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YEAR 2 - Principles of Pathology > 31. Cell Death and Repair, Inflammation, Anti-Inflammatories > Flashcards

31. Cell Death and Repair, Inflammation, Anti-Inflammatories Flashcards

1
Q

What is the innate immune response?

A
  • It is the first-line response to the presence of antigens
  • It is a non-specific immune response and instead relies on conserved molecular patterns
  • Consists of physical, chemical and cellular defenses against pathogens
  • It is required to trigger the specific immune respones
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2
Q

What are some of the barriers to infection that are part of the innate immune response?

[IMPORTANT]

A
  • Skin
  • Mucus
  • Gastric acid
  • Bile salts
  • Normal microbiota
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3
Q

What are the cells involved in the innate immune response and what are their functions?

[IMPORTANT]

A
  • Respiratory burst -> Neutrophils, Monocytes/Macrophages
  • Degranulation -> Mast cells, Eosinophils, Basophils
  • Phagocytosis -> Neutrophils, Macrophages
  • Natural killer (NK) cells
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4
Q

Summarise the concept of innate immune defense.

A
  • Cells and proteins in the damaged tissue sense the presence of bacteria via PAMPs and DAMPs.
  • The cells send out soluble proteins called cytokines that interact with other cells to trigger the innate immune response.
  • Chemical mediators cause the local venule to exudate cells, fluid and plasma proteins to the site of infection.
  • The overall effect of the innate immune response is to induce a state of inflammation in the infected tissue characterised by heat, pain, redness and swelling.
  • These symptoms, which are part of everyday human experience, are not due to the infection itself but to the immune system’s response to infection and injury.
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5
Q

Summarise haematopoiesis.

A

Note: The stem cells arise from the bone marrow.

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6
Q

What are granulocytes?

A
  • A category of white blood cells in the innate immune system characterized by the presence of specific granules in their cytoplasm.
  • They include eosinophils, basophils and neutrophils (and mast cells, in tissues).
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7
Q

What is another name for granulocytes?

A

Polymorphonuclear leukocytes (PMNs)

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8
Q

Which blood cells can enter tissues? What are they called there?

A

Note that the process by which basophils are linked to mast cells in tissues is unknown.

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9
Q

Which immune cells are only found in tissues (and not in blood)? How are they related to blood cells?

A
  • Macrophages are the tissue forms of blood monocytes
  • Mast cells are linked to basophils by some mysterious process
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10
Q

Describe the appearance of neutrophils.

A
  • Multi-lobed nucleus joined by filaments (sausage-like appearance)
  • About 10µm
  • Has some granules
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11
Q

Describe the appearance of eosinophils.

A
  • Bilobular nucleus
  • Larger than neutrophil (easy to confuse because of multilobular nuclei)
  • Very many granules
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12
Q

Describe the appearance of basophils.

A
  • Simple or bilobed nucleus
  • Nucleus is often difficult to see because of its most characteristic feature: a large number or coarse, purplish granules.
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13
Q

Describe the appearance of monocytes.

A
  • Nucleus is kidney-shaped
  • No obvious granules
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14
Q

Describe the appearance of lymphocytes.

A
  • Round nucleus
  • Some granules in natural killer cells, otherwise no granules
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15
Q

Summarise the appearance of different leucocytes.

A
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16
Q

Describe the appearance of mast cells.

A

They are very similar to basophils.

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17
Q

Are mast cells WBCs?

A

No, they are tissue-resident, but they are very similar to basophils.

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18
Q

Where are mast cells found?

A

In all tissues close to blood vessels and mucosae.

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19
Q

What do mast cells release?

A
  • Their granules contain heparin and histamine, which are rapidly released
  • They can also release LTC4, prostaglandins and cytokines (TNFa), but this release is slower
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20
Q

Why do we like and dislike mast cells?

A
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21
Q

In what sort of allergies are mast cells involved?

[IMPORTANT]

A
  • Hay fever
  • Asthma
  • Food allergies
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22
Q

What are the effects of mast cell degranulation in the:

  • GI tract
  • Airways
  • Blood vessels
A
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23
Q

What are the different ways in which mast cells can be activated?

A
  • IgE binding -> Primes the mast cell for degranulation (in a sensitized state) [IMPORTANT]
  • Antigen binding (once sensitized by IgE) -> Rapid degranulation, followed by sustained cytokine/chemokine release
  • TLR ligand binding -> No degranulation, but cytokine and chemokine release
  • Neuropeptides, C3a, C5a, venom binding -> Degranulation and cytokine/chemokine release
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24
Q

To what receptors on mast cells do IgE bind?

A

FcεRI

(This denotes that it is the Fc region of IgE being bound)

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25
Q

What is abundance of leukocytes in the blood (in cells/L)?

A

7 x 109 cells/L

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26
Q

What percentage of leukocytes are neutrophils?

A

40-70%

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27
Q

What percentage of leukocytes are monocytes?

A

6%

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28
Q

What percentage of leukocytes are lymphocytes?

A

20-40%

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29
Q

What percentage of leukocytes are eosinophils?

A

3%

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30
Q

What percentage of leukocytes are basophils?

A

1%

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31
Q

What percentage of leukocytes are each of the types?

A
  • Neutrophils -> 40-70%
  • Lymphocytes -> 20-40%
  • Monocytes -> 6%
  • Eosinophils -> 3%
  • Basophils -> 1%
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32
Q

What may elevated neutrophil counts indicate?

[IMPORTANT]

A
  • Bacterial infections
  • Stress
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33
Q

What may increased counts of each of the leukocytes indicate?

A
  • Neutrophils:
    • Bacterial infections
    • Stress
  • Lymphocytes:
    • Mononucleosis
    • Whooping cough
    • Viral infections
  • Monocytes:
    • Malaria
    • TB
    • Fungal infections
  • Eosinophils:
    • Allergic reactions
    • Autoimmune diseases
    • Parasitic worms
  • Basophils:
    • Cancers
    • Chicken pox
    • Hypothyroidism
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34
Q

What are PMNs?

