Innate Immunity

Front 1

What plays a significant roles in linking innate immunity (nonspecific), andadaptive/acquired immunity (specific)? Name its subtypes as well.

Phagocytes express receptors for ______________, alsocalled endotoxin, present in the cell wall of many Gram-negative bacterialspecies but not produced by mammalian cells.

Other receptors of phagocytesrecognize terminal _________ typical of bacterial but not mammalian glycoproteins .

Back 1

Cytokinessuch as IL-1, TNFa,IL-12, and IL-6 play significant roles in linking innate immunity (nonspecific), andadaptive/acquired immunity (specific).

Phagocytes express receptors for bacterial lipopoly- saccharide (LPS), alsocalled endotoxin, present in the cell wall of many Gram-negative bacterialspecies but not produced by mammalian cells.

Other receptors of phagocytesrecognize terminal mannose residues,typical of bacterial but not mammalian glycoproteins.

Front 2

In Innate immunity, how do the cells of Innate immunity recognize the microbes?

How are the receptors of the Innate immune system are encoded / made? Can they be produced by somatic recombination of genes?

Back 2

Via Cell Surface Receptors.
Innate Immunity: Receptors are called PRR(Pattern recognition receptors) The microbial molecuesthat they recognize are called PAMP. These PAMs are different microbial molceulesthat are expressed by different classes of microbes that are usually involvedwith activityand orsurvival or microbes . They tend to be important molecules thatare required for the microbes to infect our host cells and to survive.

The receptors of the innate immunesystem are encoded in the germline andare NOT produced by somatic recombination of genes.

Front 3

Phagocytes recognize and respond to __________ RNA,found in many viruses but not in mammalian cells, and to______________ oligonucleotides, common in microbial DNA but not abundant in mammalianDNA.

What is the difference between the Innate and Adaptive immune system response to a pathogen and the subsquent attack from that pathogen?

Back 3

Phagocytes recognize and respond todouble-stranded RNA,found in many viruses but not in mammalian cells, and to unmethylated CpGoligonucleotides, common in microbial DNA but not abundant in mammalianDNA.

The innate immune system respondsin the same way to repeat encounters with a microbe, whereas theadaptive immune system responds more efficiently to each successiveencounter with a microbe.

Front 4

T/F Certain Toll-like (TLRs) and lectinreceptors arelocated on cell surfaces, other TLRs are in endosomes

What type of Innate Receptors (PRR) do you see in the cytoplasm? (3 Types)

Back 4

True

In the Cytoplasm you have 3 differenttypes: NOD like receptors, which are specific for Bacteria microbes, RIG like cereptorswhich are specific for Viral molecules. You then also have Cytosolic receptorswhich are specific for unmethylatedCpGmicrobial DNA

Front 5

Endosomal TLR's are specific to what cellular chemical component. Give examples?

****All TLRs contain a ligand-bindingdomain composed of ______________motifs and a cytoplasmic signaling, ____________ domain. *****

________ are potent anti-viral cytokines from ourimmune systems.

Back 5

Endosomal TLR they are specific formicrobial NUCLEIC ACID, double stranded RNA, single stranded RNA, CpGDNA that is unmethylated.

**** All TLRs contain a ligand-bindingdomain composed of leucine-rich motifs and a cytoplasmic signaling, Toll-likeinterleukin-1 (IL-1) receptor (TIR) domain***

IRF-3

Front 6

TLRsactivate similar signaling mechanisms, which involve adaptor proteins and leadto the activation of transcription factors including? (2)

Back 6

NFKB and IRF-3

Front 7

A pt has an infection day one inflammation was observed. The inflammation was initiated by which transcription factors and what activates the transcription factors?

Day two the physician sees that the pt has viral infection Which transcription factor would be more activated at this point?

Back 7

Transcription factors are activated by Toll Like Receptor Cells. NF-κB(nuclear factor κB)whichpromotes expression of various cytokines andendothelial adhesion molecules that mediate inflammation.

IRF-3(interferon response factor-3)which stimulates production of type I interferons, cytokines critical forantiviral defense that block viral replication.

Front 8

Epithelia produceantimicrobial substances called _______________ andharbor ___________ that kill microbes and infected cells.

