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Immunology 2019 > Lecture 5 > Flashcards

Lecture 5 Flashcards

1
Q

PAMPs and DAMPs are inducers of ______.

A

Inflammation

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2
Q

State the sensors that PAMPs and DAMPs act on and state the mediators the mediate the inflammatory pathways

A

Sensors:
TLR’s

Nod-like receptors

C-type lectin

Mediators:
TNF-alpha

IL-6

IL-1beta

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3
Q

Define Necrosis. What is the defining characteristic of necrosis.

A

Necrosis: a passive, catabolic cell death in response to external toxic factors

Characteristic of Necrosis:
swelling and rupture of the cell membrane (cell lyse) that may cause inflammation or harm to neighboring cells

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4
Q

What type of immune reaction is inflammation and what does it have to do with necrosis and DAMPs?

A

Inflammation is an innate immune reaction

When necrosis occurs in a cell, the cell usually released DAMPs which trigger inflammation

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5
Q

Give the 5 causes/characteristics of inflammation

A
  1. increased blood supply to the affected area that causes “redness” and “heat”
  2. A increased capillary permeability that causes leaking from capillaries that causes “swelling and pain”
  3. A massive influx of neutrophils in the tissu
  4. The arrival of monocytes/macrophages (16-48 hrs)
  5. Distortion of the homeostasis and loss of function
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6
Q

State 3 “danger signals” (DAMPs) released by damaged cells that dendrites detect and then consequently activate NF-KB. (briefly explain them)

A

HMGB1: RAGE receptor binds to HMGB1 and activates NF-KB

Uric Acid: induce the NF-KB pathway

HSP’s: induce the NF-KB pathway AND the release of inflammatory cytokines (TNF-alpha and IL-1B)

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7
Q

Name 2 ways , not including just the physical barrier itself, that epithelia can kill microbes

A

Epithelia locally produce antibiotics (defensins and cathelicidins)

Epithelia harbor intraepithelial Lymphocytes that can kill microbes and cells infected with microbes

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8
Q

Describe Defensins in terms of the regions they feature.

A

Defensins are small cationic peptides that contain both cationic and hydrophobic regions (they use the hydrophobic region to stick to the surface of pathogens)

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9
Q

State where Defensins are produced AND what stimulates their synthesis.

A

Defensins are produced by epithelial cells and by granule -containing leukocytes (neutrophils, NK cells, and CTLs)

Defensin synthesis is stimulated by Cytokine and PRR receptors

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10
Q

State the 3 types of microbes that defensins show direct toxicity for. explain the process by which defensins kill these microbes

A
  1. Bacteria
  2. Fungi
  3. enveloped viruses

Defensins kill these microbes by inserting into and disrupting the functions of their microbial membranes

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11
Q

Defensins ______ activation of immune cells involved in the ____ ____ to microbes.

A

Regulate

Inflammatory Response

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12
Q

Defensins and Cathelicidins can both conduct which 2 types of activities?

A

Both are capable of microbicidal activity and chemotactic activity for immune cells (both of which have an antimicrobial end goal)

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13
Q

What are Cathelicidins produced by and what stimulates their synthesis?

A

produced by neutrophils

their synthesis is stimulated by cytokines and microbial products

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14
Q

What do Cathelicidins have to do with LPS’s (lipopolysaccharides) and Inflammasomes?

A

Some cathelicidins can bind to and neutralize LPS’s in order to neutralize excessive amounts of cytokines (released by macrophages/monocytes)

Some cathelicidins play an anit-inflammatory role by binding to DNA, which blocks inflammasome activation

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15
Q

State the 2 mechanisms by which cathelicidins can destroy microbes.

A

Cathelicidins themselves can be directly toxic to microbes

they can activate leukocytes which destroy the microbes

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16
Q

What type of immunity do cells of myeloid lineage belong to, and also cells of lymphoid lineage? what is the one cell that does not abide by this “rule”?