A
  • A type of immune cell that has granules (small particles) with enzymes that are released during infections, allergic reactions, and asthma.
  • Neutrophils, eosinophils, and basophils are PMNs.
  • For some reason, the spec calls neutrophils PMNs (almost implying that eosinophils and basophils are not, so double check this!)
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35
Q

Where does proliferation and differentiation of neutrophils take place?

A

In the bone marrow.

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36
Q

What drives DNA synthesis and granule biogenesis of neutrophil progenitors?

[EXTRA]

A
  • GM-CSF
  • G-CSF

These colony stimulating factors are glycoproteins. GM-CSF is a cytokine that acts as growth factor, stimulating the production of granulocytes and monocytes in the bone marrow, with G-CSF specifically increasing neutrophil numbers

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37
Q

Where is the reserve pool of neutrophils?

A

Bone marrow (50% of the nucleated leukocytes in bone marrow are PMNs)

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38
Q

When are neutrophils mobilised from the reserve pool in bone marrow? What is this called?

A
  • In response to infection
  • This is called granulocytosis/neutrophilia
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39
Q

What is the name for decreased neutrophil count in the blood and what may cause this? What are the dangers?

A

Neutropenia, caused by:

  • X-irradiation
  • Chemotherapy
  • Kostmann disease

These patients are susceptible to bacterial and fungal infection.

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40
Q

What is granulocytosis/agranulocytosis?

A

Increased/Decreased granulocytes in the blood, although typically this may be used to simply refer to neutrophilc counts, since they are the most abundant.

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41
Q

What happens to neutrophils that are in the blood?

A

They are mobilised to sites of infection.

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42
Q

Are neutrophils terminally differentiated?

A

Yes, so they do not synthesis DNA, although they do synthesis some limited mRNA and proteins.

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43
Q

What happens to activated neutrophils?

A

They undergo apoptosis and are cleared by tissue macrophages.

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44
Q

What are some things that may cause increased leukocyte numbers (leukocytosis)?

A
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45
Q

What are some things that may cause decreased neutrophil numbers (neutropenia)?

A
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46
Q

What lineage of haemapoietic stem cells are neutrophils derived from?

A

Hematopoietic stem cell -> Myeloid stem cell -> Myeloblast -> Granulocytes

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47
Q

What is Kostmann disease?

[EXTRA]

A

It is also known as severe congenital neutropenia:

  • A group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia.
  • SCN manifests in infancy with life-threatening bacterial infections.
  • Most cases of SCN respond to treatment with granulocyte colony-stimulating factor, which increases the neutrophil count and decreases the severity and frequency of infections.
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48
Q

What are opsonins?

A

Serum proteins that attach to the surface of microbes, rendering them more attractive to phagocytes.

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49
Q

What are some important opsonins and what part of phagocytes do they bind to?

A
  • IgG -> Binds to Fc receptor [IMPORTANT]
  • C3b (complement) -> Binds to CR3 receptor [IMPORTANT]
  • Surfactant proteins A and D -> ???
  • C-reactive protein (CRP) -> ???
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50
Q

What are the main “professional” phagocytes?

A

Neutrophils and macrophages

(Mast cells and dendritic cells also phagocytose, to a lesser extent)

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51
Q

What things can trigger phagocytosis?

A
  • PAMPs
  • DAMPs
  • Opsonins

In essence, you can think of the phagocyte as being able to recognise conserved molecules (PAMPs and DAMPs) via the PRRs it has on its surface. However, the phagocyte can also recognise opsonins using opsonin receptors,

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52
Q

Describe the mechanism of phagocytosis.

[EXTRA]

A
  • Phagocytosis is triggered by:
    • PAMPs and DAMPs binding to PRRs on the phagocyte surface
    • Opsonins (like IgG) binding to opsonin receptors (on the phagocyte)
  • A suggested mechanism for engulfing the pathogen is the zipper mechanism, where the binding points are used to gradually move the cytoplasm around the pathogen
  • Engulding occurs via pseudopods that move around the bacterium to create a phagosome. This process is dependent on actin remodelling.
  • The phagosome then fuses with a lysosome and granules, which enables digestion of the bacterium by a variety of mechanisms.
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53
Q

What cellular process is phagocytosis dependent on and how can this be experimentally demonstrated?

[EXTRA]

A
  • Pseudopods around the bacterium to create a phagosome.
  • This process is dependent on actin remodelling, which can be experimentally demonstrated by cytochalasins.
  • These are fungus-derived products that block actin polymerisation, so that formation of a phagosome is inhibited.
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54
Q

What are some problems with phagocytosis?

A
  • Regurgitation while feeding -> Can damage local cells
  • Frustrated phagocytosis (exocytosis) -> Release of toxic agents into the environment when the phagocyte fails to engulf its target
  • Surface phagocytosis
  • Bacteria evasion of phagocytosis
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55
Q

What is frustrated phagocytosis?

A

If a phagocyte fails to engulf its target, toxic agents can be released into the environment.

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56
Q

Describe the formation and events in a phagolysosome.

A
  • The phagosome fuses with a lysosome
  • It is also further acidified by activation of a V-ATPase on the surface
  • This eventually leads to digestion and destruction of the pathogen inside
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57
Q

What are the main killing mechanisms used by phagocytes following phagocytosis?

A
  • Oxygen-dependent antibacterial mechanisms -> Using oxidising radicals and halides to kill the pathogen
  • Oxygen-independent antibacterial mechanisms -> Using enzymatic and non-enzymatic mechanisms to kill the pathogen
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58
Q

What important event takes place after a phagocyte takes up a pathogen?

A

Respiratory burst

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59
Q

What is the respiratory burst and why is it required?

[IMPORTANT]

A
  • Following uptake of pathogens for phagocytosis, the oxygen demand of phagocytes increases.
  • The oxygen burst is used largely to generate NADPH from glucose via the pentose phosphate pathway. The NADPH in turn can be used to generate reactive species that kill pathogens.
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60
Q

Describe how the respiratory burst works.