Epithelia present at the portals ofentry of microbes provide physical barriers formed by __________________and by _______________ between epithelial cellsG

Back 8

Epithelia also produceantimicrobial substances (e.g., defensins) andharbor lymphocytes that kill microbes and infected cells.

Epithelia present at the portals ofentry of microbes provide physical barriers formed by keratin (in the skin) orsecreted mucus (in the gastrointestinal, bronchopulmonary and genitourinarysystems) and by tight junctions between epithelial cellsE

Front 9

What is the mechanism of Defnsins?

Back 9

DEFENSINS: They are thesovals, they are identified as Amphipathic molecules . They have clusters ofhighly charged Amino Acids so those in pink are positively charged and those ingreen are hydrophobic. They have collections of Amino Acids and have verydifferent charges. That allows them to work their way in, into the microbialmembrane. And when you have enough DEFENSINS that migrate into the membrane,the charged interactions result in those DEFENSINS altering the structure ofmembrane and form a pore in the membrane. That Microbe will Lyse and this isthe mechanism that DEFENSINS operate.

Front 10

Epithelial cells also produce ______________ thatkill bacteria

In addition, epithelia contain atype of lymphocyte called _________________. These cells belong to the T cell lineage but express_______________

Majority of the T cells express receptorsthat have an ______________ chain thatmakeup the receptor.

How are the intraepithelial lymphocytes different from T cells lymphoytes in terms of their receptor expression.

Back 10

** Epithelial cells also produce peptide antibiotics thatkill bacteria.

In addition, epithelia contain atype of lymphocyte called intraepitheliallymphocytes. These cells belong to the T cell lineage but expressantigen receptors of limited diversity

Majority of the T cells express receptorsthat have an Alpha and a Beta chain that makeup the receptor

Intraepithelial lymphocytes express Delta and Gamma chains instead of Alpha and Beta as expressed on the T lymphocytes.

Front 11

What are the two types of circulating phagocytes?

What is the most abundant leukocytes in the blood and what is their count? What is their count when an infection occurs?

Back 11

Neutrophils and Monocytes.

Neutrophils - They are normally 4,000 to 10,000. When infection occurs they increase to 20,000

Front 12

The productionof neutrophils is stimulatedby ___________, known as _______________,secreted by many cell types in response to infections.

__________ are the first cell type to respond to most infections, particularly bacterial and fungal infections.They ingest microbes in the circulation, and rapidly enter extravascular tissues atsites of infection, where they also ingest microbes anddie after a few hours.

***** ____________ cellsare a class of lymphocytesthat recognize infectedand stressed cells and respond by killing these cells and by secretingthe macrophage-activating cytokine___________ ********

Back 12

The productionof neutrophils is stimulatedby cytokines, known as colony-stimulatingfactors (CSFs),secreted by many cell types in response to infections. The CSFs act on bonemarrow stem cells to stimulate proliferation and maturation ofneutrophil precursors.

Neutrophils are the first cell type to respond to most infections, particularly bacterial and fungal infections.They ingest microbes in the circulation, and rapidly enter extravascular tissues atsites of infection, where they also ingest microbes anddie after a few hours.

****** Natural killer (NK) cellsare a class of lymphocytesthat recognize infectedand stressed cells and respond by killing these cells and by secretingthe macrophage-activating cytokineIFN-g ************

Front 13

You see a pts slide and observe this picture. What are these cells and because of the their structure what are the termed as?

T / F Some types of stress that lead tothe expression of ligands for activating receptors are DNA damage and malignanttransformation; thus, NK cells function to eliminate irreparably injured and tumor cells.

Back 13

Neutrophils - because of their multilobed nucleus structure, they are termed as Polymorphonuclear leukocytes.


True

Front 14

You see a following picture for a pts pathology. What type of cells are these? What is the normal concentration of these cells in our body?

Back 14

Monocytes - Normally they are found 500 - 1,000.

Front 15

T/F NK cells kill host cells infectedby intracellular microbes, thus eliminating reservoirs of infection.

