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Semester 2 Immunology > Immunology II: Innate Immunity & Inflammation > Flashcards

Immunology II: Innate Immunity & Inflammation Flashcards

1
Q

Who has an innate immune defenses? How long does it take for it to act?

A

Innate immune defenses exist in all individuals and act within minutes - hours after an encounter with infectious agent

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2
Q

Does innate immunity discriminate effectively between host cells and pathogens?

A

Mechanisms of innate immunity discriminate very effectively between host cells and pathogens

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3
Q

When is an adaptive immune response required?

A

Only when innate defenses are overwhelmed/bypassed/evaded is an adaptive immune response required

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4
Q

Barriers chart: What are the 3 types and the 5 places they exsist?

A
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5
Q

What are the 2 chemical barriers?

A

Lysozyme and antimicrobial peptide - defensins

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6
Q

Lysozymes: where do they present? How do they function?

A

Present in secretions (mucus, tears, milk, saliva)

Uses hydrolysis to break apart the peptidoglycan wall  lysis of bacterial cell wall

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7
Q

Antimicrobial peptide - defensins: what are they? What do they kill? What are their effects?

A

Small, heterogeneous, cationic peptides

killGram-negativeandGram-positivebacteria, some enveloped viruses, fungi

Multiple antimicrobial effects:
Destabilize membranes and Pore formation in bacterial cell walls
Proteolytic degradation of bacterial proteins
Inhibit viral binding and entry
Inhibit virus particle assembly

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8
Q

What roles aside from chemical barrier do defensins perform?

A

Defensins can act as a chemical barrier when they are secreted by epithelial cells in a variety of mucosal surfaces

Defensins and other AMPs (i.e. cathelicidins) are also stored in neutrophil granules and can be released within tissues in response to inflammation

Can kill microbes extracellularly  released when neutrophils die during inflammation

Can kill microbes intracellularly after a cell (i.e. neutrophil) phagocytoses a pathogen
Just like many molecules and cells of the immune system, defensins perform a number of roles – not just a chemical barrier

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9
Q

Describe phagocytosis and phagocytes. What is their role? What do they do? Innate or adaptive?

A

One of the first lines of defense if microbes do invade tissue

Engulf and destroy microorganisms, especially bacteria

Key role in innate immunity as they can recognize, ingest and destroy many pathogens without aid of an adaptive immune response

Phagocytosis can also occur after an antibody has bound to an antigen – the antibody can act as a “signal” that triggers efficient phagocytosis

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10
Q

What are the major phagocytes in the body?

A

Macrophages and neutrophils are the major phagocytes in the body

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11
Q

Monocytes & Macrophages:

A

Pro-monocytes (bone marrow)–>monocyte (blood)–> macrophage/macrophage-like cells (tissues)

Long-lived cells resident within the tissues

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12
Q

Neutrophils

A

Derived from hematopoietic precursors in the bone marrow

Non-dividing, short-lived cell type in blood (dominant WBC)

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13
Q

What does PRR stand for?
(chart of Phagocytosis - the basics)

A

PRR = Pattern Recognition Receptor

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14
Q

Pattern recognition- What is it? When does it occur? What does it activate? How does it happen?

A

Evolutionarily conserved mechanism for recognizing common, conserved ‘signs’ of microbial infection, physiological stress, or other damage
Recognition is immediate, does not require prior recognition, and activates several arms of the innate (and adaptive) immune response
Responses are elicited via the engagement of Pattern Recognition Receptors (PRRs) found on phagocytes, in response to:
Pathogen Associated Molecular Patterns (PAMPs)
Danger Associated Molecular Patterns (DAMPs)

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15
Q

Why does the function of macrophages rely on PRRs?

A

The function of Macrophages relies on (PRRs) which allow a limited range of immune cells to detect and respond rapidly to a wide range of pathogens that share common structures, known as pathogen associated molecular patterns (PAMPs). Examples of these include bacterial cell wall components such as lipopolysaccharides (LPS) and double-stranded ribonucleic acid (RNA) produced during viral infection.

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16
Q

Examples of PRRs? What responses do they elicit?

A

Examples of PRRs:
Toll-like receptors
Nod-like receptors
Lectins
Elicit responses such as:
Phagocytosis
Cytokine secretion

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17
Q

Step 1 of phagocytosis?