A
  • Upon uptake of a pathogen, oxygen is used to rapidly generate NADPH from glucose via the pentose phosphate pathway.
  • The NADPH in turn can be used to generate superoxide (O2-), which then forms hydrogen peroxide (H2O2) via breakdown. These are then used in the production of reactive oxygen species (ROS):
    • Superoxide and hydrogen peroxide can react with each other to produce hydroxyl radicals
    • In neutrophils, hydrogen peroxide can react with halide ions to oxidise them, which is catalysed by MPO (myeloperoxidase) in the phagolysosome.
  • The NADPH is also used in the generation of nitric oxide (NO) (see other flashcard).
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61
Q

Give some experimental evidence for the respiratory burst.

[EXTRA]

A
  • The importance of oxygen-dependent killing mechanisms can be demonstrated by culturing bacteria with neutrophils, both in the presence and absence of oxygen.
  • Faster culture growth is seen in the deoxygenated experiment.
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62
Q

What enzyme is used to catalyse the reaction of hydrogen peroxide with halide ions to oxidise them (in neutrophils)?

A

MPO (myeloperoxidase)

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63
Q

How do ROS (reactive oxygen species) generated in the respiratory burst kill pathogens?

A

They are powerful oxidising agents, and lipid oxidation is particularly effective for breaking down cell membranes.

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64
Q

What is chronic granulomatous disease?

[IMPORTANT]

A
  • Individuals have a defect in the phagocyte NADPH oxidase enzyme that catalyses the reaction of NADPH with O2 to produce superoxide.
  • The symptoms include a higher susceptibility to and frequency of infection, as well as the development of granulomas (collections of macrophages) in various tissues, both of which are due to the reduced immune capacity of phagocytes.
  • Treatment involves antibiotic use to manage infection, and cure is currently only possible via use of hematopoietic stem cell transplant.
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65
Q

What are some oxygen-independent killing mechanisms in phagocytes?

A
  • Proteases
  • Phospholipases
  • Nucleases
  • Lysozyme
  • Cationic proteins (BPI & ECP)
  • Lactoferrin
  • Defensins (Anti Microbial Peptides – AMPs)
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66
Q

How are lysozymes involved in defense mechanisms in phagocytes?

A

Lysozyme breaks down the peptidoglycan in the cell wall of bacteria.

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67
Q

How are cationic proteins involved in defense mechanisms in phagocytes?

A

Modify cell membranes, such as BPI (bactericidal/permeability-increasing protein) which acts on lipopolysaccharides.

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68
Q

How is lactoferrin involved in defense mechanisms in phagocytes?

A

Lactoferrin reduces the amount of iron available for bacterial use, which is significant because iron is an essential ion for bacterial growth. It can also bind to LPS and thus lead to cell lysis.

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69
Q

What are antimicrobial peptides and what is their function in phagocyte defence mechanisms?

A
  • Peptides (AMPs) of fewer than 50 amino acids that are an evolutionarily conserved part of the innate immune response
  • Primarily target the cell membrane and create transmembrane channels, meaning that they have broad specificity within bacteria and other pathogens.
  • They are not affected by antibiotic resistance of a bacterium.
  • Experimentally, the broad specificity of AMPs can be demonstrated by an in vitro assay.
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70
Q

Give an example of AMPs (antimicrobial peptides).

A

LL-37 and defensins

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71
Q

Describe how NO is synthesised in phagocytes and how this works as part of the defense mechanism.

A
  • NADPH (from the respiratory burst) here is also used in the generation of nitric oxide (NO), which is a substrate (along with superoxide), for the production of more reactive nitrogen species.
  • Nitric oxide synthase 2 is inducible mostly in macrophages (by inflammatory mediators).
  • Reactive nitrogen species have broad antimicrobial action by reacting with transition-metals in proteins (e.g. haemoglobin or cytochrome c) or the amino acids in a protein.
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72
Q

What are NETs?

[IMPORTANT]

A
  • Neutrophil extracellular traps
  • Neutrophils have a short lifespan (relative to macrophages), but before and during apoptosis they leave an extracellular net of DNA and histones, with proteins such as MPO bound to them.
  • These bound proteins have antimicrobial properties, so the net functions to kill pathogens outside of cells.
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73
Q

Give some experimental evidence for how some pathogens can escape NETs.

[EXTRA?]

A

(Zychlinsky, 2009):

  • These may include prevention of formation of the NET by catalase and digestion of the NET by endonuclease, along with some protection provided by the bacterial capsule
  • Studies of this rely partly on observation of NET formation in vitro and comparisons between the resistance of known bacteria to neutrophils and NET.
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74
Q

What are some positives of NET formation?

A
  • Rapid (10-120mins) -> Faster than apoptosis
  • Active against a wide range of pathogens
  • Trap bacteria locally to prevent spread
  • Work even when the neutrophil is dead
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75
Q

How can neutrophils cause host tissue damage?

A
  • ROS (reactive oxygen species)
  • Degranulation (especially elastase)
  • Activate cascades (e.g. caogulation and complement)

Conditions involving tissue damage relating to neutrophil activation include: emphysema, septic shock and ARDS.

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76
Q

Compare monocytes and macrophages.

A

Note that macrophages are derived from blood monocytes.

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77
Q

What are some functions of neutrophils?

A
  • Phagocytosis
  • Degranulation (of anti-microbial agents)
  • Production of NETs
  • Mediation of inflammation (via release of cytokines)
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78
Q

What are some functions of macrophages? How do these compare to neutrophils?

[IMPORTANT]

A

Defence:

  • Phagocytosis and killing
  • Control of inflammation -> Via cytokines and interferons
  • Antigen presentation

Tissue maintenance:

  • Tissue homeostasis via scavenger receptors
  • Tissue remodelling
  • Apoptotic cell clearance
  • Tissue repair (e.g. in wound repair)
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79
Q

Compare the functions of neutrophils and macrophages. How do they work together?