NK cells respond to _____________ producedby macrophages and secrete ___________, which activates the macrophages to killphagocytosed microbes

Back 15

True

NK cells respond to interleukin-12 (IL-12) producedby macrophages and secrete IFN-g, which activates the macrophages to killphagocytosed microbes.

Front 16

****** What dictates on the normal cell to ensure that the Macrophages do not bind to it and destroy it? ***********

Back 16

Healthy host cells express selfclass I MHC molecules, which are recognized by inhibitory receptors, thusensuring that NK cells do not attack normal host cells. 1

Front 17

What is required by the normal cells to keep the macrophages away from them? What happens if they are not present?

T/F Surfactant proteinsin the lungalso belong to the collectinfamily and protect the airways from infection.

Back 17

Class 1 MHC. NKcells are activated by infected cells in which ligands for activating receptorsare expressed (often at high levels) and class I MHC expression is reduced sothat the inhibitory receptors are not engaged.

True.

Front 18

Antibody Dependent Cellular Cytotoxicity is a process in which the receptor is __________ and the antibodies are ___________.

What is the Principal Mediator of ADCC?

**** In NK cells, Activating receptors have signalingsubunits that contain _____________________ in their cytoplasmic tails*****

In NK cells, the inhibitoryreceptors are specificfor self _______________ molecules expressed on all healthy nucleated cells and function to block signaling by activatingreceptors.

In NK cells, Inhibitory receptors containstructural motifs in their cytoplasmic domains called _________________,which become phosphorylated on tyrosine residues when the receptors bind ______________molecules.

Back 18

Another activating receptor is the FcgRIIIA receptor specific for IgGantibodies bound to cells. The recognition ofantibody-coated cells results in killing of these cells, aphenomenon called antibody- dependent cellular cytotoxicity (ADCC).

NK cells are the principalmediators of ADCC.

Activating receptors have signalingsubunits that contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic tails.

The inhibitoryreceptors are specificfor self class I MHC molecules expressed on all healthy nucleated cells and function to block signaling by activatingreceptors.

Inhibitory receptors containstructural motifs in their cytoplasmic domains called immunoreceptor tyrosine-based inhibitory motifs (ITIMs),which become phosphorylated on tyrosine residues when the receptors bind class I MHC molecules.

Front 19

Many viruseshave mechanisms to block expression of class I MHC molecules ininfected cells allowing them to evadekilling by virus- specific _______________.When this happens, NK cell inhibitory receptors called ________________ are not engaged,and if the virus induces expression of activating ligands at the sametime, the NK cells become activatedand eliminate the virus-infected cells.

Back 19

Many viruseshave mechanisms to block expression of class I MHC molecules ininfected cells allowing them to evadekilling by virus- specific CD8+ cytotoxic T lymphocytes (CTLs).When this happens, NK cell inhibitory receptors ITIMS are not engaged,and if the virus induces expression of activating ligands at the sametime, the NK cells become activatedand eliminate the virus-infected cells.

Front 20

Compliment System:

Theactivation of the complement system may be initiated by three distinctpathways, all of which lead to the production of ________ (the early steps) which is associated with __________ and ___________.

____________ initiates the late steps of complement activation, culminating in the formationof a multiprotein complex called the ___________________,which is a transmembrane channel composed of polymerized ________ molecules thatcauses lysis of thin-walled microbes.

What are the two inflammatory peptide byproducts released with the activation of complement system?

Plasma __________________ is aprotein that recognizes microbial carbohydrates and coats microbes forphagocytosisor activatesthe complement cascade by the lectin pathway. It belongs to the collectinfamily of proteins, which share homology to collagen and contain a carbohydrate-binding(lectin) domain

Back 20

Theactivation of the complement system may be initiated by three distinctpathways, all of which lead to the production of C3b (the early steps). C3b is associated with Opsoniztion and Phagocytosis.

C3binitiates the late steps of complement activation, culminating in the formationof a multiprotein complex called the membraneattack complex (MAC),which is a transmembrane channel composed of polymerized C9 molecules thatcauses lysis of thin-walled microbes.

Peptideby-products released during complement activation are the inflammation-inducingC3a and C5a.