A

Cells of myeloid lineage are a part of INNATE immunity

Cells of Lymphoid lineage are a part of ADAPTIVE immunity

NK cells are of lymphoid lineage, however they operate via the same principles of innate immunity (nonspecific)

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17
Q

State the 3 methods by which NK cells can recognize cells that they will destroy

A
  1. They detect a cell with DNA damage
  2. They detect a “stressed target cell “(a cell with tumor transformation or intracytoplasmic microbial infection)
  3. A target cell has antibodies on it’s surface
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18
Q

State the 2 types of infections that would cause an NK cell to secrete the following cytokines:
IFN-gamma

IL-10

A

IFN-gamma: they produce this in many types of acute conditions

IL-10: they produce this in specific, chronic conditions

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19
Q

Explain the relationship between NK cells and Dendritic cells.

A

NK cells lyse target cells, leaving antigen’s of the destroyed pathogen for dendritic cells to “present” in lymph nodes

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20
Q

How exactly to NK cells “Boost or dampen” macrophage and T cell responses?

A

They secrete IFN-gamma (the boost cytokine) and IL-10 (the dampening cytokine)

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21
Q

True or False:

NK cells kill cells via Phagocytosis, inducing necrosis, or apoptosis. explain.

A

False

NK cells cause only apoptosis or lysis (it also signals for macrophages to come destroy the products of the lysed cell) of damaged/infected cells.

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22
Q

NK cells and Macrophages participate in a positive amplification loop together, known as the cytokine-dependent Amplification Loop. Describe it.

A

NK cells respond to IL-12, which is produced by macrophages

NK cells secrete IFN-gamma, which tells Macrophages to KILL phagocytized microbes

Being stimulated by IFN-gamma ALSO causes macrophages to secrete IL-12

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23
Q

Describe the activating and inhibitory receptors on NK cells (include the enzymatic proteins that both receptors trigger when activated)

A

Activating Receptors of NK cells recognize ligands on target cells and activate PTKs (protein tyrosine kinases)

Inhibitory Receptors on NK cells recognize Class I MHC molecules that are ONLY expressed on healthy cells. If class I MHC molecules are present on a cell, it activated protein tyrosine phosphatase (PTP) which inhibits that activation signal.

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24
Q

What is another name for the activating receptors on NK cells? why do they have this name?

A

Activating receptor cells are also called killer cell (immunoglobulin) ig-like receptors (KIRs)

they have this name because they have an Ig fold (structural domain)

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25
Q

When NK cells recognize cellular stress, how exactly do they become activated?

A

They become activated via activating NKG2D receptors, which bind to MICA and MICB ligands

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26
Q

What are MICA and MICB ligands?

A

ligands that are upregulated upon cellular stress associated with viral infection and malignant transformation (tattle tails found on the surface of cell with these intracellular pathogenic processes ; almost like a “save yourself” signal)

MICA and MICB are NOT found on the surface of healthy cells

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27
Q

State the 2 steps by which NK cells Kill target cells. what happens after the target cell dies?

A
  1. NK cell releases perforins, which puncture holes in the target cell membrane
  2. Granzymes from the NK cell enter the perforin hole and degrade the enzymes of the enemy cell

After the target cell dies via apoptosis/lysis, a macrophage come in and engulfs/digests the target cell (the macrophage was signalled by the NK cell)

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28
Q

In terms of complement activation, state and briefly describe the 3 different activation pathways.

A

Alternative pathway: the microbe directly activates the pathway

Classical pathway: an antibody attaches to the microbe and activates the pathway

Lectin pathway: a mannose-binding lectin attaches to the mannose on the surface of the microbe and activates the pathway

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29
Q

Compare the early step 1, the early step 2, and late steps of the complement pathway

A

early step 1 is the formation of C3 convertase complexes that produce C3a and C3b in order to trigger inflammation and opsonize microbes

early step 2 is the formation of C5 convertase complexes that produce C5a and C5b which perpetuate inflammation and lead to the late steps

The late steps are the formation of MAC (membrane attack complexes)

30
Q

Explain in terms of the specific molecule(s) that activate the complement activation cascade. (include the specific type of cascade that occurs and the molecule involved)

A

a proteolytic cascade occurs

zymogen (an inactive precursor enzyme), is altered to become an active protease that cleaves the next complement in the cascade

31
Q

name the 2 other important proteolytic cascades that the complement cascade works in cooperation with

A

The blood coagulation pathways

The kinin-kallikrein system (regulates vascular permeability)

32
Q

______ of the complement activation perform the various effector functions of the complement system.

A

byproducts

33
Q

Explain what happens when C3 convertase encounters C3 (include what each molecule’s function is)

A

C3 convertase cleaves C3 into C3a and C3b

the soluble C3a fragment stimulates inflammation by acting as a chemoattractant for neutrophils (and mast cells)

The C3b fragment becomes covalently attached to the surface of the microbe in order to opsonize it for phagocytosis

34
Q

What forms the C5 convertase complex?