A
  • They have overlapping function, in terms of phagocytosis and release of cytokines.
  • However, neutrophils can also degranulate anti-microbial substances and release NETs, while macrophages can also perform tissue maintenance and antigen-presentation.
  • Neutrophils are rapidly recruited, but are short-lived and act via enzymatic responses that are short-lasting, making them more numerous in acute inflammation.
  • Macrophages are slowly recruited (they are initially monocytes in the blood) and act via changes in gene transcription that have more lasting effects, so they play a larger role in chronic inflammation.
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80
Q

Are all macrophages derived from blood monocytes?

[IMPORTANT]

A

No, some tissue resident macrophages are derived from myeloid precursors in embryonic life and proliferate in situ throughout adult life.

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81
Q

Describe the two origins of macrophages.

[IMPORTANT]

A
  • Embryonic yolk sac derived tissue macrophages (long-lived, self-renewing)
  • Macrophages that are formed by bone marrow-derived monocytes that infiltrate the tissue
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82
Q

Describe the two functional types of macrophages and what the function of each is.

[IMPORTANT]

A
  • Tissue resident (e.g. Kupffer cells) macrophages (mostly arising from embryonic yolk sac) -> Mediate homeostasis, repair and remodelling
  • Infiltrating monocytes that become inflammatory macrophages -> Antimicrobial functions
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83
Q

Do macrophages have a rigid phenotype?

A
  • Macrophage gene expression is very plastic and hence so is their phenotype
  • We know that a wide range of cytokines act on monocytes to give multiple macrophage types M0, M1, M2 in our in vitro experimental systems
  • In vivo we now appreciate that monocytes can differentiate into many different cell types including myeloid-derived dendritic cells (mDCs), Tumour Associated Macrophages (TAMs) and myeloid derived suppressor cells (MDSCs)
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84
Q

Give some examples of different tissue macrophages.

A
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85
Q

Describe the two ways in which the phenotype of macrophages can be determined.

A
  • Macrophages can differentiate during development to give various types of resident macrophages
  • They can also respond to environmental signals, including cytokines, transcription factors and epigenetic changes

Note that the diagram shows the resident tissue macrophages as being derived from bone marrow (presumably via monocytes). This used to be the dominant theory, although we now know that most come from embryonic yolk sac, so I’m not sure why this is drawn this way.

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86
Q

What is macrophage polarisation?

[EXTRA]

A

A process by which macrophages adopt different functional programs in response to the signals from their microenvironment:

  • M1 macrophages -> Promoted by IFN-γ and have a more classical pro-inflammatory and pro-immune role
  • M2 macrophages -> Promoted by IL-4 and IL-13, and have a more anti-inflammatory role and suppress immunity
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87
Q

What are some examples of diseases in which macrophages are implicated?

A
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88
Q

What is granuloma and what are two types of macrophages that may be seen there?

A
  • A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances which it is unable to eliminate.
  • Langhans giant cell -> An accumulation of several macrophages, containing a ring of macrophage nuclei
  • Epitheliod macrophages -> Look like epithelial and have a busy nucleus to secrete huge amounts of proteins
89
Q

What receptors on innate immune cells allow for detection of susbtances that are foreign and pathogenic?

A

Pattern-recognition receptors (PRRs)

90
Q

What are PRRs?

A
  • Pattern-recognition receptors
  • These are receptors on the surface of cells of the innate immune response
  • They bind PAMPs and DAMPs
91
Q

Why are PRRs so important?

A

They bind to ligands that are not variable and are present during a pathogenic infection (PAMPs and DAMPs), so they allow us to differentiate between a pathogen and a non-harmful foreign substance (e.g. a salmon sandwich).

92
Q

What cells express PRRs?

A

Mainly cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells.

93
Q

Is there a limited repertoire of PRRs?

A

Yes

94
Q

What are PAMPs?

A
  • Pathogen-associated molecular patterns
  • These are molecules that are highly conserved between pathogens, so that their detection by PRRs tells the immune cell that this is a pathogen
  • An example is LPS
95
Q

What are DAMPs?

A
  • Damage-associated molecular patterns
  • These are typically nuclear or cytosolic proteins with defined intracellular function that, when released outside the cell after tissue injury, denature and activate PRRs.
  • They essentially signal to immune cells that host cell damage has occurred and therefore trigger an inflammatory response.
  • An example is DNA.
96
Q

What types of immunity are PRRs important in?

A
  • Innate immunity
  • Acquired immunity
  • Auto-immunity
97
Q

Where are PRRs found?

[IMPORTANT for essay]

A

They are expressed mostly in innate immune cells:

  • Cytosolic PRRs
  • Cell-surface PRRs -> On both neutrophils and macrophages, but more types on macrophages

Some are also secreted into the plasma:

  • Certain acute phase reactants (floating free in the plasma) -> These tend to activate complement, which in turn activates phagocytes
98
Q

Give two examples of secreted PRRs.

[EXTRA?]

A
  • Mannose-binding lectin (MBL)
  • C-reactive protein (CRP)

Both of these are involved in complement, meaning that they trigger phagocytes indirectly.

99
Q

Give some examples of cytosolic PRRs.

A
  • NLRs (Nod-like receptors):
    • NODs [IMPORTANT]
    • NLRPs
  • RIG
100
Q

Give some examples of cell-surface PRRs.

A
  • TLRs (Toll-like receptors) [IMPORTANT]
  • Macrophage scavenger receptor
  • Lectins:
    • Dectin-1 (in macrophages and neutrophils)
    • Macrophage mannose receptor
101
Q

Compare the PRRs in/on neutrophils and macrophages.

A

Neutrophils and macrophages both have PRRs, but macrophages have more cell-surface PRRs, including mannose receptors and scavenger receptors.

102
Q

Describe the different types of receptors on phagocytes.

