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60 Cards in this Set
- Front
- Back
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What kind of system is complement?
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Complex, multicomponent system
(named C1- C9) |
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Describe the complement cascade?
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It is Constitutive, Non-Specific and must be ACTIVATED in order to fct
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What are the fcts of complement?
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Makes bacteria more susceptible to phagocytosis
Directly lyses some bacteria/foreign cells Stimulates chemotaxis Increases vascular permeability Causes smooth muscle contraction, promoting mast cell degranulation |
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What happens in the CLASSICAL path of the complement cascade
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-Start at C1q (which interacts with IgG)
-When C4b2b convertase cleaves C3 (in both classical and alternative paths) into C3a/b, the C3b combines with the convertase (C4b2b3b) -C4b2b3b splits C5 -C5a anaphylatoxic and chemotaxic -C5b is the anchor for the Membran Atack Complex (MAC) (C6 to C9) -C9 polymerizes around C5b678 to form channels that cause cell lysis |
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What kinds of molecules are C3a, C5a, C2a etc?
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Anaphylatoxins
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How is the classical pathway activated?
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Bacteria that are opsonized with IgG
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What happens to bacteria that are opsonized with C3b?
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Can activate the alternate pathway
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What do these pathways promote?
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Lysis of the bacteria/bacterial infected cells
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Which has a stronger bactericidal role: anti-bacterial IgG with C' or without complement?
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IgG + C'
(look at graph page 4) |
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What happens to bacteria when only the C3b binds to CR1 (part of complement)?
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The bacteria are NOT phagocytosed
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What can C5a do via CR1?
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It can activate macrophages to phagocytose bacteria
(look at figure on page 4) |
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Look at table page 5
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Look at table pg 5
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Which receptor-complement ptn complex is essential for macrophage phagocytosis?
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CR-1/C3
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What is LD50?
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Lethal dose which kills 50% of those tested
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Is the LD50 lower or higher in mice that are deficient in C3 or C4, when challenge with type III group B streptococci?
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LD50 is significantly lower
Normal mice should be 6.3 x 10^4 CFU -> C3 deficient 1.3 x 10^3 -> C4 deficient 2.4 x 10^3 Both the alternative and classical paths are important in this infection |
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Does deficiency of C3 but not C4 play a role in opsono-phagocytic killing of GBS (gp B strep.) in vitro?
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Yes
Look at figure pg 6 -> No C3:very little decrease in bacteria compared to normal mice with no deficiency --> Deficiency in C4 not as severe as deficiency in C3) |
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What is the structure of Mannose Binding Lectin (MBL aka MBP)?
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Collagenous region
Lectin domain |
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On what Chr is MBL encoded?
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Chr 10 as a single gene in man
(2 genes in rats and mice) |
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What are ficolins?
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Ancient form of MBL-ike molec
Found in man Have a FIBRINOGEN-like domain |
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What do ficolins do?
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Activate complement
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What are ficolins specific for?
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GlcNAc (N-acetylglucosamine)
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Look at figure pg 7
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look at figure pg 7
Ficolins have collagen-like and fibrinogen like domains |
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What are the binding characteristics of MBL?
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There are 3 sugar binding domains that are 54 aa apart
->this prevents a single mammalian-high mannose oligosac from binding) -MBL can easily bind because bacteria have repeating suga groups |
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How does MBL circulate?
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Circulates as a multimer (dimer, trimer...hexamer)
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What are MBL fcts?
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IgM-like
IgG/IgA like C1q like |
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How does MBL function in a C1q-like manner?
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Interacts with pro-ser proteases (MASP1/2)
Initiates ctivation of classical complement path MBL-MASP complexes ass't with serine protease inhibitors |
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How is MBL IgM like?
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IgM like:
-binds via multiple sites -weak binding through multiple CRD (carb rec'g dom) -Interactions |
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How is MBL IgG/IgA like?
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IgG/IgA like
-Opsonin, coats bacterial surface -interacts with 1+ collectin receptors |
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What does the classical path rec'z?
The alternative path? The lectin path (MBL)? |
Classical: Bacterial Ag
Alt path/amplification loop: complement ptns Lectin: Carbohydrates on bacterial surface |
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What is the specificity of MBL?
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Binds many oligosac in the presence of Ca2+
N-aceylglucosamine > mannose |
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What type of bacteria does MBL bind well to?
examples? |
Non-capsulated bacteria
ex: -Salmonella montevideo -Listeria monocytogenes |
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What type of bacteria does MBL have intermediate binding to?
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Streptococci
E. coli |
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What type of bacteria does MBL have low binding to?
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Capsulated bacteria
Ex: -N. meningitidis -H. influenza -Streptococcus agalactiae |
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Why does native and recombinant MBL bind to virulent S. montevideo?
