Block V, Week III
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- What are the four outcomes of viral infection?
-
1. Productive infection (release of progeny)
2. Persistent infection (virus doesn't kill cell, low level of progeny shed from cell)
3. Abortive infection (viral multiplication arrested, no progeny)
4. Latent infection w/reactivation (virus goes through cycles of latency and reactivation) - In general, what are the six stages in the (productive) viral life cycle?
-
1. Attachment
2. Penetration
3. Uncoating
4. Replication
5. Assembly
6. Egress - What is a one-step growth curve and how is it obtained for a particular virus?
- one step growth curve is a curve showing the rate of viral replication at different stages in time after the infection. The infection must be synchronized: therefore all viruses must be at the same point of the life cycle.
- Why is there a latent period shortly after infection onset?
- The latent period is due to the virus uncoating. During this time it is inactive.
- Where would you find the viral attachment proteins?
- on the capsid (naked virus) or on the envelope (enveloped virus)
- In treating viral infections, why can't we just knock out the viral receptors on the host cells?
- these receptors often perform important cell functions. to knock them out would mean death of the host.
-
Define:
1. tropism
2. host range -
1. tropism is specificity for a certain tissue (ie. hepatotoxic viruses)
3. host range is the range of different types of hosts that the virus can infect. (ie. rabies in both humans and other mammals) - How do enveloped viruses penetrate the host cell membrane?
- via membrane fusion
- How do naked viruses penetrate the host cell membrane? (2)
-
1. creating a pore-like structure in the membrane
2. receptor mediated endocytosis, then lysing the internal cellular membrane (ie. endosomal membrane) - What is viropexis?
- viropexis is another word for receptor mediated endocytosis
- What happens to the viral envelope during membrane fusion and why is this an important drawback?
- The viral envelope is incorporated into the host cell membrane. This leaves an external marker that is easily recognizable by the immune system.
- How does a naked virus penetrate via pore formation?
- The capsid proteins of the virus insert into the cell membrane creating a pore, then RNA is released through the pore into the cytoplasm.
- What occurs in uncoating?
- Uncoating releases the viral genome into the host cell cytoplasm
-
What are the 3 mechanisms of uncoating?
What is the main mechanism? -
1. conformational changes in capsid subunit
2. host or viral protease
3. acidification of endosome
acidification of endosome - How does acidification of the endosome occur?
- there are proton pumps in membrane of the endosome - they pump H+ out of the cytoplasm into the endosome (plasma membrane H+ pumps also pump out of the cytoplasm). The endosome becomes very acidic due to the increased [H+].
-
1. Where do most RNA viruses replicate?
2. Where do all DNA viruses replicate? -
1. in the cytoplasm
2. in the nucleus -
1. How are DNA viruses targeted to the nucleus?
2. How are DNA viruses transported to the nucleus? -
1. DNA viruses are targeted to the nucleus via "nuclear localization signals" found on viral protiens.
2. the DNA viruses are transported using cytoskeleton and cellular motor protiens (dynein). - What are the 3 ways a DNA virus enters the nucleus?
-
1. passage of virus through nuclear pores (small viruses)
2. release of DNA through nuclear pores (virus is too big to fit through pore)
3. Transient Rupture of the nuclear membrane - mRNA production during viral gene expression is mediated by what general type of protien?
- RNA polymerase
-
Which type of RNA polymerase do:
1. DNA Viruses use?
2. RNA Viruses use? -
1. DNA viruses use DNA-dependent RNA polymerase that is usually of host origin.
2. RNA viruses use RNA-dependent RNA polymerase, it is always of viral origin - In regards to RNA viruses: what determines if the RNA transcriptase is virion associated?
-
the polarity of the RNA determines whether there will be virion association or not.(+)ssRNA is the only RNA virus that is not virion associated.
**+ssRNA can be read by the host directly as mRNA, the other RNA virus types can't and therefore need their own "virion associated" RNA transcriptase** - What does virion associated mean?
- The RNA transcriptase enters the cell with the virion to allow expression of the uncoated viral genome.
- Which RNA polarities are virion associated? (2)
-
1. (-)ssRNA
2. dsRNA - What are the three mechanisms in which RNA viruses can undergo gene expression?
-
1. Expression of segmented genomes
2. Start-Stop expression
3. Polyprotein expression - What is the mechanism behind polyprotien expession of RNA viruses?
- translation of mRNA produces a polyprotien. The polyprotien is cleaved by proteases into the proper separate protiens.