A

C3 convertase bound to C3b fragment

35
Q

Explain what happens when C5 convertase encounters C5 (include what each molecule’s function is)

A

C5 convertase cleaves C5 into C5a and C5b

C5a is a potent chemoattractant that changes the permeability of blood vessels

C5b is attached to the microbial membrane and initiates the formation of MAC (the membrane attack complex is formed by a complex of C6, C7, C8, and C9)

36
Q

In the alternative pathway, what subunits make up an alternative C3 convertase? explain how this forms

A

Bb and C3b form alternative C3 convertase

To form this, first factor B binds to C3b, which is already attached to the surface of the pathogen

Then Factor D cleaves factor B into Bb and Ba, which leaves Bb bound to C3b and Ba floats away

37
Q

Explain why the alternative pathway is considered to be an “amplification loop” and what this has to do with “autoactivation”.

A

C3 convertase can cleave additional C3 molecules, which generates more C3b to be used to form many more C3b molecules on the surface of the antigen (autoactivation)

This same alternative pathway of amplification of C3b can occur beginning with C3b that was formed via the classical or lectin activation pathway (amplification loop)

38
Q

What is Alternative C5 convertase composed of (4 things)? which of these molecules is most involved in the stabilization of the proteins involved in the Alternative pathway?

A

Alternative C5 convertase is composed of two molecules of C3b, one Bb, and Properdin

Properdin is a serum protein that stabilizes the proteins, and allows for the successive proteolytic steps to occur more efficiently

39
Q

Explain how C5b, C6, C7, C8 and C9 interact and what they form.

A

They all form MAC(membrane attack complex)

C5b binds to C6 and C7, which then binds to the SURFACE of the microbial membrane via the C7 subunit

C8 then joins the complex, and allows the complex to INSERT into the microbial membrane

C9 molecules (1-16 of them) then come in and form a complex with themselves to form a “pore” in the membrane

40
Q

Compare planar and staple forms of IgM antibodies and their different functions. Be sure to include which of these initiates the classical complement pathway

A

The planar form of IgM simply circulates in the blood

The Staple form of IgM occurs when it (IgM is an antibody) binds to an antigen on the surface of a pathogen

The staple form is what initiates the classical complement pathway

41
Q

State what units comprise the classical C3 convertase and classical C5 convertase.

A

classical C3 convertase: C4b + C2a

classical C5 convertase: C4b + C2a + C3b

42
Q

Explain what makes the C3 convertase units in the classical and Lectin complex pathways unique when compared to Alternative convertase complexes

A

The C2a unit is what sticks around to help form that C3 and C5 convertase complexes

(the alternative pathway includes C3b in it’s C3 convertase complex, instead of C2a)

43
Q

Begin with C1q, explain it’s function, and then elaborate what is C1s, and what its function is in the Classical complement pathway.

A

C1q is a plasma protein that recognizes and bind to the Fc portion of antibodies

C1s is a serine protease that is activated when C1q binds to an Ag-Ab complexes

Activated C1s cleaves C2 and C4, creating C4a, C4b, C2a, and C2b

(remember that C2a and C4b are the classical C3 convertase in this pathway)

44
Q

Out of the alternative, classical, and lectin complement activation pathways, state which 2 are most similar and then state what the main difference between them is

A

The Lectin and classical activation pathways of the complement system are nearly identical, except in the way that they are initiated

The Classical activation pathway is initiated by antibodies binding to a pathogen

The lectin activation pathway is initiated by the detection of a terminal mannose residue

The alternative pathway is directly stimulated by the microbe (spontaneous)