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it expresses a monnaose-rich O-polysac
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What happens when MBL binds bacteria?
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Attachment, uptake and killing of the coared bacteria by phagocytes
(MBL opsonizes these bacteria and then they are ebgulfed) |
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What are the putative collectin receptor(s) on phagocytes?
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Calreticulin (60kD)
C1q receptor (126kD) |
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How is complement activated by MBL?
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-Binds C1q and C1r (also C1s if no C1q)
-Binds MASP (serine protease, 100kD ptn that is structurally similar to C1r/s) -MASP can cleave C4 and C2--> C4b2a complex with C3 convertase abillity Activation of C is independent of Ig and C1q |
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Where is MBL made in humans?
Circulate? |
Made: Liver
Circulates: in serum, also found at sites of inflammation, increases after gestation. Also has modest increase post surgery or malarial infection Has some structural features of APP in the 5' region of the gene |
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What happens if you have a MBL deficiency?
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Increased risk of infection
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What is the common cause for MBL deficiency?
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Structural mutation
-> codon 54, exon 1: substitution of Asp for Gly -> substitution co-inherited with deficiency (autosomal, co-dominant) |
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How many known mutants are tehre for MBL?
Where are they? |
3 mutants
All in exon 1 (vary with ethnic group) |
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Where are the mutations in high frequency for Africans?
Non africans? |
Africans: codon 57 (Gly to Glu)
Non: codon 54 (Gly to Asp) |
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Is a lot of mutant ptn detected?
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no, small amount
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What is the problem with MBL mutants?
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Cannot form oligomers
.: can't fix complement |
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Is MBL deficiency good or bad?
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Good points:
-Can help protect host bs infection by parasites/viruses that use C3 receptors -Less damage from inflammatory mediators Bad: MBL deficiency in combo with other deficiencies (i.e C4) can lead to pathology |
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What is C-reactive protein and Serum amyloid P
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APP (CRP: man, SAP: mouse)
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Why is CRP measured in serum?
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To see if there is an infection or inflammation
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How fast is the acute phase response of CRP and SAP?
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Fast, peaks at about 1 day
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What is the structure of CRP/SAP?
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Cyclic pentamer
Pentraxin family Non-glycosylated 206 aa Gene is on Chr 1 (also have a CRP pseudogene and SAP) |
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CRP vs SAP:
Structure |
CRP: Pentameric annular disk
SAP: Double pentameric disk |
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CRP vs SAP:
Functions |
CRP:
-binds C1q and activates C' -Binds chromatin, histone, SnRNP (nuclear) -Opsonization (enhances phagocytosis) -Enhances NK activity -Enhances chemotaxis SAP: -Binds C1q and activates C' -Binds chromatin, histone, *DNA* -*Binds* fibronectin, heparan sulfate, dermatan sulfate |
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CRP vs SAP:
Modulated by |
CRP: IL-6, IL-1 (+++/activates)
SAP: IL-6 (+), IL-1 (-/inhibits) -> IL-1 has a negative impact on SAP |
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What happens if there's too much CRP or SAP?
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CRP: not a problem cuz CRP is tightly regulated
SAP: if it deposits (rare), can lead to amyloidosis and death |
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What are the major effects of CRP/SAP on innate or adaptive immunity?
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Opsonization, phagocytosis
Chemoattraction (C5a) (powerful chemoattractants) Histamine release (C3a, C5a) Mb attack complex --> bacterial cell lysis |
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What happens if there is inapproiate host defense?
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Septic shock
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What is septic shock?
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Vascular resistance and blood P drop, despite normal-high cardiac flow
Deprives organs of oxygen and nutrients |
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What are the 4 stages of Septic Shock?
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1) Systemic inflammatory respnse syndrome: abnormal T, neutrophil count, high heart respiratory rates
2) Sepsis: bacteria in the blood stream 3) severe sepsis: organ disfunction 4) septic shock: low blood pressure, despite fluid administration |
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What are the causes and consequences of septic shock?
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-*Elevated levels of TNF, IL-1/6/8 and IFN-y (due to bact.)
-*PMNs leave blood, get leaks -*Activation of complement -Damage to blood vessels -Widespread coagulation -Hemorrhages in many parts of the body -If stage 4: prognosis poor, 70% die |
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What is the treatment for septic shock?
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Antibiotics
Anti-cytokine therapy (so far, disappointing) Fluid management *Early diagnosis essential and identification of the bacteria in question** |
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What can complement be triggered by?
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-Specific anti-bacterial Ab (through classical or alt paths)
-The lectin path (MBL via binding of specific carbs) -C-reactive ptn (via binding PC) |