- How does a dsDNA virus replicate?
- dsDNA--> dsDNA (DNA polymerase is used)
- How does a (+)ssRNA Virus replicate?
- (+)ssRNA->(-)ssRNA->(+)ssRNA (ssRNA viruses have their antigenome as an intermediate in replication)
- How does a (-)ssRNA Virus replicate?
-
(-)ssRNA -> (+)ssRNA -> (-)ssRNA
The antigenome intermediate once again... -
Assembly of progeny virions: where is the site of assembly for:
1. DNA viruses
2. RNA viruses -
1. nucleus
2. cytoplasm - What is the mechanism for capsid assembly?
- capsids self assemble
- When is nucleic acid incorporated into the virus?
- it is incorporated during assembly or after empty capsid is complete
- What type of capsid processing is sometimes required for infectivity?
- proteolytic processing
- Where is the site of envelope acquisition for enveloped viruses (the progeny)?
- envelope acquisition usually occurs at the outer cell membrane.
-
1. How do naked capsules usually escape the cell?
2. How do enveloped viruses usually escape the cell? -
1. lysis
2. budding - what is a major difference between lysing and budding that allows a virus to be more virulent?
- lysing kills the cell. A host cell can survive budding; this results in the release of thousands of progeny before it dies.
-
1. What is the significance behind viruses that have a high mutation rate?
2. Which class of virus has the highest mutation rate? -
1. a high mutation rate leads to rapid adaptations (ie. drug resistance).
2. RNA viruses are known for their "sloppiness," they lack a proofreading function -
1. Viruses can undergo genetic reassortment. What could this lead to?
2. Which type of virus undergoes genetic reassortment? -
1. genetic reassortment could lead to an antigenic shift
2. viruses with segmented genomes undergo genetic reassortment. (ie. influenza A) - Viral transformation that is associated with continued expression is known to induce?
-
oncogenesis
(EBV, HPV) - Which class of viruses are most often seen in viral induced oncogenicity?
- DNA viruses (oncogenicity induced by RNA viruses is not so common)
- How is size related to viral dependancy on their host?
- The smaller the virus the more dependent they are on their host.
- What are the 3 major functions of the viral capsid?
-
1. Protect nucleic acid from degradation
2. Provide attachment site for host cell (naked viruses)
3. provide antigens that are recognized by the host immune system (naked and enveloped) - What are the two major capsid types?
-
1. Helical
2. Icosahedral - Define monopartite in regards to the viral RNA genome.
- monopartite refers to a single RNA molecule as the genome (vs. segmented which refers to multiple RNA molecules)
- what difference do the (+) and (-) ssRNA genomes have in regards to translation?
- the (+)ssRNA can be directly translated because it is the same polarity (sense) as mRNA. (-)ssRNA is antisense to mRNA and must be converted to (+)ssRNA before translation can occur.
- in dsDNA or (+)ssRNA: What happens if the viral genome is separated from the capsid and injected into a host cell?
-
the genome alone can initiate a complete replication cycle and produce progeny viruses.
**dsDNA and (+)ssRNA are considered infectious, whereas (-)ssRNA is not. - Which enzyme is required for conversion of (-)ssRNA to (+)ssRNA?
- Virion-associated RNA polymerase
- the viral envelope is acquired via budding through which type of membrane?
- the membrane can be cytoplasmic, nuclear, rough ER or Golgi membranes
- in regards to the viral envelope: where are glycoprotiens found and what is their function?
- glycoprotiens are visualized as spikes on the viral surface. They function in receptor binding and membrane fusion.
- In some viruses a matrix protien lines the inner side of the envelope. Function?
- the matrix protien plays an important role in viral maturation
-
compare naked and enveloped virions in the following aspects:
1. stability in the environment -
1. naked - environmentally stable (can pass thru GI tract)
Enveloped - environmentally labile (succumb to acids, detergents, heat) -
compare naked and enveloped virions in the following aspects:
infectivity in regards to drying -
naked - retain infectivity after drying
enveloped - lose infectivity after drying -
compare naked and enveloped virions in the following aspects:
route of egress -
naked - escape via lysis
enveloped - escape via budding or lysis -
compare naked and enveloped virions in the following aspects:
how easily they are spread -
naked: spread easily by dust, small droplets, fomites
enveloped: spread in droplets, secretions, blood - which class of virus is resistant to detergents?
