Lecture 20 Flashcards
What term describes the situation where a microbe invades the body and survives without propagating an infection?
Latent/persistent infection
What 2 pathways does LPS (lipopolysaccharide) on the surface of a microbe activate? What surface binding protein stimulates the other pathway?
LPS activates the Alternative and Classical pathways
MBP (mannose binding protein) activates the Lectin pathway
What are CRP and SRP? describe the mechanism they carry out and which pathway they activate
CRP and SRP are both Acute Phase Proteins
They both bind to the globular heads of C1q and activate the Classical Pathway
State the cell type that releases histamine and bradykinin. What is their function?
Mast cells degranulate in order to release histamine and bradykinin
Histamine and bradykinin both enhance blood flow in order to cause local edema and irritation to the inflamed area
Explain the mechanism that C3a and C5a carry out in order to inflame tissues.
C3a and C5a bind to receptors on resident mast cells in order to trigger their degranulation
Explain the process by which Mast cells “activate the endothelium” and why they do this in response to a primary extracellular bacterial infection
Mast cells release cytokines and chemokines (IL-8) that activate the endothelium
The endothelium is activated so that Neutrophils can adhere to it and eventually enter the infection site (rolling, adhering, transmigration)
State the 3 things that are needed in order to induce chemotaxis of neutrophils to the infection site.
Complement fragments (C3a and C5a)
Chemokines (IL-8/CXCL8)
Bacterial Products (fMLP aka Formyl-Methionyl-Leucyl-Phenylalanine tripeptide)
Immature DCs engulf and internalize bacteria via ____. what do mature DCs do once they are activated?
PRRs (Pattern Recognition Receptors)(ex. TLR’s)
Activated mature DCs migrate to the local LNs via the lymphatic system
When an activated DC cell enters a LN, where in the LN does it go and why?
DCs move to the T cell zone (the center of the LN)
They do this in order to present their Ag to the T cells that are circulating through the LN, until one of the T cells is activated
Explain the process by which Lymphocytes move from the blood circulating through the LN, to the actual LN itself.
local inflammation up regulates the expression of PNAd (peripheral Node Addressin) on HEV’s and also increases the expression of L-selectin on the surface of T cells
PNAd and L-selectin interactions cause lymphocytes to enter the LN, become trapped/activated and proliferate to cause LN swelling/pain
True or False:
Treg cells will respond to primary extracellular bacterial infections in order to control the level of T cell activation. explain.
False
Treg cells only respond to T cell reactions to “autoimmune” responses
Primary extracellular bacterial infection is not an autoimmune reaction
When naive T cells are activated by a DC in a LN, what 3 subclasses of T cells could they possibly become? what determines this?
Th1, Th2, or Th17 cells
DC signals are what determines this
IL-12 = Th1 ; IL-4 = Th2 ; IL-6 = Th17 ; TGF-beta = Treg
What occurs at germinal centers in LNs?
Activated Th cells migrate towards germinal centers
once there, they interact with Ag-activated B cells in order to promote affinity maturation and Ig class switching (IgM or IgD prior to class switching)
IgM has a ___ affinity and a ____ avidity due to it’s multiple binding sites. State the 2 negative outcomes for the pathogen that occur from IgM’s involvement in the complement system.
low affinity
High avidity
- IgM activating the complement leads to MAC complexes forming and lysing the pathogen
- The pathogen is also opsonized by C3b, which comes from the complement pathway (which IgM activated)
During the resolution of an infection, what 2 steps occur?
- bacterial debris is removed by phagocytes (M2 macrophages and neutrophils)
- antibody soluble immune complexes are removed from the blood
What are the 2 principle mechanisms of infections caused by pathogenic extracellular bacteria?
- tissue damage caused by inflammation at the site of infection
- bacteria produce toxins that have diverse pathologic effects
Compare endotoxins with exotoxins (give an example of an endotoxin)
Endotoxins: components of bacterial cell walls
ex. LPS of gram-neg bacteria, which are potent activators of resident tissue macrophages, DCs, and endothelial cells
Exotoxins: substances secreted by the bacteria to interfere with normal cell functions in a variety of ways.
Some exotoxins directly interfere, while others stimulate the production of cytokines that interfere.
