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Ritchey Lectures
Innate Immunity
121
Veterinary Medicine
Professional
01/30/2015

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Term
What are the three components of Innate Immunity?
Definition
1) Physical barriers
2) Cellular Components
3) Non-cellular components
Term
Compare/contrast Innate and Adaptive Immunity concerning the following:
a) response time
b) specificity
c) memory
Definition
a) Innate=immediate, adaptive=delayed
b) innate=no, adaptive=yes
c) innate=no, adaptive=yes
Term
Is acute inflammation in response to innate or adaptive immunity? Chronic?
Definition
-acute= innate
-chronic= adaptive
Term
True or False: Aside from physical barriers, most components of the innate immune response are found in the blood.
Definition
TRUE
Term
Why is it important that most components of the innate immune response are found in the blood?
Definition
-because it is always near the potential pathogens and it is a quickly recruited source
Term
Give a few examples of places in the body that directly interact with the outside world.
Definition
-ailamentary tract
-respiratory tract
-urogenital tract
Term
Give some examples of organs that indirectly interact with the outside world
Definition
-kidney
-liver
Term
How do organs that are in no way exposed to the outside world get an infection?
Definition
-via blood or lymphatics
Term
What is the first line of defense in physical barriers?
Definition
-skin
Term
True or False: Most organisms cannot penetrate the intact skin.
Definition
TRUE
Term
In what ways is skin the first line of defense?
Definition
-wounds heal quickly to keep out pathogens
-sweat has an acid pH and sebaceous glands produce lysozyme and fatty acids that inactivate microorganisms
-upper skin layer is dead and will constantly desquamate, removing and carrying away pathogens in the process
Term
In what ways are the mucosa of the Respiratory tract, Alimentary tract, and Reproductive/Urinary tracts defended?
Definition
-resp: hair, turbinates, cilia, mucus, coughing, sneezing
-alimentary: saliva, acid pH, bile
-repro/urinary: acidic pH, urination
Term
Name an organisms that will grow in bile.
Definition
-salmonella
Term
How do normal microflora prevent pathogens from establishing themselves on skin and mucous membranes?
Definition
-they compete for nutrients and space
Term
What is a common clinical situation in which normal microflora get destroyed?
Definition
-antibiotics
Term
What happens in atrophic rhinitis in pigs?
Definition
-toxins go into turbinates and tells osteoclasts to killosteocytes and deactivates osteoblasts=> eventually destroys turbinates=> taken away physical barriers and loses filtering
Term
What are the two types of sentinel cells?
Definition
-mast cells
-mononuclear phagocytic system: macrophages
Term
What is the role of sentinel cells?
Definition
-they hang out on surveillance, looking for insults (things that do not belong)
Term
Which Pattern Recognition Receptors recognize gram-negative bacteria? Gram-positive?
Definition
-Toll-like Receptor 4
-Toll-like Receptor 2
Term
Where are neutrophils produced?
Definition
-bone marrow
Term
Where are neutrophils usually found?
Definition
-remain in circulation until needed
Term
True or False: Once neutrophils leave the blood vessels, they go back into the circulation.
Definition
FALSE, they never go back into the circulation, they die fighting
Term
What is the most prominent type of cells in most animals? In ruminants?
Definition
-neutrophils
-lymphocytes
Term
What type of cells are the first line of defense in the fight against bacterial infection?
Definition
-neutrophils
Term
Before neutrophils can phagocytose bacteria, they must first be summoned by _______ produced by sentinel cells.
Definition
-cytokines
Term
What happens when neutrophils are summoned by cytokines produced by sentinel cells?
Definition
-they leave or emigrate out of the blood vessels into the infected tissue
-they capture and destroy bacteria and foreign antigens through phagocytosis only
Term
Definition: Extravasation
Definition
-the process by white immune cells leave the bloodstream when called for an immune response
Term
What are the 3 steps of extravasation?
Definition
1) Margination and rolling
2) adhesion and diapadesis
3) Chemotaxis
Term
Definition: Chemotaxis
Definition
-the directional migration of a cell along a concentration gradient
Term
What do Slex's on neutrophils do?
Definition
-they recognize selectins on the surface of the epithelial cells
Term
What are the two types of selectins on the surface of the epithelial cells?
Definition
-P-Selectins: P standing for platelets: pre-packaged and ready to go
-E-Selectins: product of transcription/translation
Term
What is the main functional difference b/n P-Selectins and E-Selectins?
Definition
-E-selectins take hours to respond
Term
What are the components of firm adhesion of neutrophils to endothelial walls?
Definition
Firm adhesion= S-lex+ integrins+ ICAMS+ conf change induced by chemokines from Sentinel cells
Term
Explain how neutrophils roll along endothelial walls.