- naked viruses
-
Which class of virus...
1. causes host pathogenesis due to hypersensitivity and inflammation?
2. What causes the hypersensitivity and inflammation? -
1. enveloped viruses
2. cell mediated immunity is responsible for the pathogenesis - Do naked virions elicit cell mediated immunity?
- NO, they only elicit a protective antibody response
- What are the chemical criteria used for viral classification (3)?
-
1. nucleic acid composition and sequence
2. genome polarity
3. structure - What are the morphological criteria used for viral classification (2)?
-
1. capsoid shape
2. presence or absence of an envelope - after a wound occurs a thrombus is formed. What is it formed by and what is its function?
- plasma fibrin and fibronectin form the thrombus. The thrombus is a two-way barrier: it stops things from entering and exiting the wound.
-
1. what is the name of the molecule that crosslinks fibronectin?
2. benefit of crosslinked fibronectin? -
1. transglutaminases crosslink fibronectin
2. crosslinked fibronectin provides tensile strength and maintains closure. - what is the source of early growth factors at the wound site?
- platelets
- what happens to the thrombus late in wound healing?
- the thrombus undergoes proteolysis, then it is penetrated by regenerating epithelium.
- in what sequence does repair and regeneration occur in regards to wound healing?
- repair and regeneration occurs after the inflammatory response
-
1. which type of acute inflammation will leave a scar?
2. what is the molecule that lays down the scar? -
1. progressive acute inflammation (macrophage predominant inflammation)
2. collagen - what is the main function of neutrophils in a wound?
- neutrophils liquefy and remove necrotic tissue
- fibronectin and cellular debris release chemotactic factors to attract which two cell types?
-
macrophages
fibroblasts - what officially begins when macrophages appear at the site of injury?
- the repair process
- what types of things do macrophages secrete?
-
1. collagenase (assists with further liquefaction)
2. growth factors for:
- fibroblast proliferation
- collagen secretion
- neovascularization - what is the provisional matrix eventually replaced by?
- granulation tissue replaces the provisional matrix
- which cell type actively coordinates the development of granulation tissue? How does it do this?
-
macrophages
they release cytokines and growth factors - in the formation of granulation tissue, what cells are myofibroblasts and fibroblasts derived from?
- mesenchymal stem cells
- in the formation of granulation tissue, what cells do capillaries form from?
- capillaries form from the division of existing vessel endothelial cells
- what are some reasons as to why granulation tissue is so highly resistant to bacterial infection?
- granulation tissue is fluid-laden. It is highly vascularized and can therefore supply antibacterial antibodies.
- what are the three main ingredients found in the early matrix of granulation tissue?
-
1. proteoglycans
2. glycoproteins
3. type III collagen - what change do fibroblasts undergo once activated and what do they do?
-
fibroblasts change from round to bipolar upon activation.
Fibroblasts form collagen and other matrix proteins (such as fibronectin). - what is the difference between type I and type III collagen in relation to wound healing?
-
Type III collagen is formed first and is weaker.
Type I collagen is formed later and has greater tensile strength. - what is the difference between angiogenesis and vasculogenesis?
-
angiogenesis - sprouting of endothelial cells from pre-existing capillary venules.
vasculogenesis - blood vessels form de novo from angioblasts. - What are BFGF (B for Beta) and VFGF and what do they do?
- BFGF and VFGF are potent angiogenic growth factors. They associate with heparan sulfate - this is a crucial feature of angiogenesis.
- how (and in which layer) does the epidermis renew itself?
-
how - mitosis
where - at the basal layer - what is the primary source of regenerating epithelium?
- the hair follicle
- in repair and regeneration, what is the main way that the cell surface is reepithelialized?
- cellular migration is the predominant means of reepithelialization
- which specialized cell is wound contraction dependant on and where is this cell found?
- wound contraction is dependant on the myofibroblast - it is found in granulation tissue
- what is the timeframe for myofibroblast appearance at the wound site?
- myofibroblasts are first seen around day 3 of wound healing. they dissappear as repair progresses and wound has contracted.
- how do myofibroblasts exert their contractile effects?
- by forming tight junctions between myofibroblasts, this binds the cells together in a unit.
- what is the difference between the structure of myofibroblasts and fibroblasts?
