The complement activation pathway can be roughly divided into two pathways, the first one is the classical pathway, and the second one is also called the alternative pathway.It is said that the second way is the same as that advocated by L. PillemerProperdinThe system is said to be the same way as the firstcomplementThe pathway can be caused by more simple substances and can also be seen in lower animals.
Complement activation pathway
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Classic approach
complementstayBacteriolysisorhemolysisIn the process of activation during reaction, 11 components can be divided into 3 functional units, namely ① identification unit: including C1q, C1r, C1s; ② activation unit: including C2C3, C4; ③ Membrane attack units: including C5, C6, C7, C8 and C9.Complement components of the same functional unit have chemistry with each otherAffinityAfter activation, they can be combined with each other to jointly executeCytolysisThis biological function.Therefore, the complementClassic activation pathwayIt can be divided into three stages: recognition, activation and membrane attack.These three stages are generallyTarget cell3 different parts of the membrane.During the activation of complement, C2, C3, C4, and C5 are all split into two or more fragments, respectively marked with a, b, and other symbols, such as C3a, C3b, and C3c.amongC2bC3b, C4b, C5b bind to target cells directly or indirectly, participate in the process of cell lysis in the form of solid phase, and C3a, C5a dissociate in the liquid phase.complementIn the process of activation, C5, C6, C7 can also polymerize into C567 after activation, and play special biological functions together with C3a and C5a
The components involved in the classical activation pathway of complement include C1-C9.According to their role in the activation process, they are artificially divided into three groups, namely, identification units (Clq, ClrCls）, activation units (C4, C2, C3) and membrane attack units (C5-C9) play a role in different stages of activation, namely recognition stage, activation stage and membrane functional attack stage.
（1） Identification phase
Clq: Clq molecule has 6 energiesimmunoglobulinMolecularComplement fixationPoint combination part.When more than twoJunction siteWhen combined with immunoglobulin molecules, i.e. after Clq bridges immunoglobulin, subsequentcomplementComponents,IgGIt is a monomer. Only when it binds with antigen, can it make more than two IgG molecules close to each other, and provide more than two adjacent complement binding points to contact with Clq. Only whenIgMIt can bind to the antigen, change the configuration, and expose the complement binding site before binding to Clq.The ability of a molecule's IgM to activate complement is greater than that of IgG.After Clq is bridged with the complement binding point, its configuration changes, resulting in Clr andClsSequential activation of.
Clr: Clr at C1macromoleculeIt plays a role in connecting Clq and Cls.Clq can change the configuration of Clr after starting, and active Clr can activate Cls.
Cls: Clr makes ClsPeptide chainCleavage, in which one segment Cls has esterenzymatic activityIs the activity of CI.This enzyme activity can be inactivated by C1INH.
stayClassic approachOnce Cls are formed, the recognition phase is completed and the activation phase is entered.
C4: C4 is the substrate of CI.In the presence of Mg2, CI splits C4 into two fragments, C4a and C4b, and makes the combined C4b lose its binding ability rapidly.After the reaction of CI with C4, the active site of CI acting on C2 can be better revealed.
C2: C2 is also the substrate of CI, but the interaction between CI and C2 is significantly enhanced after the action of C4.C2 is cleaved by CI into two fragments C2a andC2b。When C4b and C2b are combined into C4b2b (abbreviated as C42), it is the classic wayC3 invertase。
C5 invertaseAfter cracking C5, it acts on the following otherscomplementAnd finally lead to cell damage and cell lysis.
C5：C5 invertaseTwo fragments, C5a and C5b, were produced by splitting C5.C5a is free in the liquid phase and has allergic toxin activity and chemotactic activity.C5b can be adsorbed on adjacentcell surfaceHowever, its activity is extremely unstable and easy to decay to C5bi.
Although C6-C9: C5b is unstable, it is relatively stable when it combines with C6 to form a C56 complex, but this C5b6 has no activity.When C5b6 and C7 combine to form the three molecule complex C5b67, it is relatively stable and difficult to dissociate from the cell membrane.
C5b67 can be adsorbed on the sensitized cell membrane, or on the adjacent non sensitized cell membrane (that is, the cell membrane without antibody).C5b67 is one that causes cell membrane damageKey components。When it combines with the cell membrane, it is inserted into the membranePhospholipid bilayerStructure.
