susceptible to complement. A genetic deficiency in these protection systems can result in disease. 2001 by Garland Science

Regulation of complement system by regulatory proteins

Clinical implicationsComplement deficienciesGlomerulonephritisC1 inhibitor deficiencySLEPNHSepsisAPLS1. Complement deficiency:-Increased susceptibility to pyogenic infectionsContributing factorsDeficient opsonisationDeficiency compromising lytic activityDeficient manose-binding lectin pathwayPyogenic infection:-Site of defect:- antibody production, complement proteins of classical pathway, phagocyte functionUsually bacteria is opsonised with Ab complement is then activated, phagocytosis occurs and intracellular killingKey player:- C3b Impaired lysisMAC component deficiency a/w Neisserial disease*Risk of meningococcal disease ~ 0.5% / yr (RR 5000 cf normal population)Deficient lectinDeficiency occurs due to 1 of 3 point mutations a/w reduced levels.Associated with higher risk of infection in children whilst losing passive immunity? Protective against mycobacterial infections2. GlomerulonephritisKey of C3b regulation:- whether Factor B or H binds to C3bIf C3 regulation is defective:- often a/w GN.Due to C3 nephritic factor increases stability of C3 convertase enzymes association with membranoproliferative GN ORReduced function of Factor H or I Associations with HUS (+/- low level of C3)3. C1 INHIBITOR DEFICIENCYAutosomal dominant inadequate production of physiologically adequate C1 inhibitorType 1:- 85% - reduced transcription of abnormal allele. Reduced levels of C1 inhibitorType 2:- point mutation in C1 inhibitor gene altered activity (So levels may be normal or high as not consumed)Autoantibodies against C1 inhibitorInhibits C1r and C1s, activated FXI and XIIConsumed by plasmin trigger for angioedema attacks.Rx: C1 inhibitor infusion.

4. Complement deficiency + SLEInverse correlation with position of deficient protein in activation sequence of the classical pathwayHomozygous def of C1q, C1r and C1s + C4 strongly a/w SLE (93%, 57%, 75%)Cf. def of C2 10% prevalence.Protective role exists for those in whom activation of classical pathway up to C4 cleavage occurs. 5. PNH:-Acquired stem cell disorderDeficiency of PIG-A (somatic mutation) required for synthesis of glycosyl-PI phospholipid.Important for anchorage of proteins to cell membranesIn PNH lack of GPI-linked proteins (including complement-regulating surface proteins) - eg DAF (i.e CD55) which regulates formation of C3 convertase and CD 59 restricts formation of MAC.Deficiency on RBCs:- does not allow protection against terminal complementClinically: chronic haemolysis, fatigue, pain, thrombotic events. median age early 30s; median survival as low as 10-15 yrs.

6. Complement system + sepsisC5a anaphylatoxin strong chemoattractant.Sepsis excessive early production of C5a upregulated proinflammatory response. Role for blockade of C5a with antibodies shown to improve survival of septic mice. Use in IHD to assist cardiac reperfusion

7. Complement + APLSNature medicine 2004:-Previous mouse models shown that complement activation plays an important role in pregnancy + fetal growth restrictionLikely induced by activation thru aPL antibodies (classical pathway)Anticoagulation alone insufficient in completely averting miscarriageHeparin use - ? Additional role via inhibition of complement.