- myofibroblasts bind together in a unit, fibroblasts are solitary cells
- what cell types can myofibroblasts be derived from? (3)
-
1. pericyte
2. fibroblast
3. stem cell - what is the decrease in the size of a wound dependant on?
- the presence of myofibroblasts
- healed wounds have what percentage of the strength of the original unwounded site?
-
75%
takes about 1 yr to gain this much function. - approximately what percentage of the original strength is present in a 2 week old wound?
- 20%
- what do platelets release when they are activated and what does this molecule facilitate?
- platelets release PDGF, which facilitates adhesion, coagulation, vasoconstriction, repair and clot reabsorption.
-
What is the cell?
arrives at wound site early and migrates rapidly using small focal adhesions... - leukocyte
-
What is the cell?
is rapidly recruited from the bone marrow and invades the wound site within the 1st day... - neutrophil
-
What is the cell?
invades wound site within 1st day, releases granule contents resulting in degradation and destruction of non-viable tissue - neutrophil
- arrive shortly after neutrophils but persist longer.
- macrophage
- What are the two main macrophage actions:
-
1. phagocytose debris
2. orchestrate developing granulation tissue by release of cytokines and chemoattractants -
when do the fibroblasts, myofibroblasts, pericytes and smooth muscle cells arrive on the scene?
what recruits these cells? -
day 3 to 4.
recruited by growth factors and matrix degradation products. -
what is:
1. lamellipodia
2. where are these seen
3. function? -
1. broad, wavelike membrane extensions
2. leukocytes
3. locomotion for migrating leukocytes -
what are:
1. filopodia
2. where seen -
1. narrower and slower than lamellipodia, fingerlike extensions.
2. fibroblasts, smooth muscle cells - during cell movement the leading edge of the cell interacts with what molecule?
- integrin
- what are the 4 components of the ECM?
-
1. collagen fibers
2. elastin fibers
3. ground substance
4. fibronectin - what is important about fibronectin?
- it can associate with the integrin receptor on the surface of the cell.
- define: basement membrane
- thin, well-defined layers of specialized ECM that separate the cells that synthesize it from the connective tissue.
- what cell types produce basement membranes?
-
1. epithelium
2. endothelium
3. adipocytes
4. muscle cells
5. Schwann cells - which type of collagen is found in the basement membrane?
- collagen type IV
- besides collagen, what is the other predominant ECM molecule that is found in the basement membrane?
- laminin
-
what happens when:
1. the equilibrium between collagen deposition and degradation has been restored
2. capillary formation is complete
3. inflammatory cells are diminished - remodeling begins
- what is the class of main digestive enzymes during remodeling?
- metalloproteinases (MMP)- function in matrix degradation during remodeling
- what is the reason for digesting matrix proteins during remodeling?
- degradation allows cellular migration through the stroma
- MMPs are synthesized as zymogens. what activates them?
- already activated MMPs or serine proteases
- what regulates MMP activity?
- MMP activity is regulated by TIMPs. (a series of endogenous tissue inhibitors of metalloproteinases)
- the reaction of vascularized living tissue to local injury is known as________?
- inflammation
- why is inflammation considered a protective process?
-
inflammation:
neutralizes the cause of injury
rids the body of necrotic tissue - acute inflammation is characterized by ______________ and lasts how long?
- neutrophils, lasts minutes to a few days
- chronic inflammation is characterized by which cell types and lasts how long?
- characterized by macrophages and lymphocytes, lasts days to years
- Regarding morphology of inflammation: One type of inflammation is generally more variable and the other is generally more uniform. Which is which?
-
acute - uniform
chronic - varied - what are the four cardinal signs of inflammation as described by Celcus?
-
1. Rubor (redness)
2. Tumor (swelling)
3. Calor (heat)
4. Dolor (pain) - what is the additional cardinal sign of inflammation that was added later by Virchow?
- Functio laesa (loss of function)
-
in inflammation what does the following effect have:
1. vasodilation
2. structural changes in microvasculature -
1. increased blood flow
2. allows plasma cells and leukocytes to leave the capillary. - when inflammation first begins, what do the blood vessels do (only for a short while)
- vasoconstrict
- Why is there slowing and stasis in the microvasculature during inflammation?
- because of the increased vascular permeability
-
1. what is exudate?
2. what does it commonly cause? -
1. protein rich fluid that leaks out of vascular system during inflammation
2. swelling is often due to exudate -
1. what is transudate?