Plasma mannose-binding lectin (MBL) is aprotein that recognizes microbial carbohydrates and coats microbes forphagocytosisor activatesthe complement cascade by the lectin pathway. MBL belongs to the collectinfamily of proteins, which share homology to collagen and contain a carbohydrate-binding(lectin) domain->

Front 21

_____________ bindsto phosphorylcholineon microbes and coats the microbes for phagocytosis bymacrophages, which express a receptor for it and it also enhancesactivation of the alternative pathway of complement

Back 21

C-reactive protein (CRP) bindsto phosphorylcholineon microbes and coats the microbes for phagocytosis bymacrophages, which express a receptor for CRP. CRP also enhancesactivation of the alternative pathway of complement

Front 22

Plasma Mannose binding lectin is a protein that either coats the microbes for phagocytosis or initiates the compliment cascade by the ________ pathway?

The circulating levels of the two plasma proteins of Innate Immunity: ____________ and __________(name) increase rapidly after infection. This protective response is calledthe acute phase responseto infection.

Back 22

Lectin pathway.

Mannose Binding Lectin and C-Reactive Protein

Front 23

_______________ and ____________ responding to microbes produce cytokines that stimulateinflammation (leukocyte recruitment) and activatenatural killer (NK) cells toproduce the macrophage- activating cytokine ____________.

__________________ are soluble proteins that mediate immune and inflammatory reactionsand are responsible for communications between leukocytes and between leukocytes and other cells.

Mostof the molecularly defined cytokines are called ________________,by convention, implying that these molecules areproduced by leukocytes and act on leukocytes.

Back 23

Dendriticcells and macrophages responding to microbes produce cytokines that stimulateinflammation (leukocyte recruitment) and activatenatural killer (NK) cells toproduce the macrophage- activating cytokine IFN-g.

Cytokines are soluble proteins that mediate immune and inflammatory reactionsand are responsible for communications between leukocytes and between leukocytes and other cells.

Mostof the molecularly defined cytokines are called interleukins,by convention, implying that these molecules areproduced by leukocytes and act on leukocytes.

Front 24

*** What are the two cytokines that are expressed in both Innate and Adaptive Immunity ***

What are the Three Cytokines that are involved in recruiting blood neutrophils andmonocytes to sites of infection.

T / F: Severe, disseminated gram-negativebacterial infections sometimes lead to a potentially lethalclinical syndrome called septicshock, characterized by low blood pressure (the defining feature of shock), disseminatedintra- vascular coagulation, and metabolicdisturbances.

Back 24

TGF Beta and IFN-Gamma

TNF, IL-1, and Chemokines are theprincipal cytokines involved in recruiting blood neutrophils andmonocytes to sites of infection.

True

Front 25

At high concentrations, _____________ promotes thrombus formation on the endothelium and reduces bloodpressure by a combination of reduced myocardialcontractility and vascular dilatation and leakiness.

Migration of Blood Leukocytes:
Neutrophils and monocytes migrateto extravascular sites of infection by bindingto _________________ andin response to ______________ thatare produced on encounter with microbes, vascular coagulation, and metabolicdisturbances.

Inherited deficienciesin ______________ and ____________ ligands leadto defectiveleukocyte recruitment to sites of infection and increased susceptibility to infections.These disorders are called _____________________.

Back 25

At high concentrations, TNFpromotes thrombus formation on the endothelium and reduces bloodpressure by a combination of reduced myocardialcontractility and vascular dilatation and leakiness.

Neutrophils and monocytes migrateto extravascular sites of infection by bindingto endothelial adhesion molecules andin response to chemokines(chemoattractant cytokines) thatare produced on encounter with microbes.



Inherited deficienciesin integrinsand selectin ligands leadto defectiveleukocyte recruitment to sites of infection and increased susceptibility to infections.These disorders are called leukocyte adhesion deficiencies (LADs).

Front 26

At the site of infection macrophages and dendritic cells produce ______________ and __________ receptors which leukocytes utilize to bind.

T/ F Selectinsmediate strong tethering and rolling ofblood neutrophils on the endothelium, integrinsmediate weak adhesion ofneutrophils, and chemokines activatethe neutrophils and stimulate their migration through the endothelium to thesite of infection.