A

A pattern-recognition-receptor (PRR) binds to a microbe or bit of debris, OR an opsonin created by another cell binds to the microbe
A microbe
A bit of debris
An opsonin
An opsonin is basically a soluble, secreted PRR that enhances the effectiveness of phagocytosis
An opsonin coats a microbe, the phagocyte has receptors for parts of that opsonin

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18
Q

Step 2 of phagocytosis?

A
  1. The microbe is engulfed – the PRR receptors signal the cell membrane to approach, coat and then surround the sites where the receptor is bound
    Forms a phagosome
    Mediated by intracellular signalling events and actin polymerization – see diagram
    PI3 kinase seems to be important here
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19
Q

PRRs that trigger phagocytosis

A
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20
Q

What is an example of a lectin receptor?

A

Mannose receptor

Lectin receptors
(lectin receptors recognize “carbohydrate patterns”)

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21
Q

What are 2 examples of scavenger receptors?

A

SR-A and SR-B

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22
Q

What is an example of a complement receptor?

A

CR3

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23
Q

What is the receptor for the constant region of an antibody?

A

Fc receptors

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24
Q

Steps 3 and 4 phagocytosis?

A

3 & 4. Microbe killing – phagosomes fuse with lysosomes as well as (in neutrophils) primary and secondary granules
Phagosomes have many molecules that are effective at cellular killing – a little more later
Major groups include:
Reactive oxygen species
“pore”-forming proteins or peptides
Hydrolytic enzymes
pH changes – i.e. acidic environment of the lysozyme

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25
Q

Step 5 phagocytosis?

A

The microbe remnants are either digested and used, or can be excreted from the phagocyte

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26
Q

What are the options for microbe killing?

A

After the microbe has been phagocytosed, the phagosome will dock with a lysosome and/or neutrophil granules

Lysosomes can pretty much break down anything (acid hydrolases)

The low pH of a lysosome is also unpleasant for many bacteria

This complex becomes associated with the membrane of the phagolysosome

Uses a large amount of oxygen (respiratory burst)
If a particle is too large to phagocytose, macrophages will surround it and “place” their NADPH oxidases close to it to try to kill it

Macrophages in particular are also capable of killing cells by inducing the synthesis of nitric oxide at high concentrations

Neutrophils have a multitude of pore-forming molecules within their granules – these granules will fuse with the phagosome

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27
Q

What do macrophages place near to a particle when it is too large to phagocytose?

A

NADPH oxidase

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28
Q

Which type of phagocytic cell is capable of killing cells by inducing the synthesis of nitric oxide at high concentrations?

A

macrophages

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29
Q

Which type of phagocytic cell has a multitude of pore-forming molecules within their granules – these granules will fuse with the phagosome?

A

neutrophils

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30
Q

Phagocytosis visual

A
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31
Q

What amino acid are defensins rich in?

A

cysteine

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32
Q

Are defensins a neutrophil or macrophage?

A

Neutrophil

33
Q

What form voltage-dependent pores in bacteria that are permeable to water?

A

Neutrophil granules

34
Q

Microbe killing via neutrophils

A

Neutrophil granules:
Defensins are very rich in cysteine
Form voltage-dependent pores in bacteria that are permeable to water
Cause lysis
Cathepsin - a type of protease
Cathelicidins – another pore-forming molecule
Causes lysis, multitude of different structures
Lysozyme – a glycoside hydrolase
Doesn’t require an acidic pH
Found in a variety of glandular secretions
Great at killing gram +(ve) bacteria
Lactoferrin – iron-binding protein that interferes with iron metabolism in microbes
Neutrophils can do a neat trick – when they’re in an environment with many bacteria (they’re “surrounded”) they can can lyse and release their DNA into the ECF
Known as a NET – a neutrophil extracellular trap
NETs are “sticky” – most bacteria are trapped in the chromatin
Histones are toxic to many bacteria
The granule contents will remain close to the NETs and help with killing bacteria, even after the neutrophil itself is dead

35
Q

What is an iron-binding protein that interferes with iron metabolism in microbes>

A

lactoferrin

36
Q

Which neutrophil granule is a glycoside hydrolase?

A

Lysozome

Doesn’t require an acidic pH
Found in a variety of glandular secretions
Great at killing gram +(ve) bacteria

37
Q

Cathepsin is a type of what?