2. what are the normal components of transudate? -
1. fluid with low protein content (this fluid leaks out of vascular system on a regular basis). it is non-inflammatory.
2. transudate consists of mainly H2O and albumin -
1. define edema
2. define pus -
1. excess fluid in interstitial tissue or serous cavity (can be transudate or exudate)
2. exudate rich in neutrophils - what forms the gaps in the microvasculature?
- contraction of endothelial cells
-
where do these gaps in microvasculature most commonly occur?
(which type of vessel) - venules
-
1. describe leukocyte dependent injury of the vasculature.
2. what is the timeframe for this injury in regards to inflammation? -
1. leukocytes have a toxic effect when they adhere to the vascular wall, this damages the vessel.
2. it is a late inflammatory response - what are the three main cytokines that leak via gaps in the vasculature?
-
IL-1
TNF
IFN-gamma - which cell type can intervene in allergic reactions and can kill parasites?
- eosinophils
- a macrophage precursor is called a ___________.
- monocyte
- what are the two main functions of macrophages?
-
1. phagocytosis
2. synthesis of chemical mediators - which cell types (2) produce histamine and play a key role in anaphylaxis?
-
mast cells
basophils - what three things make up the sequence a leukocyte goes through before it can undergo diapedesis?
-
1. margination
2. rolling
3. adhesion (pavementing) - what two things does the leukocyte do in order to increase the avidity of binding in adhesion?
-
1. redistributes adhesion molecules to cell surface
2. induces adhesion molecules on endothelium - what is chemotaxis?
- migration along a chemical gradient
- what type of chemotactic agent would bacterial products be?
- exogenous agent
- give an example of 3 endogenous chemotactic agents
-
C5a
LTB4
cytokines - leukocytes move via which structure?
- pseudopods (lamellapodia)
- IgG Fc, C3b and collectins are all examples of?
- opsonins
- what happens to the newly engulfed toxic agent?
- killing or degradation via fusion of the phagosome with the lysosome
- what most commonly mediates oxygen dependant degradation?
- ROS (HOCl)
- how do lysozymes mediate oxygen independent microbial killing?
- by hydrolyzing the coating of bacteria
- where is MBP found and what does it do?
- MBP is found in eosinophils, it is cytotoxic to parasites
- what are the three functions a leukocyte can have a defect in?
-
1. defect in adhesion
2. defect in phagocytosis
3. defect in microbiocidal activity - what would be observed in a defect of leukocyte adhesion? (2)
-
1. recurrent bacterial infections
2. impaired wound healing - Chediak-Higashi syndrome is a defect in which leukocyte function?
- defect in phagocytosis (degranulation and killing)
- chronic granulomous disease (CGD) is a result of a defect in which leukocyte function?
- defect in microbiocidal activity
-
1. what is "frustrated" or "surface" phagocytosis?
2. why is this important? -
1. when a leukocyte cannot phagocytose a microbe (most often due to its large size).
2. This can cause additional damage because lysozyme is released into the tissue. -
give an example of chronic inflammation caused by:
1. organisms producing delayed hypersensitivity
2. prolonged exposure to toxic agents
3. autoimmunity -
1. TB
2. silica, asbestos
3. SLE, RA - what are the three types of mononuclear cells?
-
1. macrophages
2. lymphocytes
3. plasma cells - what is characteristically seen in chronic inflammation that is attempting to heal?
- damaged tissue (from acute inflammation) is replaced by connective tissue
- chronic granulomatous inflammation is caused by a granuloma. What is a granuloma and what surrounds it?
- a granuloma is a nodular collection of epitheliod cells (specialized macrophages). These epithelial cells are surrounded by lymphocytes.
- what are the two major causes of chronic granulomatous inflammation (general)
-
1. T-cell mediated immunity (TB-a delayed hypersensitivity rxn)
2. poorly digestible irritants, foreign body rxn (sutures, sliver) - There are six morphologic patterns of inflammation. Describe serous inflammation
- effusion, an outpouring of thin fluid derived from serum
-
There are six morphologic patterns of inflammation.
Describe fibrinous inflammation -
exudate rich in fibrin
organization is seen -
There are six morphologic patterns of inflammation.
Describe Suppurative (purulent) inflammation -
mainly neutrophils present
lots of necrotic cells
edema -
There are six morphologic patterns of inflammation.