State 3 exotoxins and their effects
Diphtheria Toxin: shuts down protein synthesis in infected cells
Cholera Toxin: interferes with water/ion transport
Tetanus Toxin: inhibits neuromuscular transmission
State the 3 principle mechanisms of innate immune response to extracellular bacteria
Complement activation
Phagocytosis
Inflammation
Bacterial peptidoglycans are found on Gram ___ bacteria and stimulate which pathway(s)? Bacterial LPS are found on Gram __ bacteria and stimulate which pathway(s)?
peptidoglycans are found on gram + bacteria
LPS are found on gram - bacteria
Both peptidoglycans and LPS activate the Alternative and Classical pathways
Complement activation results in _____ and enhanced ____ of the bacteria. How are C3a and C5a related to complement activation?
opsonization
phagocytosis
C3a and C5a are by products of complement activation that recruit and activate Leukocytes (inflammation)
Which specific bacteria is particularly susceptible to destruction via MAC complexes?
Neisseria
What factor cleaves C3b and C4b in order to prevent them from forming active convertases (controls activation)? What respective factors need to be present in order to help this factor? (list the 4 things needed in addition the the factor for both C3b abd C4b cleavage to occur)
Factor I cleaves C3b and C4b
C3b: Factor I, MCP, CR1, and Factor H
C4b: Factor I, MCP, C4BP, and CR1
Which protein inhibits the assembly of new C3 convertases and shortens the half-life of those that have already formed? For the classical and alternative pathways, list the 3 factors that must be present to accomplish this.
DAF (decay accelerating factor): inhibits the assembly of new C3 convertases and shortens the half-life of those that have already formed
Classical pathway: DAF, CR1, and C4BP
Alternative pathway: DAF, Factor H, and CR1
Which protein inhibits the assembly of the MAC lytic complex? include both names for this protein.
MAC-inhibitory protein (CD59)
State the 3 steps of the phagocytic process that occurs to opsonized microbes
- Recognition of the opsonized microbe and Attachment to the phagocytic receptors on the surface of the phagocytic cell
- Engulfment into a phagosome
- Fusion of the phagosome and a lysosome in order to form a phagolysosome that kills/degrades the microbe
What is the major mechanism employed by bacteria in order to Evade humoral immune destruction in the body? State 5 mechanisms that are used to conduct this survival mechanism by microbes.
Variation of surface antigens
- Change in surface Ags over time
- Sialylation of LPS (covers LPS up)
- Secretion of “decoy” membrane blebs
- Producing Pili on it’s surface with variable V and G regions on them (disguise)
- Secretion of IgA protease (destroys IgA, the toughest Ig)
For Pneumococcus, Neisseria meningitidis, state the mechanism of immune evasion is it known for. What about the mechanism of Catalase-positive staphylococci?
Pneumococcus, Neisseria meningitidis: resistance to phagocytosis
Catalase-positive staphylococci: Scavenging of ROS
Adaptive (humoral) immunity to extracellular pathogens produces ____ and activates ______ in order to protect the body.
Put the following adaptive immune system functions for extracellular defense into the category of antibodies or complement activation.
Phagocytosis of C3b-coated bacteria Neutralization Opsonization and Fc-receptor mediated phagocytosis Lysis of the microbe Inflammation
Antibodies
Complement
Antibodies:
Neutralization
Opsonization and Fc-receptor mediated phagocytosis
Complement:
Phagocytosis of C3b-coated bacteria
Inflammation
Lysis of the microbe
Which type of immunity is effective for combating extracellular bacteria? State the 2 functions it has on the microbes themselves and how it deals with toxins that the extracellular microbe may produce.
Humoral Immunity
Functions to block infection and eliminate the microbes themselves
Neutralizes any toxins the microbe my create
What type of responses against extracellular bacteria are directed against cell wall Ags and secreted/cell associate toxins.
Antibody responses are directed against cell wall Ags and secreted/cell associate toxins
State the 3 effector mechanisms of Abs
- toxin neutralization
- Opsonization and Phagocytosis
- Complement activation via the classical pathway
The following pathogens all have what in common? Streptococcus pneumoniae, Neisseria meningitidis, and haemophilus influenzae.