Phagocyte Receptor:
T/F TLRs andother patternrecognition receptors onneutrophils and macrophages recognize microbes inthe blood and extravascular tissues and initiate responses that function todestroy the microbes.

Back 26

E-Selectin and ICAM 1 (Watch the video extravasation)

F Selectinsmediate weak tethering and rolling ofblood neutrophils on the endothelium, integrinsmediate firm adhesion ofneutrophils, and chemokines activatethe neutrophils and stimulate their migration through the endothelium to thesite of infection.

True

Front 27

The process of coating microbes for efficient recognition byphagocytes is called ____________________.

The receptors thatar einvolced mainly in activating the phagocytes are: (3)

Back 27

Opsonization

Receptors that are involved mainly in activating phagocytes include: Toll Like Receptors, reeptors for Formyl Methionine and receptors for cytokines mainly IFNgamma and Chemokines.

Front 28

Phagocyte Receptors:
Somereceptors mainly activate the phagocytes; these include __________, receptors for _________________,and receptorsfor cytokines, mainly ____________.

•Othersare involved in phagocytosis of microbes and activation of the phagocytes; these include ______________ receptors and ____________ receptors.

Back 28

•Somereceptors mainly activate the phagocytes; these include TLRs, receptors for formylmethionine peptides,and receptorsfor cytokines, mainly IFN-g and chemokines.

•Othersare involved in phagocytosis of microbes and activation of the phagocytes; these include mannosereceptors andscavenger receptorsv

Front 29

What is one of the receptors on the phagocytes that bind antibody coated bacteria, responsible for triggering phagocytosis?

What are the 3 chemicals that account for intracellular killing of the mirobes within the phagosomes and what are their contents that lead to the killing of microbes (turn up the heat)?

Back 29

FC receptors.

1) Phagocyte (NADPH) oxidase-convertsO2to superoxide anion and free radicals

2) iNOS(inducible nitric oxide synthase)-convertsarginine to nitric oxide (NO)

3) Lysosomal proteases

Front 30

T/F TypeI interferons (IFN-α, IFN-β, IFNG) are produced by plasmacytoiddendritic cells and virus-infected cells in response to intracellular TLRsignaling and other sensors of viral nucleic acids.

How does Neisseria tricks the innate immunity to evade?

How does Streptococci, tricks the innnate innate response to evade it?

Please answer the same for Pneumonocicci and Straphilococci and Pseudomonas?

How does Listeria elude the innate immunity and what about Mycobacteria?

Back 30

False: IT is only IF Alpha and IF Beta.

IF Gamma compared to these IF Alpha and Beta, is a relatively weak antiviral cytokine. IF Gamma will respond to the microbial molecules.

Neisseria: inhibits the complimentactivation. It does it by expressing Sialic Acid and that is going to inhibittwo proteolytic activities, that are present in the early step whichinhibitisC3 and C5 convertases.

Streptococci: Expresses protein called M protein at prevents C3B binding to asurface. It also prevents C3B binding to its compliment receptor. (Whatsthe name of the receptor on phagocytes that recognizes C3B bound to microbes.

Pneumounococci: Capsular polysacchrides inhibits phagocytosis.

Staphallococci: Production of Catalase which breaks down ROS intermediates (AbuuuuuKick)

Pseudomonas: Synthesis of modified LPS which resists action of peptide antibiotics.

Listeria monocytogenesproduces a protein that enables it to escape from phagocytic vesicles and enter thecytoplasm of infected cells, where it is no longersusceptible to reactive oxygen species and nitric oxide (which areproduced mainly in phagolysosomes).

The cell walls of mycobacteriacontain a lipid that inhibits fusion of vesicles containing ingestedbacteria with lysosomes.

Front 31

Inexperimental situations or for vaccination, adaptive immune responses may beinduced by antigens without microbes. Inall such instances, the antigens have to be administered with substances,called ______________,that elicit the same innate immune reactions as microbes do.

Thecomplement system is activated by microbes and generates proteins, such as ____________, which become attached to the microbes.

Back 31

Adjuvants

* Thecomplement system is activated by microbes and generates proteins, such as C3d, which become attached to the microbes. D