[IMPORTANT as summary]

A
  • Opsonic
    • Phagocytic receptors -> These bind to opsonins (such as IgG and complement components) that are marking out pathogens for phagocytosis (e.g. Fc receptors and CR3)
  • Non-opsonic:
    • PRRs
      • Phagocytic receptors -> These bind to PAMPs/DAMPs and trigger phagocytosis (e.g. lectins and macrophage scavenger receptor, mostly in macrophages)
      • Non-phagocytic -> These bind to PAMPs/DAMPs and assist with phagocytosis, but do not trigger it (e.g. TLRs). They also lead to release of cytokines (e.g. NLRs).
    • Cytokine receptors -> Involved in cytokine release and killing mechanisms (not phagocytosis)
    • GPCRs -> Mostly involved in recruitment of the phagocyte

Don’t deep the whole phagocytic/non-phagocytic thing. Just remember that TLRs and NLRs are not phagocytic like you might expect. Thus, in the diagram, phagocytic receptors refer to opsonic receptors and PRRs apart from TLRs and NLRs.

103
Q

What are the main PRRs on phagocyte whose activation does not trigger phagocytosis?

A
  • TLRs
  • NLRs (such as NOD)

TLRs may stimulate, but do not trigger phagocytosis, while NOD receptors lead to the release of cytokines.

104
Q

What are the opsonic receptors? What are the main ones?

A

They are receptors on phagocytes that bind to opsonins that are marking out cells for phagocytosis:

  • Fc receptors (on neutrophils and macrophages) -> Bind to the Fc region of IgE immunoglobulins
  • CR3 -> Binds to iC3b, which is part of the complement cascade
105
Q

What cells express scavenger receptors?

[EXTRA]

A

Macrophages

106
Q

What are scavenger receptors and what is their function?

[EXTRA]

A
  • They are a type of PRR found on macrophages
  • They trigger phagocytosis
  • They bind to non-native LDL, and features of bacteria (e.g. LPS)
107
Q

Give some experimental and clinical relevance of scavenger receptors.

[EXTRA]

A
  • (Brown, 1983) found that scavenger receptors lead to the uptake of modified LDL by macrophages to give foam cells.
  • Clinically, this is relevant in the development of atherosclerosis (and possible subsequent myocardial infarction or stroke), since macrophages that are recruited to fatty deposits in arteries can convert ingested LDL to cholesterol and become foam cells that form the plaque. Depending on conditions, the foam cells can then promote further foam cell formation.
108
Q

What are lectins and how are they related to immunity?

A
  • They are carbohydrate-binding proteins that are highly specific for sugar groups of other molecules
  • They act as phagocytic receptors
  • They include, for example, dectin-1 and macrophage mannose receptor
109
Q

State two examples of lectins on phagocytes and what they do.

[EXTRA]

A
  • Dectin-1
    • Found on macrophages and neutrophils
    • Binds to fungal polysaccharides
    • Stimulates phagocytosis and release of TNF-α
  • Macrophage mannose receptors
    • Found on macrophages
    • Bind to mannose and fucose at the ends of glycoproteins and glycolipids, which are predominantly found in bacterial cells
    • Stimulates phagocytosis
110
Q

Give some experimental evidence to show the importance of dectin-1.

[EXTRA]

A

Dectin-1 knockout mice are more susceptible to fungal infection.

111
Q

What does TLR stand for?

A

Toll-like receptor

112
Q

How were TLRs discovered?

[EXTRA]

A
  • The Drosophila Toll gene is required for dorso-ventral axis formation in fly embryos.
  • Toll is also important for the Drosophila response to fungal but not bacterial pathogens.
  • Unlike Drosophila Toll, the 10 mammalian TLRs have no role in development.
113
Q

What are TLRs and what is their function?

A
  • They are a type of PRR that is non-opsonic and non-phagocytic.
  • Activation leads to amplification and changes to transcription that are pro-inflammatory.
  • This leads to inflammatory cytokine production, proliferation and sometimes greater adaptive immunity.
114
Q

How many TLRs are there in humans?

A

10

115
Q

Draw a table to summarise the different human TLRs in terms of the ligands, cells carrying the receptor and location of the receptor in the cell.

A
116
Q

Do macrophages and neutrophils express TLRs?

A
  • Macrophages express at least TLR2, TLR4 and TLR9.
  • Neutrophils only express TLR2 and TLR4, in very small amounts.
117
Q

What are some notable TLRs that you might mention in an essay?

A
  • TLR2:TLR6 dimer -> Recognises teichoic acids
  • TLR4 -> Recognises LPS
  • TLR5 -> Recognises flagellin
  • TLR3, TLR7, TLR8, TLR9 -> Recognise genetic material inside cells

(Note: Not all of these are expressed by macrophages and neutrophils. In an essay, it is best to be clear about this.)

118
Q

Summarise how TLR4 works.

A
  • LBP transfers LPS to the immune cell (macrophage) CD14 receptor
  • CD14 facilitates TLR4 recognition of LPS
  • This requires MD-2 (bound to TLR4)
  • Inside the cell, TLR4 binds MyD88, which sets of a phosphorylation cascade
  • This ultimately results in NF-κB entry into the nucleus, stimulating transcription of cytokines
119
Q

What is responsible for most cytokine release from macrophages (and to a lesser extent neutrophils)?

A

TLR signalling

120
Q

What are some of the pro-inflammatory cytokines secreted by macrophages in response to microbial products? What is the function of each?

[IMPORTANT]

A
  • TNF-α
    • Activates vascular endothelium, increasing cell and metabolite entry
    • Fever
  • IL-1β
    • Activates vascular endothelium and recruitment of lymphocytes, increasing cell and metabolite entry
    • Fever, along with IL-6.
  • IL-6
    • Fever
  • IL-12 (in chronic inflammation)
    • Actives macrophages (via IFN-γ production) and NK cells
  • CXCL8
    • Recruits neutrophils and basophils
121
Q

Give an example of an anti-inflammatory cytokine that counteracts the pro-inflammatory cytokines produced by macrophages in response to microbial products.