A

protease

38
Q

Which pore-forming molecule causes lysis, and has a multitude of different structures?

A

cathelicidins

39
Q

What is it called when a neutrophil can lyse and release their DNA into the ECF?

A

NET- a neutrophil extracellular trap

NETs are “sticky” – most bacteria are trapped in the chromatin

Histones (released after neutrophil activation) are toxic to many bacteria

The granule contents (also released) will remain close to the NETs and help with killing bacteria, even after the neutrophil itself is dead

40
Q

Questions to know

How do phagocytes recognize that something is a “target” for phagocytosis? What’s an opsonin and how are they involved in this process?
How do phagocytes kill a phagocytosed pathogen? What is the role of:
Lysosomes
Free radicals (how are they produced? Which ones are involved?)
Anti-microbial peptides
How can a NET add to host protection beyond phagocytosis?

A

How do phagocytes recognize that something is a “target” for phagocytosis?
The PRRs on phagocytes recognizes the PAMPS or DAMPS.

What’s an opsonin and how are they involved in this process? opsonin is a super secreted PRR on the cell that enhances the effectiveness of phagocytosis

How do phagocytes kill a phagocytosed pathogen? What is the role of:
Lysosomes: use hydrolysis to break peptidoglycan wall which leads to lysis off bacterial cell wall. Also increasing acidity by lowering pH

Free radicals (how are they produced? Which ones are involved?) produced by the NAPDH oxidase complex through oxidations —> respiratory burst—> free radicals which cause oxidative damage to microbe. Nitric oxide (Perioxinitrate generated) and superoxide (hypochlorite and hydroxyl radical generated). Macrophages also synthesize nitric oxide. Granule contents may be released into EC tissue i NOS (inducible nitric oxide synthase. MPO (myeloperixidase) ROS (reactive oxygen species)
Anti-microbial peptides
How can a NET add to host protection beyond phagocytosis? Once the neutrophil is dead, the net still surrounds it and the body ones are toxic (suicide bombers)

41
Q

Toll-like receptors

A

Cytokines secreted in response to TLR’s include:
Inflammatory cytokines (IL-1b, IL-6, CXCL8, IL-12, TNFa)
Cytokine – a (small) protein messenger, secreted by a vast array of cells, that can:
Influence the differentiation of a wide variety of cells, including leukocytes
Mediate – activate or inactivate – the activity of many cells, including leukocytes
Increase or decrease the production of a wide variety of stem/hematopoietic cells
More cytokine overview in the e-learning module
Interferons
Interferon (IFN) alpha, beta, and lambda (IFNa, IFNb, IFNl)
Autocrine and paracrine signaling molecules that are effective in activating macrophages, NK cells, and inducing an antiviral state
More on interferons in subsequent lectures

42
Q

What is a cytokine? What are its roles?

A

Cytokine – a (small) protein messenger, secreted by a vast array of cells, that can:
Influence the differentiation of a wide variety of cells, including leukocytes
Mediate – activate or inactivate – the activity of many cells, including leukocytes
Increase or decrease the production of a wide variety of stem/hematopoietic cells

43
Q

What are interferons?

A

Interferon (IFN) alpha, beta, and lambda (IFNa, IFNb, IFNl)
Autocrine and paracrine signaling molecules that are effective in activating macrophages, NK cells, and inducing an antiviral state

44
Q

Consequences of TLR signaling

A

The phenotype of individuals with specific gene mutations/polymorphisms can tell us about the overall importance and function of that gene
Example: MyD88  An essential adaptor in TLR signaling
Patients with MyD88 deficiency:
Suffer frequent and severe bacterial infections
Antiviral responses generally unaffected
Patients with constitutively active MyD88:
Develop various blood disorders and blood cancers:
Overproduction or dysregulated production of IgM
B cell lymphoma, marginal cell lymphoma

45
Q

What deficiency leads to patients suffering frequent and severe bacterial infections, while
antiviral responses generally unaffected?

A

MyD88 deficiency

46
Q

What happens when a patient has constitutively active MyD88?

A

Develop various blood disorders and blood cancers:
Overproduction or dysregulated production of IgM
B cell lymphoma, marginal cell lymphoma

47
Q

Nod-Like Receptors

A

Family of intracellular receptors found in the cytoplasm that detect products derived from the intracellular degradation of phagocytosed pathogens (e.g. components of bacterial cell wall)
Also recognize DAMPs associated with cellular stress
activates expression ofinflammatory cytokines

48
Q

Steps of Acute Inflammation (Step 1)

What happens? What is released?