Describe an ulcer and what produces it. - a local defect or excavation of the surface of an organ, produced by sloughing of inflammatory necrotic tissue
-
There are six morphologic patterns of inflammation.
Describe an abscess - a localized collection of neutrophils with liquified necrotic tissue in the center
-
There are six morphologic patterns of inflammation.
Describe membranous inflammation - exudate seen on the surface
-
describe non-oxygen dependent bacterial killing by defensins
(what releases them, what do they kill) - defensins are released by PMNs and some lysozomes - they kill tons of things (gram + and - bacteria, fungi, some enveloped viruses)
- describe non-oxygen dependent bacterial killing by lactoferrin
- lactoferrin competes with bacteria for iron (lactoferrin is an iron chelator)
- what is responsible for the Rubor seen in inflammation?
- Rubor=redness: caused by dilation of blood vessels
- what is responsible for the Calor seen in inflammation?
- Calor=heat: caused by increased blood flow to area of injury
- what is responsible for the Dolor seen in inflammation?
-
Dolor=pain: caused by:
1. increased pressure (accumulated interstitial fluid)
2. mediators such as bradykinin - what is responsible for the Tumor seen in inflammation?
- Tumor=swelling: caused by an extravascular accumulation of fluid
-
define:
1. lymphokine
2. monokines -
1. soluble factors released from lymphocytes, are involved in the immune system
2. soluble factors released by monocytes and macrophages, are involved in the immune system - lymphokines and monokines are collectively known as?
- cytokines
- what are chemokines?
- chemokines are a subset of cytokines involved in chemotaxis
- besides regulating the immune response what are the other functions of chemokines? (2)
-
1. cell growth and differentiation
2. tissue repair and remodeling - what do I mean when I say that cytokines are pleiotropic?
- they act upon many different cell types
- What are the three families of cytokines/receptors?
-
1. TNF related
2. Chemokines
3. Hematopoietins (Type I) - What are two examples of TNF related cytokines?
-
TNF
Fas - what are the two main functions of TNF receptors?
-
1. activation of gene expression
-or-
2. influence cell death via death domain - What is the difference between a Type I and a Type II TNF receptor?
-
TNF Type I receptor - functions in activation of gene expression
TNF Type II Receptor - contains death domain - What are 5 examples of Hematopoietins (Type I) cytokines?
- IL-2,3,4,5,6
- describe the structure of the hematopoietin receptors
-
1. made up of 2 or more subunits
2. lots of redundancy because sub-units are shared by several members - Which cytokine receptors share a common beta chain?
- IL 3,4,5,13
- Which cytokine receptors share a common gamma chain?
- IL 2,4,7,9,15
- In general, describe the Jak-Stat paradigm
-
IL-R associates with Jak
Jak binds to Stat
results in modulation of gene expression - describe the structure of chemokine receptors
-
7 transmembrane helices
interacts with G proteins - what are 3 examples of chemokines?
- IL-8, MIP, MCP
-
in regards to chemokines:
1. what does its function of chemokinesis mean?
2. what does its function of chemotaxis mean? -
1. stimulation of leukocyte motility
2. direction of leukocyte movement - what are the two classes of cytokines?
-
CXC
CC -
What is the difference between CXC and CC?
(which cell types does each attract) -
CXC - predominately atract neutrophils
CC - predominately attract macrophages and monocytes - what are 3 early pro-inflammatory cytokines?
-
IL-1
IL-6
TNF-alpha - which cytokine is known as the bridge cytokine because it bridges innate and acquired immunity
- IL-12
-
in relation to a viral infection, put the following in chronological order:
NK cell mediated killing of infected cells
T-cell mediated killing of infected cells
production of IFN-alpha and beta, TNF-alpha, IL-12 -
1. production of IFN-alpha and beta, TNF-alpha, IL-12
2. NK mediated killing
3. T cell mediated killing - what are the pro-inflammatory cytokines we need to know? (5)
-
1. IFN-alpha and beta
2. IL-1
3. IL-6
4. IL-12
5. TNF-alpha - what are the four effects of IFN-alpha and beta?
-
1. inhibit viral replication
2. increase NK cells lytic ability
3. increase MHC class I expression
4. decrease MHC class II expression - what is the source of IFN-alpha vs. the source of IFN-beta?
