complement – Flashcards
Unlock all answers in this set
Unlock answersquestion
| what is complement? |
answer
| a group of proteins (~30), whose functions "complement" the antigen-binding function of antibodies. |
question
| what does complement consist of? what does it do generally? |
answer
| essentially a proteolytic cascade, many complements exist in plasma in inactive/zymogen form. when activated, (usually by proteolytic cleavage), the next component in the cascade is cleaved -> leads to the deposition or "fixing" of complement components to the pathogen surface. |
question
| what are the major functions of complement? |
answer
| opsonization, direct lysis of target cells/pathogens, and chemoattraction/activation of inflammatory cells |
question
| what are the three pathways for activating complement, (in order of activation)? |
answer
| alternative pathway, lectin pathway, and the classical pathway |
question
| what is the alternative pathway? |
answer
| this pathway is triggered at sites of microbial infection and does not involve Ig deposition on the pathogen surface. this pathway is an element of the innate immune system and is more evolutionarily primitive. |
question
| what is the lectin pathway? |
answer
| this pathway is activated by binding of plasma protein to mannose-containing peptidoglycans, (MBP), on microbial surfaces. the lectin pathway does not involve Ig deposition on a pathogen surface |
question
| what is the classical pathway? |
answer
| the classical pathway is an innate effector mechanism involved in humoral aquired immunity. is triggered as an effector mechanism when certain isotypes of Ig or C-reactive protein bind to a pathogen. |
question
| what is the most important action that occurs in the complement cascade? why? |
answer
| cleavage of C3 to C3a and C3b. this generates biologically active products and subsequent covalent attachment of C3b to microbial cell surfaces or antibody bound to antigen |
question
| what is a problem with pts lacking C3? why? |
answer
| pts lacking C3 are prone to successive severe infections. it plays an important step in amplification of the complement cascade. |
question
| what happens when C3 is cleaved into Ca and Cb? |
answer
| C3b becomes covalently bound to the pathogen surface, opsonizing it and organizing the formation of protein complexes that damage the pathogens membrane, (MAC). the soluble C3a fragment functions as a chemoattractant to recruit effector cells including phagocytes |
question
| how is the alternative complement pathway activated? |
answer
| the alternative pathway is triggered when a hydrolysis product of C3 is deposited on a pathogen surface |
question
| how is the lectin complement pathway activated? |
answer
| the lectin pathway is initiated when mannose binding protein, (MBP), binds to mannose on the pathogen surface. (MBP is structurally similar to C1 in the classical pathway) |
question
| what are the 3 ways the classical pathway can be activated? |
answer
| IgM bound to targets cells, 2 or more IgG bound to target cells, or C reactive protein, (pentameric protein similar to C1 -> acute phase reactant) |
question
| what is the order of activation in the classical pathway |
answer
| C1,4,2,3,5,6,7,8,9 |
question
| what is the first complex activated in the classical pathway? what is it composed of? what part do Igs have receptors for? |
answer
| C1 which is composed of C1q, r, and s. IgG and IgM have receptors for C1q |
question
| how do IgM or CRP, (C reactive protein), bind to C1? |
answer
| pentameric IgM is planar, (and thus soluble), until it binds to the pathogen surface which is when it changes to "staple form", and it is then capable of binding C1q at multiple sites. CRP is also pentameric with multiple binding sites for C1q. (C1q is the "lunar landing module" looking part of C1 that has 5 legs that bind to the 5 arms of IgM/CRP) |
question
| are there versions of IgG that bind C1q better than others? |
answer
| yes, IgG1 and IgG3 fix complement in the classical pathway better than IgG2 |
question
| how does IgG activate C1? |
answer
| when at least 2 IgG are in close enough proximity, C1q binds to them |
question
| what happens within C1 when C1q is activated? is this regulated? |
answer
| activated C1q activates C1r activates C1s which has proteolytic activity on C4 and C2. proteolytic activity of C1r and s is inhibited by C1 INH. |
question
| what can happen with deficiency in C1 INH? |
answer
| hereditary angioneurotic edema, which is autosomal dominant causing intermittent skin and mucosal edema, (abdominal pain, vomiting, diarrhea, airway obstruction), all caused by increased breakdown of C2, (C2 kinin, a proteolytic fragment of which is responsible for edema) and C4. |
question
| where does classical C3 convertase come from? |
answer
| after cleavage of C4 and C2, C4b fragments that are covalently attached to the pathogen surface BIND C2a. C4b2a is the classical C3 convertase. |
question
| what does C3 convertase do? why is this an important step? |
answer
| activates C3 which splits in to C3a+b. C3b becomes attached to the target cell membrane. C3a becomes a soluble chemoattractant. this is an important amplfication step because you can keep cleaving C3 with the convertase. |
question
| what happens to some of the C3b created by the action of C3 convertase? |
answer
| some C3b binds to C4b2a to form C3b2a4b, otherwise known as C5 convertase |
question
| what does C5 convertase do? |
answer
| C5 convertase makes C5a+b, C5a is an anaphylatoxin and C5b stays at the membrane |
question
| what are C5a, (and C3a to a lesser degree)? |
answer
| anaphylatoxins cause smooth muscle contraction, degranulation of mast cells/basophils, release of histamine/other vasoactive amines, and increase vascular permeability |
question
| what is C5a's effect on neutrophils? |
