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104 Cards in this Set
- Front
- Back
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What is complement?
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Heat labile component of normal plasma that augments opsonization and killing of bacteria by Ab
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What system is complement a part of?
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Innate
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What kind of factors and cells make up the innate system?
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Humoral Factors: Complement, clotting factors: opsonize, damage, localize, send signals to cells
Phagocytic cells: (macrophages, neutrophils) engulf and destroy Cytotoxic cells: (NK cells) kill infecter cells Signalling cells: (Mast, mac, neutrophils) produce regulatory molec which alter local and distant cell behaviour and recruit leukocytes |
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What is the B1 (CD5 B cell)?
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Innate immune responder
doesn't need T cell help Express surface molec CD5 Limited specificity Self renewing in the periphery Produces IgM within 48 hours Responds to polymers like polysacc |
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What happens when B1 binds a bacterial capsid or cell wall?
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Receives a signal (IL5) from accessory cells
B1 secretes IgM anti-polysac Ab IgM binds polysac capsule Activation of complement and removal of bacteria |
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How do different Igs differ?
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# of CH domains
# of di-S bonds Flexibility of the hinge region Different sites for glycosylation |
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What are the class properties of the dif Ig's?
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Ig A: minor serum component
IgA dimer: major secretory component IgD: B cell surface Ig IgE: Binds IgE receptor, Ag triggers mast cell degranulation, very low lvl in serum IgG: Predominant circulating Ab after booster immunization, actiates complement IgM: Predominant circulating Ab 1st immunization, efficiently activates complement |
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What happens when an Ab bind Ag?
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Ab undergoes conformational changes
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How many Ag-bound IgM does it take to activate complement?
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1
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What are the 3 paths to activate complement?
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1) Classical
2) MB-Lectin 3) Alternative |
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What happens once complement is activated?
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Recruitment of inflammatory cells
Opsonization of pathogens Killing of pathogens |
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What are the 3 ways complement prtects vs infection?
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1)Makes large # of activated complement ptns that bind covalently to pathogens & opsonize them for engulfment by phagocytes
2) Small part of complement ptns are chemoattractants that attract phagocytes to the site of complement and activate them Last parts of complement path damages certain bacteria by making pores in them |
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What initiates the classical path?
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C1q binds pathogen surface
i)binds directly to surface components of bact ii) Binds to C-reactive ptn iii) Binds Ab-Ag complex, linking innate and adaptive |
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What initiates the Lectin path?
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Carb binding ptns bind to various carbs on the surface of pathogens (includes the lectin MBL and ficolins)
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What does MBL bind?
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Binds mannose containing crbs on bact/viruses
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What do ficolins bind?
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NAGs of pathogen surface
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What initiates the alternative path?
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Binding of spontaneously activated complex component C3 in plasma to the surface of a pathogen
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What do the early events of complement lead to?
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get C3 convertase (a protease)
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What is a zymogen?
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Pro enz, inactive form of the enz
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What happens to the complement zymogens?
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Get cleaved into 2 fragments
->larger fragment (b) is a serine protease that stays on the path surface and activates other zymogens -> smaller fragment (a) is released and acts a a souble mediator of inflammation |
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What does C3 convertase do?
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Converts C3-> C3b and C3a
C3b: main effector molec of complement C3a: peptide mediator of inflammation |
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What does C3b do?
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Acts as an opsonizing agent, binds covalently to pathogens, target it for death by phagocytes with receptors for C3b
Binds C3 convertase to make C5 convertase |
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What does C5 convertase do?
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Converts C5--> C5a/b
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What is C5a?
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Most important and potent inflammatory peptide
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What does C5b do?
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Active fragment
Initiates the late events of complement |
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What happens in the late events?
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Polymerize rxns where terminal components interact to make a mb-attack complex
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What does the mb attack complex do?
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Makes a pore in the mb of a pathogen, which leads to the death of the pathogen
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What is the sequence of complement ptns for the classical path?
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C1, C4, C2, C3, C5, C6, C7, C8, C9
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How is C3 convertase formed in the classical and lectin path?
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C2 complexed with C4
(C4bC2a) |
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How is C3 convertase made in the alternative path?
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C3b + Bb (C3bBb)
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How does the alternative path connect to the other 2?
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Acts as an amplification loop for all 3 paths(its initiated by the binding of C3b)
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How is complement regulated?
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Keyactivated complement components are quickly inactivated if not bound to a pathogen surface on which their activation was initiated
Many pts in path where regulatory ptns act on complement componenets to stop accidental activation of complement on host cell surface |
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How does C1q link humoral to complement?
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Binding Ab:Ag
Can also be activated by innate |
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What is a natural Ab?
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Ab produced by immune system in absence of infection
have broad specificity for self and microbial Ag can react with pathogens and activate complement by binding C1q Mostly IgM |
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What makes up the C1 complex?
Wha is the C1q? |
1 C1 molec bound to 2 each C1r and C1s
(C1q= hexamer, made up of 2 trimers, forms a globular domain that surrounds the C1r:C1s complex) |
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What happens when mre than 1 C1q binds path/Ab cst region?