45
Q

Compare MBL and the C1q component of the classical complement pathway. (include MASP1 and 2 as well as C1r and C1s)

A

MBL (mannose-binding lectin) has a hexameric structure that is very similar to the structure of the C1q component of the classical pathway

MASP1 and MASP2 (mannose-associated serine protease) are basically the Lectin pathway counterparts to the C1r and C1s of the classical pathway
(Both conduct downstream protease activity to advance the pathway)

46
Q

State what composes the Lectin pathway C3 convertase and C5 convertase

A

classical C3 convertase: C4b + C2a

classical C5 convertase: C4b + C2a + C3b

(identical to classical pathway)

47
Q

True or false:
The MAC that is assembled at the end of the complement pathway is identical for all 3 activation methods of the complement pathway. explain.

A

True

the MAC (membrane attack complex) is identical bc the 3 different pathways all have the same result, which is forming MAC’s on pathogens to destroy them

48
Q

Explain what DAF(decay-accelerating factor) is and it’s function

A

DAF is a “regulatory protein” (inhibits, disassembles, or cleaves convertases)

It serves to prevent the complement pathway from becoming activated on the surface of mammalian cells by blocking C2a and C4a from interacting and becoming C3 convertase

49
Q

State and briefly describe the 3 regulatory proteins that prevent the complement pathway from occurring on the surface of mammalian cells.

A

DAF (decay-accelerating factor): blocks C2a and C4a from forming C3 convertase

CR1: is an intramembranous cofactor for FI (Factor I) found on phagocytes

FI: prevents the assembly of C3 and C5 convertase complexes
(FI is also known as C3b/C4b inactivator)

50
Q

State and briefly describe the 3 functions of the Complement pathway AFTER C3b has been deposited on the surface of a the microbe (one of the three is not directly involved with the C3b molecule)

A

Formation of the MAC, which causes lysis of the microbe

A phagocyte recognizes the C3b on the surface of the microbe and conducts phagocytosis of the microbe

The soluble subunits C5a and C3a cause “inflammation” that attracts leukocytes to kill the microbe (this one doesn’t really have to do with the C3b on the surface of the pathogen)

51
Q

Once C3a and C5a molecules initiate an inflammatory response, state how the following cells respond to it:
Mast cells and basophils:

Neutrophils:

Monocytes and Macrophages:

A

Mast cells and basophils: secrete vasoactive substances

Neutrophils: Release LOTS of chemokines, PG’s, ROS, RNS, and utilize adhesion molecules

Monocytes and Macrophages: release IL-1, IL-6, PG, ROS, RNS, and utilize adhesion molecules

52
Q

Compare the level of inflammation that is caused by C2a, C3a, C4a, and C5a. (there are 2 tricks in here)

A

C2a has an unknown function

C3a causes moderate inflammation

C4a is “not found” whatever that means

C5a creates the most potent inflammatory response

53
Q

Name the 4 specific effects that accompany the inflammation that occurs due to soluble complement fragments (C3a and C5a)

A
  1. contraction of smooth muscles
  2. increased permeability of blood vessels
  3. Degranulation of basophils
  4. Chemotaxis, and the release of O2 radicals/lysosomal enzymes
54
Q

Explain what an anaphylatoxin is and give 2 examples of it

A

anaphylatoxin: a substance that triggers inflammation

ex. C3a and C5a

55
Q

Say a microbe already has C3b on it’s surface, and a phagocyte finds it, what happens? (3 steps)

A

The C3b on the surface of the microbe binds to Cr1 on the surface of the phagocyte, and the microbe is internalized.

once the microbe is internalized into a phagosome, the phagosome fuses with lysosomes to form a phagolysosome

The microbe in the phagolysosome is then killed by reactive oxygen species, reactive nitrogen species, and proteolytic enzymes.

56
Q

What is one way that microbes may survive, even after they are captured in a phagosome, within a phagocyte? explain why this works.

A

microbes that express “catalase” can survive inside of phagocytes

catalase makes O2 and H2O out of H2O2
(H2O2 usually kills microbes because it becomes either HOCl, which is bleach, or OH with a damaging free radial)

57
Q

State the 2 things that resident tissue macrophages are stimulated by. THEN state the 2 things that the activation of macrophages leads to.