-
IFN-alpha: macrophages
IFN-beta: fibroblasts - what is the stimulus for both IFN-alpha and beta?
- viral infection
-
1. what is the source of TNF-alpha?
2. what two cells are the target of TNF-a?
3. what is the stimulus for TNF-a? -
1. early - macrophages
later - TH1 cells
2. macrophages and neutrophils
3. LPS - what does TNF-alpha accomplish by targeting and stimulating macrophages?
-
chemotaxis
production of TNF-a, IL-1, IL-6, NO. - what does TNF-alpha accomplish by targeting and stimulating neutrophils?
- bacterial lysis
- functionally, which two cytokines is TNF-alpha equivalent to?
- IL-1 and IL-6 (IL-6 has a lesser effect on neutrophils)
-
1. what molecule triggers most of the cytokine production?
2. what other molecule can induce cytokine production? -
1. NFKB
2. LPS -
regarding IL-12:
1. what is the source?
2. what is the target?
3. what effect does it have on NK cells?
4. what effect does it have on T cells? -
1. macrophages and dendritic cells
2. NK cells and T cells
3. production of IFN-gamma and cytolysis
4. CD4+ T cell differentiation -
Regarding TNF-alpha:
1. cell of origin?
2. target cell?
3. effector function? -
1. macrophages (early) and T cells (later)
2. macrophages and neutrophils
3. induce adhesion molecule expression, facilitate chemotaxis, cell lysis via neutrophils -
Regarding IL-2:
1. cell of origin?
2. target cell?
3. effector function? -
1. activated T cells only (TH0, TH1, CTL)
2. principle T cell growth factor
3. mainly T cell proliferation (also B cell growth, NK cell growth) - Is the manner in which IL-2 activates T cells autocrine or paracrine?
- both autocrine and paracrine
-
In an activated T cell:
1. what is the result of adding an alpha chain to the IL-2 receptor (making it IL-2R.alpha.beta.gamma)
2. what is the result of having only an IL-2R alpha chain? -
1. upregulation of IL-2 (receptor has increased affinity)
2. IL-2 downregulation (receptor has decreased affinity) - what would a deficiency in IL-2 result in?
- decreased T cell function
- what is unique about the interferon (IFN) gamma receptor?
- it must be a dimer to be biologically active
-
regarding IFN-gamma:
1. cell of origin?
2. target cells? -
1. TH1, CTL and NK cells
2. T cells, B cells, macrophages, other leukocytes - what effect does IFN-gamma have on T cells? (2)
-
1. correlates with IL-12 to induce a TH1 response
2. Inhibits IL-4 induced TH2 responses - what effect does IFN-gamma have on B cells?
- stimulates differentiation
- what effect does IFN-gamma have on macrophages?
-
1. activation
2. upregulation of MHC class I and II responses - what would a deficiency in IFN-gamma result in?
- an increased susceptibility to mycobacterial infections
-
Regarding IL-4:
1. cell of origin?
2. target cell?
3. effector function? -
1. activated T cells
2. B and T cells
3. primary growth factor for B cells.
Enhances synthesis of IgE.
Responsible for TH2 response, Inhibits IL-2, IL-12, IFN-gamma TH1 type responses - what effect does IL-4 have on B cells? (3)
-
1. activation and growth
2. upregulation of MHC class II
3. Stimulation of IgG and IgE synthesis - what effect does IL-4 have on macrophages and mast cells?
- inhibits activation of macrophages, stimulates mast cell growth
- what would a deficiency of IL-4 result in?
- and absent TH2 type response
-
regarding IL-10:
1. cell of origin?
2. target cell?
3. effector function? -
1. TH2, B cells, macrophages, keratinocytes
2. TH1 cytokines (IL-2,3,12, IFN-gamma, TNF-alpha)
3. Indirectly favor TH2 functions (via suppressing IL-12 and IFN-gamma). - IL-10 is STRUCTURALLY similar to which cytokine?
- IFN-gamma (function is opposite: IFN-gamma favors TH1 response, IL-10 favors TH2 response)
-
What effect does IL-10 have on:
1. B cells
2. macrophages
3. mast cells -
1. upregulation of MHC class II
2. inhibits cytokine release
3. stimulates mast cell growth - What would a deficiency in IL-10 result in?
- an alteration of the TH1:TH2 balance (in favor of the TH1 response)
-
regarding TGF-beta:
1. produced by?