answer
| C5a is a chemotaxin for neutrophils, meaning it attracts them |
question
| what does C5b do? |
answer
| initiates the membrane attack complex |
question
| what is the membrane attack complex? |
answer
| cell-bound C5b initiates binding of C6+7 to the surface, then C8 inserts itself into the membrane, followed by C9 proteins coming and forming a hole |
question
| what infection is there increased susceptibility to as a result of terminal complement component deficiency? |
answer
| neisseria infection |
question
| how is the alternative pathway initiated? |
answer
| hydrolysis of a thioester bond in C3 occurs constitutively, but when pathogens are present, the level of hydrolysis rises. |
question
| in the alternative pathway, how is the thioester bond hydrolysed? |
answer
| when C3 is first made in the liver, a thioester bond is sequestered in the hydrophilic innards of the protein. however, in the aqueous environment of the plasma, conformational change occurs and the thioester bond is exposed/hydrolyzed yeilding a molecule called iC3 |
question
| what does iC3 do in the alternative complement pathway? |
answer
| iC3 binds to inactive serum factor B, making it more susceptible to cleavage by factor D, (resulting in smaller Ba and larger Bb). Factor Bb has protease activity and cleaves more C3 into C3a and C3b -> iC3Bb is a soluble C3 convertase |
question
| what factors are unique to the alternative pathway? |
answer
| B and D |
question
| what happens to C3b once cleaved in the alternative pathway? |
answer
| C3b is deposited on the pathogen surface, and when it does, more factor B is recruited, facilitating it's cleavage by Factor D. resulting Bb complexes with C3b, creating C3bBb, an alternative C3 convertase on the cell's surface |
question
| how is C3 regulated in the alternative pathway? why does the alternative pathway require tight control? |
answer
| properdin, factor H, decay accelerating factor, and membrane co-factor protein. the alternative pathway requires tight control via these factors, b/c the alternative pathway is more primitive and happens semi-spontaneously |
question
| how does properdin regulate C3 in the alternative pathway? |
answer
| properdin increases the speed and power of complement activation by binding the C3 convertase C3bBb on the pathogen surface and prevents its degradation by proteases. properdin -> "positive" |
question
| how does factor H regulate C3 in the alternative pathway? |
answer
| factor H counteracts properdin by facilitating cleavage of C3b to iC3b by Factor I, (iC3b cannot form the C3 convertase) |
question
| what happens if there is a Factor I deficiency? |
answer
| formation of C3bBb, (C3 convertase), is unchecked until C3 runs out, and when faced with bacterial infection there is less C3b deposited. pts with this are more susceptible to ear infections and abscesses caused by encapsulated bacteria. (this looks like pts with C3 deficiency) |
question
| what is the C3 convertase in the classical complement pathway? what is the C3 convertase in the alternative complement pathway? |
answer
| the classical C3 convertase is: C4b2a, the alternative C3 convertase is: either iC3bBb solubly or C3bBb which is attached to the cell surface |
question
| what does decay accelerating factor do in the alternative pathway? |
answer
| DAF binds to C3b in the alternative C3 convertase, causing dissociation and inactivation, protecting human cells |
question
| what does membrane co-factor protein do in the alternative pathway? |
answer
| MCP binding to C3b makes it susceptible to the action of factor I, (similar to factor H), protecting human cells |
question
| what do DAF and MCP have in common in the alternative pathway? |
answer
| decay accelerating factor, (DAF), and membrane co-factor protein, (MCP) both function to protect human cells from the complement pathway |
question
| what is the C5 convertase in the alternative pathway? |
answer
| C3bBb + another C3b = C3bC3bBb, a C5 convertase |
question
| what happens when C5 convertase cleaves C5 in the alternative pathway? |
answer
| when C3bC3bBb cleaves C5, the same thing happens as in the classical pathway: C5a is a chemotaxin for neutrophils, meaning it attracts them. cell-bound C5b initiates the MAC w/binding of C6+7 to the surface, then C8 inserts itself into the membrane, followed by C9 proteins coming and forming a hole |
question
| where is complement receptor 1 found? what complements does it bind? what does it do? can anything enhance its action? |
answer
| CR1 is expressed on many cell types including macrophages, neutrophils, and RBCs, (facilitates transport of immune complexes to spleen for clearance). CR1 binds mostly C3b but also C4b on pathogen surfaces, (high affinity). it facilitates uptake and destruction of a pathogen, (C3b/C4b act as opsonins). when the Fc region of IgG binds phagocytes or in the presence of IFN-gamma, CR1 is markedly enhanced. |
question
| where is complement receptor 2 found? what is it a component of? what does it bind to? |
answer
| CR2 is found on follicular dendritic cells and B cells. it is a component of of the B cell receptor complex, (co-receptor), and binds to degradation products of C3b, (C3d) on microbial surfaces, delivering activation signals to B cell and helps form an innate to aquired immune response bridge. |
question
| what are CR3 and CR4? what do they bind? where are they expressed? |
answer
| complement receptors 3 and 4 are beta-integrins and bind iC3b. they are both expressed on phagocytes and promote phagocytosis of microbes opsonized with iC3b, CR3 is involved with adherence of leukocytes to endothelial cells at sites of inflammation via binding to ICAM-1 |
question
| if CR3 and CR4 are beta-integrins, what else are they called? |
answer
| CR3 is also called CD11b/CD18 and Mac-1 CR4 is also called CD11c/CD18 |