A

Alteration of vascular caliber - vasodilation
Leads to increases in blood flow at the capillary bed due to arteriolar dilation, dilation of precapillary sphincters
Nitric oxide and histamine release
A variety of prostaglandins (PGI2, PGE2, PGD2)
Platelet activating factor (at low concentrations – higher concentrations cause vasoconstriction)
Complement
-C5a and C3a stimulate histamine release

49
Q

At low concentrations, nitric oxide is a potent what? At high concentrations, it’s capable of what?

A

vasodilator (why Viagra is a profitable drug)

destroying both microbes and host cells since it’s a free radical

Higher concentrations produced by an inducible nitric oxide synthase in macrophages

50
Q

Vasodilation

A

Arterioles and pre-capillary sphincters dilate leading to vastly increased blood flow in inflamed tissue
Vasodilation and fluid loss (due to increased permeability) lead to slower blood flow
Known as vascular congestion
This helps with margination of leukocytes

51
Q

Production of arachidonic acid metabolites and their roles in inflammation. Pathways FIGURE.

A
52
Q

Prostaglandins and leukotrienes are produced when?

A

PLA2 generates arachidonic acid from membrane phospholipids

53
Q

Which prostaglandins cause vasodilation and increase vascular permeability? What is their important role?

A

Different types of cyclooxygenases produce different types of prostaglandins from arachidonic acid

important acute inflammatory mediators

54
Q

Different types of 5-lipoxygenase produce different types of leukotrienes from arachidonic acid that seem particularly important in what tissue?

A

lung

55
Q

LTB4 is an important ________?

A

chemotactic agent

56
Q

What increase vascular permeability and smooth muscle constriction (think asthma)?

A

Other LTs

57
Q

Lipoxins are generated from what? By what? To do what?

A

Lipoxins are generated from arachidonic acid by 12-lipoxygenase – they decrease inflammation

58
Q

Steps of acute inflammation: Step 2

What mediators are released during this step?

A

Enhancement of vascular permeability
Capillaries and venules become more “leaky” with the release of a number of mediators
Histamine and serotonin (released by activated platelets, a link between inflammation and clotting)
Prostaglandins (PGD2 and PGE2)
Leukotrienes (LTC4, LTD4, LTE4)
Platelet activating factor
C3a and C5a
Bradykinin
a wide variety of proteins and mediators can enter the interstitial space from the bloodstream

59
Q

Vascular permeability

A

Increased vascular permeability is due to contraction of endothelial cells
Occurs mainly in venules
Often short-lived

Another mechanism is endothelial damage
Can be caused by trauma, burns, microbial damage
Can also be caused by leukocyte-mediated damage to the endothelium (often longer-lived)

Increased transcytosis can also result in leakage of plasma components into the interstitial space

60
Q

Transcytosis: what is it? What can move across? How?

A

Active, vesicle-mediated transport across the capillary endothelial cell

Large molecules can move across the endothelium via:
1.) Pinocytosis (caveolin pathway)
2.) Receptor-mediated endocytosis

61
Q

Mechanisms of increased vascular permeability CHART

A
62
Q

Lymphatics

A

As interstitial fluid accumulates during inflammation, pressure increases in the interstitial space and lymphatic drainage increases
Normally only a small amount of interstitial fluid is produced in non-inflamed tissue
Excess fluid, microbes, debris, and leukocytes all migrate into the lymph during inflammation
The lymphatic vessels themselves can become inflamed – known as lymphangiitis

63
Q

Steps of acute inflammation: Leukocyte migration

A

Emigration and activation of leukocytes
Neutrophils, monocytes, eosinophils, and basophils will all migrate from the circulation into inflamed tissue
Steps:
1. Margination
2. Rolling
3. Adhesion
4. Diapedesis
5. Chemotaxis of leukocytes to sites of injury or infection

2 and 3 are mediated by binding of selectins and cellular adhesion molecules to their respective ligands on leukocytes

64
Q

Chemokine or cytokine?