[IMPORTANT]

A
  • IL-10
  • Downregulates the expression of helper T-cell cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages.
  • Enhances B cell survival, proliferation, and antibody production.
  • Inhibits pro-inflammatory cytokines TNF-α, IL-1β, IL-12 and IFNγ secretion.
122
Q

Compare the importance of opsonic receptors and phagocytic PRR receptors in phagocytosis.

A
  • Opsonic receptors are critical for phagocytosis
  • Phagocytic PRR receptors can be considered a back-up to this
123
Q

What are NLRs and what is their function?

[IMPORTANT]

A
  • NOD-like receptors
  • This is a family of cytosolic PRRs, including NOD1/2 and NLRPs
  • Found in macrophages (and maybe neutrophils?)
  • NOD1/2 -> Lead to release of cytokines
  • NLRPs -> Are a component of the inflammasome, a molecular assembly that regulates IL-1 and IL-18 secretion in response to intracellular bacterial toxins.
124
Q

In general, what is the cause of inflammation?

A
  • When there is damaged tissue (due to infection or otherwise), the cells there detect the damage and send out cytokines
  • These recruit immune cells and induce a state of inflammation
  • Thus, the symptoms experienced are not due to the infection, but much rather the immune response itself
125
Q

What are the 4 cardinal signs of inflammation? What do they lead to?

[IMPORTANT]

A
  • Swelling (tumor/oedema)
  • Redness (rubor)
  • Heat (calor)
  • Pain (dolor)

Inflammation leads to loss of function.

126
Q

What is pus?

A

An accumulation of fluid, living and dead white blood cells, dead tissue, and bacteria or other foreign invaders or materials.

127
Q

What is an abcess?

[IMPORTANT]

A
  • A localized collection of pus in any part of the body, often caused by an infection by pyogenic bacteria.
  • An abscess is a circumscribed cavity filled with pus (purulent exudate) that is associated with liquefactive necrosis of related solid tissue.
128
Q

What makes abcesses difficult to treat?

A

Their interiors have little or no vascularization, making it difficult to deliver therapeutic agents effectively.

129
Q

What are the different possible fates of an abcess, in order of desirability?

[IMPORTANT]

A
  • Resolution with no scarring
  • Resolution with scarring
  • Rupture external
  • Rupture internal -> Leading to a septic embolus
  • Cyst formation (neutral outcome)
130
Q

What are the best treatment options for abcesses?

A

Surgical drainage and antibiotics

131
Q

Summarise how inflammation begins.

A
  • PAMPs are present in infection and DAMPs are released by tissue damage
  • Resident macrophages, mast cells and dendritic cells release chemical mediators in response
  • These increase the permeability of local venules
  • This causes cells, fluid and plasma proteins to enter the site of injury/infection
132
Q

What are some of the cells that can begin acute inflammation at the site of infection/damage?

A

Resident macrophages, mast cells and dendritic cells.

133
Q

What are the cells that are released into the site of infection as part of the acute inflammatory exudate?

A

Rapidly recruited:

  • Neutrophils
  • Platelets

Recruited soon after:

  • Monocytes (that become macrophages)
  • T-lymphocytes

If the site is of allergic inflammation:

  • Eosinophils/Basophils
134
Q

What are the different proteins that are released into the site of infection as part of the acute inflammatory exudate?

A
  • Albumin
  • Antibodies
  • Complement proteins
  • Coagulation factors
135
Q

What is responsible for much of the swelling at sites of acute inflammation?

A

Albumin released as part of the exudate leads to osmotic pressure that pulls water in.

136
Q

What are the main stages of leukocyte recruitment in inflammation?

A
  • Margination
  • Leukocyte rolling
  • Leukocyte activation
  • Leukocyte tight adhesion
  • Diapedesis (Leukocyte extravasation)
  • Chemotaxis
137
Q

Describe the concept of how neutrophils and macrophages know where to go during acute inflammation.

A
  • The cells at the site of inflammation send out cytokines and other molecules to partially activate neutrophils and macrophages passing through an adjacent venule
  • This triggers them to cross the blood vessel barrier
  • Once crossed, the neutrophils and macrophages follow chemokines, pathogen molecules and other molecules to the site of infection
  • Here they are fully activated
138
Q

What is margination of leukocytes?

A
  • It is the process of leukocytes being forced to flow along the outside of venules.
  • This is the first step in their recruitment to sites of inflammation.
139
Q

What are some of the vasoactive substances that act on the local venule during inflammation?

A
  • Histamine -> Vasodilation, Vascular leakage
  • Serotonin (5HT)
  • Bradykinin (BK)
  • Platelet Activating Factor (PAF) -> Vasodilation
  • Prostanoids
    • Prostaglandins (e.g. PGI2 - prostacyclin) -> Vasodilation
    • Thromboxanes (e.g. TxA2)
140
Q

For histamine, summarise:

  • Where it is released from
  • How it is stored
  • Receptors it acts on
  • Actions
A
  • Released from mast cells
  • Stored in granules with heparin
  • Acts via histamine receptors -> H1-H4
  • Actions:
    • Increased vascular permeability (H1)
    • Smooth muscle cell contraction (H1)
    • Vasodilatation (H1)
    • Cardiac stimulation (H2)
    • Stimulation of gastric secretion (H2)
141
Q

Give some experimental evidence for the importance of histamine in inflammation.

[EXTRA]

A

“Triple reaction of Lewis” a.k.a. “Wheal and flare”:

  • When skin is gently scratched for some time, there are 3 stages to the reaction:
    • Initial red line
    • Flare around the line
    • Light wheal replaces the line
  • This same response can be obtained by injecting histamine
142
Q

For platelet activating factor (PAF), summarise:

  • Where it is released from
  • How it is synthesised
  • Receptors it acts on
  • Actions
A
  • Released from activated inflammatory cells
  • Derived from phospholipids via phospholipase A2
  • Acts on GPCRs
  • Main actions:
    • Vasodilatation
    • Aggregation of platelets
    • Increased vascular permeability
    • Leukocyte chemotaxis
    • Leukocyte activation
    • Bronchospasm
143
Q

What is leukocyte rolling?