Describe the surface of these 3 types of pathogen
Streptococcus pneumoniae, Neisseria meningitidis, and haemophilus influenzae are all “Encapsulated Bacteria”
Encapsulated bacteria’s surface is rich in TI polysaccharide, which means that they are primarily eliminated by Abs.
Mature B cells can secrete ___ upon recognition of an Ag. What signal must it receive in order to undergo class switching and _____ _____?
IgM
Affinity Maturation
CD40/CD40L is the signal that B cells must receive in order to secrete anything besides IgM (or IgD)
(CD40 is on the B cell ; CD40L is on the T cell)
Compare the following subsets of CD4+ helper cells.
Th1:
Th2:
Th17:
Th1: produce IFN-gamma to cause macrophage activation (to phagocytose and kill microbes)
Th2: produces a variety of cytokines to induce the production of antibodies
Th17: produce IL-17 and TNF to cause inflammation
What cytokine is known to stimulation the production of opsonizing and complement fixing IgG Antibodies?
IFN-gamma
State the 2 injurious consequences of host responses to extracellular bacteria. These types of responses are usually ____-limited and controlled.
- inflammation
- Septic Shock
usually self-limited and controlled
Septic shock is a consequence of what? What is septic shock commonly characterized by?
disseminated bacterial infection (by gram - or gram + bacteria)
(uncontrolled high levels of immune response)
Septic shock is commonly characterized by collapse of the circulatory system and intravascular coagulation
(from very high levels of immune reactions taking place in the blood and causing clotting)
Which 2 cells types can cause tissue damage in a pt in septic shock by local production of ROS and lysosomal enzymes? Which of these 2 cell types is responsible for secreting the cytokines that cause the “early phase” of septic shock?
Neutrophils and Resident tissue macrophages
Resident tissue macrophages are responsible for secreting the cytokines that cause the “early phase” of septic shock
Describe the mechanism of shock using the following cytokines and their interactions
TNF-alpha, TF (tissue factor), iNOS, and IL-18
Resident tissue macrophages secrete all of them
TNF-alpha upregulates TI and iNOS
TF induces a coagulating effect
iNOS (nitric oxide synthase) creates oxygen radicals
IL-18 induces IFN-gamma in order to further stimulate resident tissue macrophages
What is the function of PAI-1 (Plasminogen activator inhibitor-1)?
induces a procoagulant effect
For the following mediators of septic shock, classify them as either a cytokine or chemokine (less chemokines).
IL-6 IL-12 MCP IL-15 IL-18 TNF-alpha IL-1 HMGB1 IL-10 IL-8 MIP
Cytokines: IL-1 IL-6 IL-12 IL-15 IL-18 TNF-alpha HMGB1 IL-10
Chemokines:
IL-8 (most potent chemokine for Neutrophils specifically)
MIP (macrophage inflammatory Protein)
MCP (Macrophage Chemoattractant Protein)
Describe what it means to be a “lipid mediator” involved in causing septic shock (2 functions)
Lipid mediators activate vascular endothelium (regulate their tone) and activate the extrinsic coagulation cascade.
Compare the functions of IL-10 and TNFbeta. Which of these is known as the global suppressor of resident tissue macrophage function?
IL-10: functions to inhibit/control both innate and adaptive immune responses
TNFbeta: either anti-inflammatory or a chemoattractant for fibroblaste (to promote tissue repair of the collateral damage caused by immune reactions)
IL-10 is known as the global suppressor of resident tissue macrophage function.
What is the function of MCP-1 and IL-8 during a septic shock reaction? Which cell secretes these 2 substances?
they both serve as chemoattractants for WBC’s and immune cells
Macrophages secrete both MCP-1 and IL-8
MPO, NO, ROS, TNFalpha, and IL-6 are all products of what cell type? describe all of these in terms of their function
Neutrophils
MPO, NO, and ROS are all reactive oxygen radicals
TNFalpha and IL-6 are both acute phase proteins that promote inflammation
What type of MHC molecule do Superantigens (SAgs) act on? describe the specifics of the mechanism of a superantigen and the effect that the Ag specificity of the TCR has on it.