Definition
-roll via weak connections to S-lex, thus many interactions bind and break
-to get strong adhesion, use beta integrins on neutrophils on the surface of endothelial cells (beta integrins bind weakly to ICAMS, but iva chemokines secreted by sentinel cells will switch to strong binding)
Term
What is the purpose of CD31?
Definition
-platelet endothelial cell adhesion molecule (PECAM): creates nooks and crevices that facilitates the pseudopodia of neutrophils can grab onto in the intracellular gaps b/n the endothelial cells to get through
Term
Once in tissue, neutrophils will start migrating towards chemotactic molecules- this directed migration is termed ________.
Definition
-Chemotaxis
Term
Is there any pattern to neutrophils migration?
Definition
-yes, they migrate to the area with the highest concentration of chemotactic molecules
Term
Neutrophils are activated during migration by _______ (produced by Macrophages), by _______ (produced by NK cells), and by C5a
Definition
-TNF-alpha
-IFN-gamma
Term
What happens when chemokine receptors are activated?
Definition
-they cause breakdown and reassembly of cell's cytoskeleton so that it can have directional movement towards where the concentration gradient of the chemokines is
Term
What are the bacterial products of chemotaxis?
Definition
-N-fMLP
-C5a: component of complement
-LTB4: pdt of arachodonic acid pathway
Term
Once the neutrophil encounters a bacterium, it must adhere to it. This can occur ONLY if the bacterium is __________.
Definition
-opsonized by Ab or C3b
Term
True or False: Neutrophils have both Fc receptors (CD32) and complement (CR) receptors for C3b (CD35).
Definition
TRUE
Term
As the opsonins contact the receptors, the cytoplasm of the neutrophils (________) flows over the bacterium, engulfing the bacterium into a cytoplasmic vacuole called a _________.
Definition
-pseudopod
-phagosome
Term
What are the two integral enzymes in oxygen dependent killin?
Definition
-NADPH oxidase (catalyzed first rxn)
-Myeloperoxidase (in neutrophils)
Term
What is the gist of oxygen dependent killing?
Definition
-take oxygen, use cascade rxn to shove electrons onto it
Term
Myeloperoxidase in neutrophils prefers _________ and the myeloperoxidase in eosinophils prefers _________.
Definition
-chlorine
-bromine
Term
What are the 4 main components of oxygen-independent killing?
Definition
-bacterial permeability increasing protein
-lysozyme
-defensins
-lactoferrin
Term
Describe cationic proteins.
Definition
-innate immune response
-no specificity
-like to poke holes in membranes
Term
What does Lactoferrin do? Why can it sometimes cause problems?
Definition
-sequesters Fe so that microorganisms cannot use it
-can ometimes keep Fe away from our own cells, thus when patients have chronic inflammation, will cause anemia (due to lack of iron to make RBCs)
Term
What is Neutrophil elastase?
Definition
-enzyme that degrades lots of things (broad spectrum activity)
Term
What is acid hydrolases?
Definition
-breaks down the carcasses of stuff
-inactive unless in an acidic pH
Term
What type of cells are the first to reach and attack pathogens?
Definition
-neutrophils
Term
What functionally happens when neutrophils die?
Definition
-in dying, they attract blood monocytes to the area
Term
Neutrophils have a limited reserve of energy. When are they most active? When do they die?
Definition
-most active immediately upon release from bone marrow
-they rapidly get exhausted and can undertake only a limited number of phagocytic events
Term
True or False: Neutrophils do not process Ag: they do not present Ag to Th cells or CTL via MHC.
Definition
TRUE
Term
Describe the nuclei of eosinophils.
Definition
polymorphonuclear
Term
Eosinophils are abundant at sites of _______, _______, or _______/________.
Definition
-allergic
-parasitic
-yeast/fungal disease
Term
What is the most abundant protein in the eosinophilic granule?
Definition
-major basic protein
Term
What is the purpose of eosinophils?
Definition
-neutralization of mast cell derived mediators (histaminase, arylsulfatase)
Term
Cytology of canine mast cell tumors will contain ________.
Definition
-eosinophils
Term
Macrophages start as ________ in bone marrow and enter the blood as _________.
Definition
-monoblasts
-monocytes
Term
Macrophages circulate for a few days and then leave circulation to become __________ and __________.
Definition
-Sentinel cells
-responding cells in inflammatory rections
Term
Different macrophage names: When circulating, called ________ and when in tissue called _________.
Definition
-monocytes
-macrophage
Term
What are the 5 functions of macrophages?
Definition
1) sustained phagocytic activites
2) process and present antigen
3) amplify and modulate specific immune responses by secreting cytokines
4) repair and heal damaged tissue by removing damaged and dead cells
5) control inflammation
Term
True or False: Neutrophils serve as link between innate and adaptive immune response.
Definition
-FALSE: macrophages
Term
Do macrophages die immediately after they complete their job?
Definition
-no
Term
Describe the receptors on macrophages.