A

The rolling of leukocytes along venule walls due to weak attractions.

144
Q

What proteins enable leukocyte rolling?

[EXTRA]

A

Selectins

145
Q

Describe the mechanism of leukocyte rolling.

[EXTRA]

A

Selectins enable weak interactions between the venule wall and the leukocyte:

  • Endothelial cells express
    • P-selectin
    • E-selectin
    • L-selectin ligands
  • Leukocytes express
    • L-selectin
    • P-selectin ligands
146
Q

How is the endothelium signalled to allow for leukocyte rolling?

A
  • P-selectin -> Released from Weibel-Palade bodies by histamine or thrombin
  • E-selectin -> Transcription upregulated by TNF-α, IL-1, LPS
147
Q

In acute inflammation, how quick is leukocyte recruitment?

A

Seconds

148
Q

What are some classic pro-inflammatory cytokines?

A
  • TNF-α
    • Activates vascular endothelium, increasing cell and metabolite entry
    • Fever
  • IL-1
    • Activates vascular endothelium and recruitment of lymphocytes, increasing cell and metabolite entry
    • Fever, along with IL-6.
  • IL-6
    • Fever
149
Q

How does leukocyte (neutrophil and monocyte/macrophage) activation occur in acute inflammation?

A
  • It occurs via GPCRs on the leukocytes
  • The molecules that stimulate these mostly include cytokines, C5a, PAF and others

Note that partial activation occurs during recruitment of the leukocytes, while complete activation occurs at the site of inflammation.

150
Q

What does (partial) activation of leukocytes during recruitment in acute inflammation do?

A
  • Leads to altered conformations of cell surface integrins on the leukocytes
  • The integrins can now form tight interactions with cell adhesion molecules on endothelial cells
  • Thus, the leukocytes adhese to the vessel wall
151
Q

Describe how tight adhesion of leukocytes to the endothelium occurs (during acute inflammation).

A

ICAM interactions:

  • Integrins on the leukocyte surface undergo a conformational change upon activation of the leukocyte
  • This allows the integrins to bind to cell-adhesion molecules on endothelial cells
  • This ICAM interaction is necessary to halt leukocyte rolling and start diapedesis

(NOTE: The diagram also shows the selectin interactions involved in leukocyte rolling)

152
Q

Give some clinical relevance of leukocyte adhesion to the endothelium.

[EXTRA]

A
  • The β-2 integrin subunit may be absent in patients with leukocyte adhesion deficiency (LAD)
  • In these cases, neutrophils and macrophages cannot access the site of inflammation
  • The first sign of this may be seen in babies, where there is a lack of neutrophils entering the stump of the umbilical cord
153
Q

Describe how macrophages are activated.

[IMPORTANT]

A

Classical activation:

  • Produces M1 macrophages, which have a pro-inflammatory and pro-immune role
  • Activated by IFN-γ (during recruitment) and LPS

Alternative activation:

  • Produces M2 macrophages, which have a more anti-inflammatory role and suppress immunity
  • Activated by IL-4 and IL-13 (during recruitment)

(Check whether the cytokines act during recruitment!)

154
Q

What is the name for leukocytes crossing the blood vessel wall to enter a site of inflammation?

A

Diapedesis

155
Q

How do neutrophils and macrophages perform diapedesis?

A
  • They must cross the basement membrane
  • Neutrophils do this by secreting neutrophil elastase, while macrophages use collagenases
  • Then they must move between endothelial cells, using CD31
156
Q

What are chemokines?

A

A family of small cytokines that can induce chemotaxis in nearby responsive immune cells.

157
Q

What is chemotaxis?

A

Movement of a cell in a direction corresponding to a gradient of increasing or decreasing concentration of a particular substance.

158
Q

What receptors on leukocytes detect chemoattractants?

A

GPCRs

159
Q

What are some chemoattractants involved in attracting leukocytes to the site of inflammation? What are their receptors?

A
  • Bacterial products, namely N-formylmethionine (fMLP - an amino acid used to initiate protein synthesis in bacterial cells) -> mFLP receptor
  • Cytokines and chemokines (e.g. IL-8, CCL5, etc.) -> IL-8 receptor, CCR5, etc.
  • C5a (a chemoattractant product of complement) -> C5a receptor
  • Platelet-activating factor (PAF) -> PAF receptor
160
Q

Describe how leukocytes move during chemotaxis and describe their appearance.

A
  • It moves by cytoskeleton remodelling
  • The protrusions at the front are called pseudopods, while the tail at the back is called the uropod
161
Q

What are some ways in which we can experimentally study leaukocyte recruitment in acute inflammation?

A
162
Q

Describe how a Boyden chamber assay can be used to study leukocyte recruitment.

[EXTRA]

A
  • There is a membrane between two chambers, with small holes in it
  • Chemoattractant (CCL5, in this case) is placed in one chamber, while leukocytes expressing a certain type of chemokine receptor are placed in the other chamber
  • The graph shows that the rate of crossing of leukocytes is greatest when the leukocytes are made to express CCR5, which is the receptor for CCL5
163
Q

Summarise the main roles of inflammatory mediators.

A
164
Q

How long does acute inflammation last and what is its purpose?

A
  • Minutes to days
  • It acts to recruit neutrophils to the site of infection and activates them. These neutrophils and other molecules in turn activate other leukocytes.
165
Q

How does fever arise in inflammation?

A
  • Heat is one of the cardinal signs of acute inflammation. This effect is local and is caused mainly by vasodilatation.
  • Some cytokines generated at sites of inflammation can:
    • Act distally to cause systemic inflammation
    • Act at the hypothalamus to raise the set point
  • e.g. TNF & IL-1
  • Localised mechanisms of acute inflammation if initiated throughout the body will give rise to fever and shock.
166
Q

Which bacteria most commonly cause sepsis?