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conformation change in (C1r:C1s)2 complex-> activation of autocatalytic enz act in C1r
Active C1r cleaves C1s to its active serine protease |
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What does the active C1s do?
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CleavesC4 and C2 to get C4b and C2a
Tog they make C3 covertase (makes C3a/b) |
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How is complement initiated in the lectin path?
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Lectin path homologous to classical
MBL binds mannose residues and other sugars on the pathogen surfaces Forms a complex with 2 protease zymogens MASP1/2 (MASP2 likeC1r/s) When MBL complex binds to pathogen surface, MASP2 is activated to cleave C4 and C2 ->then does the same as the classical complex to make C3 convertase from C4 and C2.... |
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What happens to ppl who don't have MBL and MASP2?
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Get many infections in childhood
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What are ficolins?
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Related to C1q and MBL
3 ficolins:L,M, H Have fibrinogen like domain ->binds carbs and gives specificity for NAGs |
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What is complement activation confined to?
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Activating events are on the same site of pathogen surface so that C3 activation is on the pathogen and not the host or in the plasma
-> this is assured through covalent binding of C4b to path surface |
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What happens if the C3b cleavage product isn't covalently bound to the pathogen surface?
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It's inactivated
.: only opsonizes surface where complement is taking place |
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Why is C3b more efficient when Ab is bound to the pathogen?
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Phagocytes have receptors for complement and Ab
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What initiates the alt path of complement?
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Hydrolysis of C3
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Where does alt path initiation take place?
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On micobial surfaces in the absence of Ab
Does not depend on pathoen binding ptn for initation |
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Where in the body is C3 most abundant?
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plasma
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What is tickover?
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Spontaneous cleavage (of C3)
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When C3 is hydrolyzed in the alt path, what can it bind?
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Plasma factor B
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What is created when C3(H2O) binds factor B?
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Get factor D
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What is factor D and what doe it do?
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Protease
Cleaves B-> Ba and Bb |
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What does the C3 convertase look like in the alt path?
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C3(H2O)Bb (fluid C3 convertase)
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What does complement activation depend on in the alt path?
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Stability of C3bBb complex
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How are host cells protected vs complement?
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Various negative reg'l ptns
these ptns interact with C3b and prevent convertase from forming or make it quickly diss't |
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What is the Decay a factor (DAF or CD55)?
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Competes with factor B for binding of C3b on cell surface and can displace a Bb that's already made
Can also stop convertase by converting of C3b--> iC3b (inactive) w/ plasma fctor I wit the help of mb cofactor of proteolysis (MCP or CD46) |
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What is CRI?
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Complement receptor type I
Has similar activties to DAF and MCP (but has limited tissue distribution) |
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What does factor H do?
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Binds C3b and competes factor B to displace Bb from convertase and acts as cofactor for factor I
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How is C3 convertase stabilized?
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When complement is activated on a foreign surface/damaged host cell
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What is properdin (factor P)?
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Binds C3bBb convertase and enhances stabililty -> amplification of complement activation
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Wha happens wen C3bBb is stable?
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Can bind pathogen and opsonize or reinitiate pathogen to make more C3bBb
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What is the main effect of complement activation?
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deposits lots of C3b on surface of pathogen, forms covalent bonded coat that can signal the ultimate destruction of pathogens by phagocytes
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What makes up the C5 convertase?
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Classical: C3b binds C4bC2a-> C4bC2aC3b
Alternative: C3b binds C3 convertase-> C3b(2)Bb |
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Where does C5 bind?
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Receptor site on C3b
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What cleaves C5?
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C2a or Bb cleaves C5-> C5a/b
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Why is there only a limited number of C5 cleavage?
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Only cleaved when C5 binds C3b if its bound to C3 convertase
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What are C3a and C5a?
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Anaphylatoxins (inflammatory mediators)
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What do complement receptors on phagocytes do?
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Bind pathogens opsonized with complement (C3b major opsonizer, C4b has minor role)
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What is CR1/CD35?
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C3b receptor, expressed on macrophages and neutrophils
C3b binding CR1 can't stimulate phagocytosis alone, but can lead to phagocytosis in the presence of other immune mediators that activate macrophages |
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What affect dos C5a have on macrophages?
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Activate macrophages to eat bacteria bound to CR1
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What do CR2/3/4 bind to?
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Inactive forms of C3b that are attached to the pathogen surface
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What happens when iC3b is bound to CR3?
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Stimulates phagocytosis
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What is C3dg? What does it bind?
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Breakdown of C3b
Binds CR2, found on B cells |
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What happens if too much C3/4/5a are produced?
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Anaphylactic shock
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What do the anaphylatoxins induce?
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Smooth muscle contraction and increase vascular permeability
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What do C3/5 a induce?
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Adhesion molec on endothelial cells lining blood vessels
Activate mast cells from submucosal tissues to release mediators (histamines, TNF-α) |
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What happens following changes induced by C3/5a?
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Recruit Ab, complement and phagocytic cells to the site of infection
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What affect does C5a have on neutrophils and macrophages?