MHC class II molecules
SAgs binds to the variable portion of different TCR Beta chains, regardless of the peptide specificity of the TCR
Explain how the mechanism of SAgs contributes to the huge numbers of T cells that SAgs can activate (include the term that describes the high level of T cell activation that commonly occurs due to SAgs)
Since many T cell TCRs express a Beta chain from a particular Vbeta family, “Polyclonal Cell Activation” occurs when a SAg reacts with a specific beta chain
For the following SAg disease, describe the specific bacteria that cause it.
Food Poisoning
Staphylococcal SAgs cause Food poisoning bc they are potent GI toxins
For the following SAg disease, describe the specific bacteria that cause it. Describe the type of syndrome this is
TSS (toxic shock syndrome)
S. aureus causes TSS and is considered a “capillary leak syndrome”
Which hypothesized SAg disease is an acute multi-system vasculitic of unknown etiology?
Kawasaki Disease (KD)
What is the most severe form of invasive streptococcal infection? Which specific bacteria is responsible for this?
Streptococcal TSS (Toxic shock syndrom)
S. pyogenes causes Streptococcal TSS
What disease is a post-infection cause of preventable pediatric heart disease? What causes this (include the autoimmune mechanism it carries out)
ARF (Acute Rheumatic Fever)
ARF is caused by Abs formed against Streptococcus pyogenes that react with myosin and laminin components of heart valves
This is a form of “Molecular mimicry”
True or False:
Responses to Intracellular and Extracellular infections can cause tissue injury. explain
Intracellular Bacteria and Viruses are inaccessible to Abs. explain.
True
True
(no explanation needed)
Which type of interferons are activated in cells when they are infected with an intracellular viral infection (type I or type II)? Give the best example of this type of cytokine and state the 2 local effects it has on virally infected cells.
Type I interferons
IFN-alpha is an example of a Type I interferon
IFN-alpha causes inhibition of viral gene replication and up-regulation of MHC class I molecule (which express viral peptides on the cell surface)
What effect does IL-2 have on NK cells? explain the reason behind this
it activates them
IL-2 is known as the major growth factor for T cells and IL-15 is known as the major growth factor for NK cells.
Since IL-2 and IL-15 are similar, IL-2 can stimulate NK cells
State the 2 cytokines from Th1 cells that activate NK cells in a viral infection and the epithelium-derived cytokine that also stimulates NK cells during a viral infection.
Th1 cells secrete IL-2 and IFN-gamma in the later stages of a viral infection
IFN-alpha is epithelial derived and occurs early in the viral infection
What is the role of DCs in a viral infection? what about Resident tissue macrophages other and APCs?
DCs engulf and present single stranded RNA from the virus
Resident tissue macrophages and other APCs present viral proteins
Where are langerhans cells found and what do they do?
Langerhans cells are DC’s that are found in the skin
they transport Ags that penetrate the skin and bring them to the nearest LN
State the systemic effects of Il-1 and TNF-alpha once they enter the bloodstream. Also state the general type of substance that upregulates ICAM-1 and why.
IL-1 and TNF-alpha cause systemic fever and arthralgia/myalgia
Cytokines up regulate ICAM-1 in endothelium to allow immune cells to leave the blood and enter tissues
Explain how DCs enter LNs, and where in the LN they migrate.
DCs enter LNs via the lymphatic system and migrate to the T cell zone
When a viral peptide is being presented to a Th cell, by an APC, state what MHC class will present to the TCR. Also state the stabilizing molecule for the MHC-TCR interaction will be there. What interaction must occur to provide costimulation of this interaction?
MHC class II
CD4 will stabilize the MHC class II-TCR interaction
CD80/86-CD28 provides the costimulatory signal
(CD80/86 from APC ; CD28 from Th cell)
Th1 cells secrete which 2 cytokines in order to activate CTLs? What type of presentation must DC’s conduct in order for CTLs to recognize viral peptides?
IL-2 and IFN-gamma
DCs conduct "Cross presentation" in order to present the viral epitopes in MHC class I surface molecules (same viral epitopes are presented in both MHC class I and Class II during cross presentation)
What stage of Th and CTLs exhibit the following attributes after leaving the LN?