A

Cytokine – a (small) protein messenger, secreted by a vast array of cells, that can:
Influence the differentiation of a wide variety of cells, including leukocytes
Mediate – activate or inactivate – the activity of many cells, including leukocytes
Increase or decrease the production of a wide variety of stem/hematopoietic cells

Chemokine – structurally-related family of small cytokines that:
Bind to cell-surface receptors (usually leukocytes)
Induce movement of leukocytes along the chemokine concentration gradient
Mediate adhesion of leukocytes for the purposes of:
Differentiation
Inflammation/migration

65
Q

What are the 2 major chemokine families?

A

CXC
CXC chemokines attract neutrophils, are angiogenic, and are very similar in structure
The “X” indicates the location of a disulphide bond
CC
Act on/attract a wide variety of other leukocytes

66
Q

The chemokine receptor expression based on cell type CHART

A
67
Q

What step in leukocyte migration do leukocytes migrate towards vessel wall?

A

1.) margination

68
Q

Which step in leukocyte migration is the formation & dissociation of adhesion bonds between leukocytes and endothelial cells?

A

2.) rolling

**Activation by chemokines presented on endothelial cells is required before the leukocyte can form stable adhesion

69
Q

Emigration and activation of leukocytes

A

Selectin-mediated rolling of leukocytes willenhance exposure to chemokines that are bound to, and presented by, proteoglycan-like molecules on the surface of the endothelial cell

Mediated by binding of selectins and cellular adhesion molecules to their respective ligands on leukocytes

70
Q

What stimulates the activation of the leukocytes? (hint: endothelial cell presents it)

What does this do?

A

Endothelial cell presents a chemokine that stimulates activation of the leukocytes

This increases affinity of leukocyte integrin for it’s ligand, allowing stable/tight adhesion bonds to form

71
Q

In what step of leukocyte migration is the formation of tight/stable adhesion bonds between leukocytes and endothelial cells?

A

Step 3: stable/ tight adhesion

72
Q

What step of LM does the leukocyte migrates through endothelium ?

A

4.) Diapedesis/ Transmigration

73
Q

What step in LM do chemotaxis of leukocytes to sites of injury or infection?

A

Step 5: chemotaxis of leukocytes

74
Q

Putting it all together FIGURE

A
75
Q

Adhesion molecules and their ligands CHART

A
76
Q

Which inflammatory mediators increase the ability of leukocytes to migrate to a target?

A

Histamine, Thrombin
Rolling
Selectin expression by endothelial cells

TNF & IL1
ICAM expression by endothelial cells

Chemokines
Increased integrin affinity

77
Q

Chemotactic agents

A

All of these agents are produced in higher concentrations at sites of cellular damage/pathogen invasion

Leukotriene B4
Bacterial products containing N-formyl-methionine
Activated complement (particularly C5a)
More on this in the e-module
Chemokines (IL-8, RANTES, eotaxin)

Leukocytes can “follow the breadcrumbs” to the site of pathology via the chemotactic agent concentration gradient

78
Q

For leukocyte emigration QUESTIONS to answer.

What molecules cause loose adhesion of leukocytes to the vascular endothelium?
What binds to what?
How about tight adhesion?
What cells are integrins found on? How about ICAMS?
What causes expression of the molecules above?
What is the role of a chemokine in:
Tight adhesion?
Migration of a leukocyte to a site of inflammation?
What is a chemotactic agent? Name a few

A

What molecules cause loose adhesion of leukocytes to the vascular endothelium? Selectins (E/P on endothelial cells, L on leukocytes)
What binds to what? Leukocytes and endothelial cells
How about tight adhesion? Integrins
What cells are integrins found on? WBC How about ICAMS? Endothelial
What causes expression of the molecules above? INTEGRINS: Histamine, thrombin, chemokines (IL-8) ICAMS: TNF & IL-1
What is the role of a chemokine in:
Tight adhesion? Sends message from endothelial cell to activate WBC in order for WBC to put out a tighter receptor (integrin), induce formation of integrin by changing surface markers
Role of chemokine Migration of a leukocyte to a site of inflammation? Via chemotaxis (follows breadcrumbs)
What is a chemotactic agent? Any chemotactic agents that Produce more at damage or pathogen invasion. Name a few: leuk. B4, bacterial products with N-formyl-methionine, activated complement (c5a), chemokines (IL-8, RANTES, EOTAXIN)

Semester 2 Immunology (8 decks)

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