Definition
1) PRRs
2) Fc receptors and C3b receptors
3) receptors (MHCII) and coreceptors necessary for their role in antigen presentation
Term
What is the function of C3b receptors on macrophages?
Definition
-opsonizing component of the complement pathway
Term
Monocytes and resting macrophages are effective phagocytes, their phagocytic activity is greatly enhanced when activated by the cytokine _______ produced by NK cells and Th cells.
Definition
-Interferron-gamma
Term
What is the major function of IFN-gamma?
Definition
-to activate macrophages
Term
Activation of Macrophages accompanied by which of the following:
a) enhanced phagocytic activity
b) decreased amts of cytoplasmic lysosomes
c) increased expression of Ab and Complement receptors
d) increased secretion of proteases
e) increased amount of cytoplasmic lysosomes
Definition
a,c,d,e
Term
If macrophages are activated further by bacterial products such as LPS and mannose, they become ___________.
Definition
-activated macrophages
Term
The transition from normal macrophages to activated macrophages is accompanied by what 3 principal changes?
Definition
1) increase in size, movement, and phagocytic activity
2) they can engulf whole cells
3) increased expression of MHC class II molecules and coreceptor molecules
Term
In persistent chronic infections, activated macrophages are known as _________ which can fuse into _________.
Definition
-epitheloid cells
-giant cells
Term
How long do giant cells stick around?
Definition
-they are completely insult-driven, thus as soon as the intigens are gone, everything quits
Term
Definition: IFN famma-interleukon 12 loop
Definition
-macrophages receive signals from interfeuron gamma to ramp up their level of activation
-in response to IFN gamma, they send message back to helper cells to tell them to keep it coming via interleukon 12
Term
How does NO relate to macrophage function?
Definition
-macrophages produce large amounts of NO
-sustained production of NO permits macrophages to efficiently kill bacteria, fungi, protozoa, some helminthes, and more importantly, tumor cells
Term
True or False: Macrophages are necessary for proper healing of wounds.
Definition
-TRUE
Term
Why are macrophages necessary for wound healing?
Definition
-secrete proteases which break down CT
-regulate collagenase and fibroblast activity through IL-1 secretion
-once damaged tissue is removed, macrophages secrete growth factors for collagen synthesis by fibroblasts, and for growth of new vessels
Term
What are natural killer (NK) cells?
Definition
-large granular lymphocytes that make up 10-15% of circulating leukocytes (they are CD56+)
Term
What do NK cells do?
Definition
-they contain enzymes that destroy virus infected cells, cancer cells, and cells infected with intracellular protozoa and bacteriia
Term
NK cells are activated by _____ and _____ which are manufactured by viral infected cells.
Definition
-IFN-alpha
-IFN-beta
Term
How are IFN-alpha and IFN-beta manufactured?
Definition
-when TLRs (3 &7) recognize any viral nucleic acid, they stimulate the cell to start pumping out IFN-alpha and IFN-beta
Term
NK cells are also activated by cytokines released by macrophages, especially _____ and _____.
Definition
-IL-12
-TNF-alpha
Term
What are the 4 receptors that NK cells have are associated with killing?
Definition
1) activating Rc: natural cytotoxic receptors that recognize changes in cell surface proteins caused by metabolic stress or intracellular infection2) Inhibiting Rc: receptors that recognize MHC I molecules on cells surface
3) receptors (CD16) for the Fc protion of the Ab: these recognize cells opsonized by Ab (for ADCC)
4) Fas ligands (FasL) receptors: recognize trimerized Fas molecules on stressed immune cells
Term
True or false: Inhibiting Rc signals will always override the Activating Rc signals o NK cells.
Definition
TRUE
Term
Describe the activating receptors of NK cells.
Definition
-the natural cytotoxic receptors (NCRs) recognize a wide variety of glycoproteins on normal cells- they can somehow know from their distribution and quantity if these cells are stressed (cancer, infection, old age)
Term
Describe the inhibitory receptors of NK cells.
Definition
-the inhibitory receptors recognize MHC class I molecules on the surface of cells
Term
Describe the pathway by which NK cells kill.
Definition
-after NK cells have attached, they secrete perforin
-perforins aggregate to form powes in the cell membrane similar to the MAC formation by complement
-next, NK cell secretes granzyme that enter the cell through the pore
-the granzyme binds to cell proteins (death proteins) inducing programmed cell death (apoptosis)
Term
How do NK cells recognize their prey?
Definition
-activating and inactivating Rc- inactivating Rc always overrides
-Fc Rc for Ab thaht opsonize target
Term
What is the name of the pathway by which NK cells kill?
Definition
-perforin-granyzme pathway
Term
The complement system is the branch of the innate immune system response that is key in protecting hosts against _________.
Definition
-bacterial infection
Term
What are the two things that complement proteins recognize?