A
  1. microbial products like LPS (TLR4)
  2. NK cell-derived IFN-gamma
  3. activation of transcription factors
  4. synthesis of proteins (caused by the activation of transcription factors)
58
Q

What is the one thing that nearly all cytokines of innate immunity have in common? which one is the special case, and why?

A

Nearly all of them are produced by macrophages

IFN-gamma is the only one that is NOT produced by macrophages. IFN-gamma is created by NK cells (remember the positive feedback loop that NK cells and macrophages conduct on one another)

59
Q

Explain what TNF and IL-1 do in terms of their local and/or systemic actions during inflammation. Also state what they both secrete.

A

they act “locally” on leukocytes and endothelium to induce “acute inflammation”

AND they both induce the expression of IL-6 (from leukocytes and other cell types)

60
Q

Explain what TNF and IL-6 do in terms of their local and/or systemic actions during inflammation (3 things)

A

they mediate protective systemic effects of inflammation, including the following:

Fever

Acute-phase protein synthesis by the liver

leukocytosis in the bone marrow

61
Q

State the 3 pathologic abnormalities that systemic TNF can cause, which lead to septic shock

A

decreased cardiac function

Thrombosis and capillary leak

Metabolic abnormalities due to insulin resistance

62
Q

Compare the potency, in terms of the inflammatory reaction that they cause, between IL-1 and IL-6

A

IL-6 is much more potent than IL-1, and therefore would create much more of an inflammatory response (pound for pound)

63
Q

Name the 2 Acute phase proteins (plasma proteins) that belong to the pentraxin family.

A

CRP (C-reactive protein)

SAP (Serum amyloid P)

64
Q

Compare the levels of CRP and SAP between healthy and ill people. explain any differences and what molecules control the expression of CRP and SAP.

A

healthy people have very low levels of CRP and SAP, however their concentration can increase up to 1000-fold during infections

this increase in concentration is due to cytokines IL-1 and IL-6 (produced by phagocytes), which signal the liver to synthesize more CRP and SAP

65
Q

State which plasma protein recognizes phosphorylcholine and which recognizes phosphatidylethanolamine. why?

A

CRP recognizes phosphorylcholine

SAP recognizes phosphatidylethanolamine

both phosphorylcholine and phosphatidylethanolamine are found on the membrane of bacterial and apoptotic cells

66
Q

Explain the significance of the relationship between C1q and CRP/SAP

A

CRP/SAP can both activate the complement pathway by binding to C1q and initiating the “classical” component pathway

(they can basically impersonate IgM antibodies, which normally initiate the classical complement pathway)

67
Q

Describe the functions of IFN-alpha and IFN-beta in INFECTED cells (include how they are produced)

A

upon viral infection, cellular TLR’s recognize viral nucleic acids/proteins

TLR-mediated signaling activates transcription factors (IRF proteins) to produce IFN-alpha and IFN-beta.

IFN-alpha and IFN-beta then bind to receptors in the nucleus in order to express genes that make the cell more susceptible to CTL-mediated killing (CTL = cytotoxic T cells)

68
Q

Describe the functions of IFN-alpha and IFN-beta in UNINFECTED cells (include how they are produced)

A

IFN-alpha and IFN-beta produced by neighboring cells that ARE virally infected can bind to receptors on the membrane of UNinfected cells, in order to activate JAK-STAT signalling pathways

these activated JAK-STAT pathways induce the expression of genes whose products interfere with viral replication (specifically, the protein synthesis that is needed to create more viruses)

(basically saves the cell before it gets infected with the virus)

69
Q

What is the important bridge between innate and adaptive immunity? what does this “bridge” cause (2 things)?

A

Pathogen recognition through PRRs

This causes activation and maturation of APC’s, which allow them to present Ag’s to naive T cells

Secreted cytokines assist with the development and maturation of the T cell after it is presented an Ag

70
Q

what provides the first signal for the activation of lymphocytes? what about the second signal?

A

Ag recognition by B cells provides signal 1 for the activation of the lymphocytes

Molecules induced by innate immune responses to microbes provide the 2nd signal

Immunology 2019 (22 decks)

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