- virus-specific TCRS
- Up regulated adhesion molecules (LFA-1)
- up regulated production of cytokines
Also describe the pathway these cells take to exit the LN.
Effector Th and CTL’s have the following attributes
- virus-specific TCRS
- Up regulated adhesion molecules (LFA-1)
- up regulated production of cytokines
These cells exit the LN via the lymphatics and eventually make their way into the blood. (then they use their up regulated LFA-1 to enter the inflamed areas of tissue)
Explain the relationship between the Fc portion of an Ab and NK cells in combating virally infected cells
Abs, once bound to a virally infected cell, can lead NK cells to the infected cell that needs destroyed
NK cells have Fc-receptors on them that interacts with the Fc portion of Abs to conduct ADCC (Ab-dependent Cell-Mediated Cytotoxicity)
For Innate and Adaptive immune reactions, state the cells that interact with Macrophages and how they interact differently.
Innate:
Macrophages stimulate NK cells with IL-12 and NK cells reciprocate the stimulation with IFN-gamma for Macrophages
Adaptive:
T cells secrete IFN-gamma and CD40L in order to activate Macrophages
Compare IFN-gamma and IFN-alpha in terms of when they are expressed during a viral infection
IFN-gamma: expressed later in the infection (with IL-2)
IFN-alpha: expressed early in the infection by endothelial cells
resistance of bacteria to degradation, once they are captured in phagocytes, is overrun by which NK cell-produced Cytokine?
IFN-gamma
compare the Endogenous and Exogenous pathways of Ag presentation (include which MHC class, where in the cell it is loaded, and what cell types it is presented to)
Endogenous pathway: presents proteins from intracellular pathogens loaded onto MHC class I in the ER, AFTER they are degraded into peptides by proteasomes They are then presented to CTLS to be killed.
Exogenous pathway: pathogens are engulfed into a phagosome, loaded onto MHC class II molecules, and presented to Th cells
For the following intracellular pathogen, describe their mechanism of evasion.
Mycobacterium Tuberculosis:
Legionella pneumophila:
Mycobacterium leprae:
Listeria monocytogenes:
Mycobacterium Tuberculosis: Inhibition of phagolysosome formation (gets phagocytosed and survives in the vesicle of the APC)
Legionella pneumophila: Inhibition of phagolysosome formation (gets phagocytosed and survives in the vesicle of the APC)
(“plays keep away”)
Mycobacterium leprae: Inactivation of ROS and NOS species via phenolic glycolipid)
Listeria monocytogenes: Disruption of phagosome membrane via hemolysin protein and escaping into the cytoplasm
(“Jailbreak”)
What type of Th cells will activate phagocytes to kill ingested microbes? What type of Th cells will inhibit this classical pathway of resident tissue macrophage activation?
Th1 cells will activate phagocytes to kill ingested microbes
Th2 cells (or really any other Th cell) will inhibit the Th1 pathway of activation
What is Dectin 1? What type of pathogen is Dectin 1 known to detect? What was previously thought to be the only receptor for this pathogen type?
Dectin 1 is an APC receptor that detects Beta-glucan (Dectin 1 is the PAMP and Beta-glucan is the PRR)
Dectin 1 detects fungal pathogens and triggers antifungal innate immune responses (Th1 and Th17 are innate)
Mannose receptors were previously thought to be the major fungi receptor
Compare the outcome of an innate and of an adaptive immune response to a fungal pathogen.
Innate (Th1 and Th17) responses are REQUIRED for clearance of fungal pathogens
Adaptive (Th2) responses usually result in INCREASED susceptibility to fungal infections
For Th1, Th2, and Th17, state the cytokines that create them and the cytokines they secrete after they develop.
Th1: IL-12 stimulates differentiation
Secretes IFN-gamma (macrophage activator)
Th2: IL-4 and IL-5 stimulate differentiation
Triggers antibody creation
Th17: TGF-beta and IL-6 stimulate differentiation
Secretes IL-17 and IL-22 (Neutrophil and Epithelial cell activator)
Dectin 1 binds and internalizes beta-glucans, and then what happens?
Dectin 1 mediates activation of NF-KappaB
NF-KappaB then causes the secretion of inflammatory cytokines and the production of ROS