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inc adhesion to wall, ability to eat and migrate to infection
inc expression of CR1 and 3 |
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What kind of receptors do C5/3 a act through?
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Transmb receptors that activate G ptns (like chemokines)
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What is assembly of the terminal components of complement?
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Mb attack complex
form a pore in the lipid bilayer mb that destroys the mb integrity (stops H+ gradient) |
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What are the steps involved in mb attack complex formation?
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-Cleave C5 by C5 cnvertase, release C5b which initiates assembly of later complement components and their insertion into the cell mb
-C5b binds C6 (C5bC6)-> binds 1 C7 -> conf change, exposes hydrophobic site on C7, which inserts into the mb -C8 and C9 also have hydrophobic sites that are expressed when they bind the complex -C8 binds C5b, exposees hydrophob domain that inserts into the lipid bilayer -C8 induces polym of C9 -> pore forminstruucture -Mb attack complex ha a hydrophobic external face and hydrophyllic internal channel |
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What happens if someone is deficient in C5-C9?
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Only lead to susceptiility to Neisseria species
.: opsonizing and inflammatory actions of earlier components are more important for host defense vs infection |
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What is Serpin?
What does it do? |
Plasma Serine protease inhibitor; C1 inhibitor (C1INH)
C1INH binds active C1r:C1s, makes them diss't from C1q (this limits the amount of time C1s can cleave C4 and C2, also limits spontaneous activation of C1 in plasma) |
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What is hereditary angioneurotic edema?
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C1INH deficiency disease, get chronic spontaneous complement activation
-> lot of cleave C4 and C2 -Small fragment C2 cleaved to C2 kinin -> extensive swelling ->produce a lot of Bradykinin cuz no inhibition of kallikrein (reg'l by C1INH) => correct disease by replacing C1INH ->large frag of C4 and C2 don't make the C3 convertase cuz of slow inactivation of C4 |
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What does Serpin I do?
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Circulates in active form, but can only cleave C3b or C4b if it is bound to a mb cofactor ptn
(cleaves C3b-> iC3b -> C3dg & C4b-> C4c + C4d) |
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What has cofactor affinity for cofactor I?
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MCP and CR1
(also C4b-binding ptn (C4BP)) |
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What happens if you have a Factor I deficiency?
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Complement ptns are depleted, get many bacterial infections
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What do DAF and MCP do to prevent complement on host cells?
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Cofactors of C3b at cell surface
Compete with factor B to bind C3b bound to cells If B wins, getmore complemen If DAF/MCP binds: C3b->iC3b->C3dg |
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What stops C2 from binding C4?
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Competitive inhibition
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What promotes diss't of C4b2b and C3bBb convertases that have already formed?
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DAF and CR1
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What does CD59 (protectin) do?
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Inhibits binding of C9 to C5b678 complex
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What is Paroxysmal Nocturnal Hemoglobnuria?
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caused when ppl have a somatic mutation in a gene on X-chr so that CD59 and DAF don't work
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What happens to a RBC without CD59?
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Can be killed by spontaneous activation of complement
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What if there's a deficiency in C1qrs,2,4?
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Defective classical path
-> SLE, Glomerulonephritis, Pyogenic infefctions |
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What if there's a deficiency in C3?
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Both paths
-> Glomerulonephritis, pyogenic infections, immune complex disease |
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What if there's a deficiency in prperdin, factor D?
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defective alt path
-> pyogenic infections |
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What if there's a deficiency in C5,6,7,8
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Defective mb attack complex
-> disseminate neisserial infections |
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What if there's a deficiency in C1INH?
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Deregulated C3 consumption and kinin prod'n
-> SLE, Hereditary Angioneurotic edema |
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What if there's a deficiency in Factor I/H?
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Deregulated C3 consumption
-> pyogenic infections, immune complex disease |
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What if there's a deficiency in DAF and CD59-GPI anchor deficiency?
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Increased susceptibility to erythrocytes lysis'-> PNH
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What are the complement receptors ass't with?
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Cr1/3/4: Phagocytosis of particles ass't with complement
CR1:inhibition of complement cascade CR2: Enhancement of B cell activation CR1/2/3: Ag capture on follicular dendritic cells C3a/5aR: stimulation of cells via G ptn signalling paths CR1/C1qR: Clearance of immune complexes |
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What affect does CR1 have on erythrocytes?
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Protects RBC by promoting decay of C3 convertase
Allows RBC to pick up immune complexes and transport them to the liver and spleen |
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How does CRP initiate complement cascade?
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Member of Pentraxin family
Binds phophorylcholine part of bact/fungal cell wall LPS Opsonin Binds C1q collagen like parts and can initiate complement activation via C1 |
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How does MBL initiate complement?
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Collectin family
18 CRDs: Ca2+ dependent carb recognition domain acts as opsonin ass't with serine proteases (MASP1/2) |
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What induces synthesis of acute phase ptns?
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IL6 (made from activated macrophages)
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What are some examples of acute phase ptns?
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MBL
CRP |