If C5b67 does not bind to the appropriate cell membrane, C5b in it can still decay and lose the activity of binding to the cell membrane and splitting cells.
Although C5b67 has no enzyme activityMolecular arrangementThe method is conducive to adsorbing C8 to form C5678.Where C8 is C9Junction siteTherefore, C5-9 continues to form, that iscomplementIt can attack the cell membrane and damage the cell membrane.
When C5b, C6 and C7 bind to the cell membrane, the cell membrane remains intact;Only after C8 adsorption did slight damage occur to cellsContentsStart to leak.The damage process of cell membrane was accelerated only after binding C9, so C9 was considered to be the promoter of C8.
（1） Preparation stage under physiological conditions
Under normal physiological conditions, C3 andB factor、D factorAnd can produce very little C3B and C3bBb（Bypass routeOfC3 invertase）, but quicklyH-factorandI factorThe C3 and subsequentcomplementComposition.Only when the effects of factor H and factor I are blocked, can the bypass pathway be activated.
C3: C3 in plasma can be naturally and slowly lysed to continuously produce a small amount of C3b, and C3b released into the liquid phase is rapidly inactivated by factor I.
B factor(fB): C3b produced slowly in the liquid phase can combine with factor B to form C3bB in the presence of Mg2.
Factor D (fD): inactiveD factorAnd active factor D (factor BInvertase）。Factor D acts on C3bB, which can split factor B in the complex to form C3bBb (C3 invertase) and Ba free in the liquid phase.C3bBb can split C3 into C3a and C3b, but in fact this enzyme is not efficient and stable,H-factorThe Bb in the replaceable C3bBb complex can dissociate C3b from Bb, and the dissociated or dissociated C3b is immediatelyI factorInactivation.Therefore, C3bBb is kept at a very low level under the physiological condition that there is no activating substance, and it cannot lyse C3 in a large amount, nor activate subsequentcomplementComposition.However, the low rate of C3 cracking and the formation of low concentration C3bBb are of great significance.It can be compared to being in a state of "shooting at the target".
P factor (fP):ProperdinAnd combines with C3bBb to form C3bBbP (C3 invertase).
C3 plays an important role in both activation pathways.C3 is the most abundant in serumcomplementComposition, which is also needed to adapt to its role.Whether in the classical pathway or the bypass pathway, when C3 is activated by the activator, its pyrolysis product C3b canB factorandD factorA new C3bBb was synthesized with the participation of.The latter further cracked C3.This process is triggered once there is abundant C3 in plasma and sufficient B factor and Mg2.It may be activated to produce significant amplification effect.Some people call this C3Bb dependentpositive feedbackPath, or C3b positive feedback path.
lectin pathway
Complement activationOne of the pathways ofmannanbinding lectin（mannan-binding lectin,MBL）Or fibrin (FCN) directly recognizes multiplePathogenic MicrobesSuperficialmannose, N-acetylmannose, N-acetylglucoseAmmoniaFucoseEqual to the endGlycosylSugar structure.MBL-MASP complex andpathogenMASP-1 and MASP-2 are activated independently by the combination of surface sugar structure.Activated MASP2 exerts its SP activity, cleaves C4, and the generated C4b segment covalently binds to the surface of the pathogen. Through interaction with C2, the latter is also cleaved by MASP2, forming C3 invertase C4b2a, which then activates complementCP；ActivatedMASP1It can directly cleave C3 to produce C3b, form C3 invertase C3bBb or C3bBbP under the action of fD and fP, and produce C5 invertase C3bBb3b, which is activatedcomplementAP。
New discovery approach
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Properdin pathway
Process: fPSpecific recognition→ Non covalent binding on the surface of target cells → Recruitment of C3b and fB in body fluid → Formation of C3bBP → Formation of C3bBbP under the action of fD.
Proteolytic pathway
someproteaseOr factors can directly activate complement.
M Φ (inductive) andPMN(Constitutive) expression membrane typeSerine protease, which can cleave C3 and C5 to produce C3a and C5aImmunomodulationPlay an important role in.