Definition
1) structural molecules: present only on the surface of pathogens (ex: sugars)
2) opsonized pathoges: Fc ob both IfM and IgG are recognized
Term
True or False: Complement is very specific and therefore only recognizes a narrow range of pathogens.
Definition
FALSE, complement is non-specific and recognizes a broad range of pathogens
Term
What is the defining characteristics of the complement system that makes it a part of the innate immune system?
Definition
-complement proteins are everywhere in the entire body and are nonspecific, thus they respond quickly and without memory
Term
What are the main 4 characteristics of the complement cascade?
Definition
1) they are always readily available in the blood and tissues
2) circulate in inactive forms
3) become activated in microseconds
4) are activated sequentially in a cascade fashion
Term
What are the 3 pathways of complement?
Definition
-Alternate Pathway
-MBL (Lectin) Pathway
-Classical Pathway
Term
Generally describe the complement chart.
Definition
classical pathway+lectin pathway+ alternative pathway= complement activation= recruitment of inflammatory cells+ opsonization of pathogens+ killing of pathogens
Term
Which pathway of complement links the adaptive immune system to the innate immune system?
Definition
-classical pathway
Term
Briefly, how does the classical pathway of complement work?
Definition
-C1 is the first protein and it recognizes the Fc region Igm and IgG that have attached to the surface of pathogens
-then lots of cutting happens until C3 convertase is deposited on the pathogen surface to opsonize it for phagocytosis by macrophages
Term
to be activated, C1 must be bound to ___ IgM(s) and ___ IfF(s) in the ________ pathway of complement.
Definition
-one
-two
-classical
Term
What is the function of C3 convertase?
Definition
-to cleave as many C3 ocmpleent proteins as possible into C3a and C3b
-binds to surface of pathogens to opsonize it for phagocytosis of macrophages
Term
___ is the most abundant complement protein in the blood and tissues.
Definition
-C3
Term
True or False: C3 spontaneously and continually breaks down into C3a and C3b.
Definition
TRUE
Term
True or False: C3a is very reactive and will bind avidly to any amino and hydroxyl groups which are plentiful on the surface of pathogens.
Definition
FALSe, C3b is very reactive and will bind avidly to any amino and hydroxyl groups which are plentiful on the surface of pathogens.
Term
How is C3 convertase forms? What does it do?
Definition
-when C3b binds to a pathogen, protein B attaches too it to form C3 convertase (C3bBb)
-C3 convertase cleaves all C3 in the vicinity into C3a and C3b
Term
Briefly, how does the MBL Pathway work?
Definition
-MBL bind to mannose on pathogens to activate serine protease which causesC3 convertase formation
Term
What does MBL stand for?
Definition
-Mannose Binding lectin (MBL)
Term
How do normal cells prepare themselves agains C3bBb?
Definition
-have Factor proteins on their surface that bind C3bBb and inactivate it
-Facotr I in plasma also binds to and inactivates C3bBb
Term
True or False: Although iC3b is inactivated and cannot activate the terminal pathway, it is still an opsonin
Definition
TRUE
Term
How does complement cause an inflammatory response?
Definition
-small complement fragments (anafalatoxins) are released and bind to mast cells, causing them to release histamine
-most active: C5a, followed by C3a
Term
What are the 3 pro-inflammatory cytokines that activated macrophages secrete?
Definition
-Il-1, IL-6, and TNF-alpha
Term
What do pro-inflammatory cytokines (IL-1, IL-6, and TNF-alpha) do?
Definition
-they induce the synghtesis and secretion of acute-phase proteins by the liver
Term
What are 5 types of acute-phase proteins?
Definition
-fibrinogen
-C-reactive proteins
-MB-lectins
-Iron-binding molecules
-Serum amyloid A
Term
How does Fibrinogen behave as an acute-phase protein?
Definition
-acts as a temporary scaffold for wound repair
Term
How do c-reactive proteins behave as acute-phase proteins?
Definition
-bind both bacteria and phagocytic cells
-they behave as opsonins and activators of complement
Term
How do MB-lectins behave as acute-phase proteins?
Definition
-bind mannose on bacteria and activate Complement
Term
How do iron-binding molecules behave as acute-phase proteins?
Definition
-bind iron in the blood and make them unavailvable to bacteria, thus inhibiting bacterial replication
Term
What is the clinical significance of acute phase proteins?
Definition
-they are used as serum markers of inflammation
Term
What do acute phase proteins grossly do when you are sick?
Definition
-tell brain to raise body temp: fever
-promote the release of sleep-inducing molecules: lethargy
-also suppress appetite: anorexia
Term
How do acute phase protiens induce catabolism of proteins?
Definition
-during systemic infections, protein catabolism occurs via skeletal m digestion to supply AAs needed to feed inflammatory response
-controlled by TNF/IL-1
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