2. general function? -
1. virtually all cells of the immune system
2. general suppressive function - why are TGF-beta levels elevated late in an immune response?
- TFG-beta downregulates the immune response
- TH1 cells produce which cytokines (2)?
-
1. INF-gamma
2. IL-2 - TH2 cells produce which cytokines (2)?
-
1. IL-4
2. IL-5 - What happens in a TH1 response?
-
CELL MEDIATED IMMUNITY.
macrophages are activated
CD8 cells are formed - What happens in a TH2 response?
-
ANTIBODY MEDIATED IMMUNITY.
B cells make antibody (B is 2nd letter of the alphabet) -
1. when a TH1 cell produces IFN-gamma the result is...
2. when a TH1 cell produces IL-2 the result is... -
1. an activated macrophage
2. CD8 (cytotoxic) cell - a TH-o (naive helper T cell)would have to be exposed to which cytokines in order to become a TH1 cell?
-
IL-12
IFN-gamma - a TH-o (naive helper T cell) would have to be exposed to which cytokine in order to become a TH2 cell?
- IL-4
- Which type of infection would induce a TH1 response?
- intracellular viral or bacterial (these induce dendritic cells to be the APCs)
- Which type of infection would induce a TH2 response?
- pathogens not inducing dendritic cells (ie. parasites)
- what is the role of the Ag binding affinity in the TH1/TH2 decision?
-
Binds strongly --> TH1
Binds weakly --> TH2 - TH1 cytokines have what role on TH2 activation and growth?
-
they inhibit
likewise, TH2 cytokines inhibit TH1 activation and growth -
which type of response is this?
graft and tumor rejection
host defense against bacterial, viral or fungal infection? - TH1 (T cell mediated/ cell mediated immunity)
-
which type of response is this?
host defense against infection by opsonization
autoimmunity - TH2 (B cell mediated/ Antibody mediated immunity)
- which immune response mediates chronic inflammation of the airways (as in asthma or hayfever)
- TH2
- which immune response mediates an acute allergy?
- TH1
-
define SCID
molecular cause? -
(severe combined immunodeficiency disease)
mutation in IL-2 and Jak receptors,
result=can't make T cells. - define 5q minus syndrome
-
deletion in long arm of chromosome 5: result is error in development of hematopoietic stem cells,
lack of IL development - a patient that presents with increased susceptibility to mycobacterium infections and is also more prone to allergic reactions may have what kind of deficiency?
-
IL-12 deficiency
(could also be an IFN-gamma receptor deficiency but less likely) - which disorder is a virtually complete immunodeficiency?
- SCID
- Elevated levels of IL-4 are commonly seen in which disorders?
-
Hodgkin's lymphoma
chronic lymphocytic leukemia - after a parasitic infection a patient would have high levels of which cytokines?
- IL-10, IL-3, IL-4 (mastocytosis)
- in general what happens to cytokine levels in autoimmune diseases?
- they increase significantly
- what are the 5 portals of entry for viral infection?
-
1. skin
2. conjunctiva
3. respiratory tract
4. alimentary tract
5. urogenital tract - what is the innate defense present in the skin? (3)
-
outer layer is dead cells
constant shedding
dry - what is the innate defense present in the conjunctiva? (2)
-
tear flow
lid wiping - what is the innate defense present in the respiratory tract? (4)
-
mucoid proteins
turibinate baffles cause virus to get trapped in mucus
mucociliary cells
alveolar macrophages - what is the innate defense present in the alimentary tract? (4)
-
mucoid proteins
acid
bile
proteases - what is the innate defense present in the urogenital tract? (4)
-
mucus
phagocytic cells
mechanical flushing by urine
acid environment (vagina) - how is virulence of a virus measured?
- LD50 (the number of viruses required to kill 50% of the animals following viral infection)
- what is changes in viral virulence usually associated with?
- alterations/mutations in viral proteins (ie. 1918 flu pandemic)
- How do viruses inhibit cell function? (3)
-
inhibit:
1. protein synthesis
2. DNA synthesis
3. RNA synthesis - how do viruses destroy cellular integrity? (5)
-
1. syncitia (giant cells)
2. inclusion bodies (viral factories)
3. vacuolation
4. chromosome condensation
5. apoptosis - what is the difference between a local infection and a disseminated infection?
-
local - confined, short incubation period
disseminated - spread, prolonged incubation period