A

Gram-negative

167
Q

How can bacterial infection lead to sepsis?

[IMPORTANT]

A
  • LPS binds to TLR4 on monocytes (with the help of CD14)
  • This leads to systemic release of TNF-α, IL-1, IL-6 & IL-8
  • This leads to fever, endothelial damage, capillary leakage and hypotension
  • This leads to systemic activation of the coagulation cascade (DIC)
  • Overall, this leads to hypoperfusion and therefore multiorgan system failure

(Note: Other TLR ligands can also lead to sepsis)

168
Q

What is endotoxic shock?

A

It is another name for septic shock -> It shows the importance of endotoxins in this process.

169
Q

Draw a diagram to show the effects of pro-inflammatory mediators released in small and large amounts.

A

This shows that acute inflammation on a local scale is beneficial, while on a larger scale it can lead to systemic effects (e.g. fever). At very high levels, it leads to septic shock.

170
Q

What are some of the cytokines and other signalling molecules implicated in septic shock?

A
  • TNF-α
  • IL-1
  • IL-6
  • IL-8
  • NO
  • PAF
171
Q

Give a summary of various cytokines.

A

Note that this is not a complete list. Add some better flashcards on this.

172
Q

Give some clinical relevance of the identification of septic shock.

A
173
Q

Give some clinical relevance of the importance of cytokines.

[EXTRA]

A

TNF (tumour necrosis factor) inhibitors are highly effective in treating illnesses characterised by chronic inflammation, such as rheumatoid arthritis.

174
Q

What are the main forms of RCD (regulated cell death)/programmed cell death?

A
  • Apoptosis
  • Necrosis
  • NETosis
  • Pyroptosis
175
Q

What are some causes of cell injury?

A
  • Infectious agents
  • Chemical agents
  • Oxygen deprivation
  • Physical agents (heat, radiation, trauma)
  • Genetic defects
  • Immune cell activation (CTL, ADCC)
  • Aging (cellular senescence)
176
Q

What are some mechanisms of cell injury?

A
  • Loss of cell membrane integrity
  • Decreased ATP concentration
  • Protein unfolding and protein aggregation
  • Protein trafficking defects
  • Cation imbalance (Na+, Ca2+, H+)
  • Loss of integrity of the genome

Note: The cellular response to injury depends upon the type of injury, its duration and its severity and the consequences of injury vary depending upon the cell type.

177
Q

What are some biochemical changes that occur in cell injury?

A
  • ATP depletion -> Leading to rapid shutdown of homeostatic pathways
  • Generation of Reactive Oxygen Species (ROS) -> Activates multiple signalling pathways, kinases, phosphatases, NF-kB, phospholipases
  • Changes in membrane permeablility -> Leads to breakdown of concentration gradients of ions and metabolites
  • Loss of calcium homeostasis
  • Mitochondrial damage
178
Q

What are some subcellular responses to cell injury?

A
  • Lysosomal catabolism - heterophagy and autophagy
  • Induction of smooth endoplasmic reticulum (p450)
  • Alterations in mitochondrial number and function
  • Abnormalities of cytoskeleton
  • Induction of stress proteins e.g. Heat Shock Proteins (HSPs) & other chaperones
179
Q

What is autophagy?

[EXTRA]

A
  • Autophagy is a cell survival mechanism that aims to derive energy by eliminating defective organelles.
  • It very rarely result in cell death.
  • It can be triggered in starvation and can delay or prevent programmed cell death.
180
Q

Draw a model for the mechanism of autophagy.

[EXTRA]

A

In essence, a membrane forms around proteins, damaged organelles and pathogens in the cytosol. This creates an autophagosome. It fuses with a lysosome to release ATP and precursors for protein synthesis.

181
Q

Describe how protein damage in cells can be repaired.

[EXTRA?]

A
  • If the proteins are not dealt with, they may lead to cell death
  • Thus, the proteins are either repaired using chaperone proteins, or they are tagged by ubiquitin and degraded using a proteasome
182
Q

Give some features of reversible cell injury.

A
183
Q

What is necrosis?

A
  • Necrosis is a form of irreversible cell injury that leads to cell death by autolysis (self-digestion).
  • It is usually caused by external factors, such as trauma.
184
Q

In general, how does necrosis work?

A
  • Necrosis does not use an apoptotic pathways, but instead features external factors (e.g. trauma) that lead to irreversible cell damage
  • Damage to the cell leads to damage to the cell membrane and organelles, accompanies by an influx of calcium
  • This leads to the loss of cell components, denaturation of proteins and hydrolytic digestion of cell components, destroying the cell
185
Q

Describe the different ways the nucleus can appear due to necrosis.

A
186
Q

Give some examples of the different types of necrosis.

A
  • Liquefactive necrosis -> Cell structure is destroyed by digestion, leading to the formation of a viscous liquid mass
  • Coagulative necrosis -> Cell structure is intact, but there is coagulation due to to protein degradation, where albumin tranforms into a firm state.
  • Caseous necrosis -> A combination of coagulative and liquefactive necrosis, with incomplete digestion leaving behind granular particles.
  • Fat necrosis -> Associated with acute pancreatitis.
187
Q

What does the spec say about necrosis?

A
  • Necrosis: damage to the cell raises intracellular calcium and activates hydrolytic enzymes.
  • Result: Cell death and the release of inflammatory mediators.
188
Q

What is a good indicator of whether a cell has undergone necrosis?

A

The appearance of its nucleus.

189
Q

Compare the clearance of apoptotic and necrotic cells by macrophages.

A

Apoptotic:

  • Macrophage detects apoptotic cell using scavenger receptors and phosphatidyl serine receptors, which detect ligands in the membrane that have been exposed by blebbing
  • This leads to changes in gene expression that are more anti-inflammatory (or no changes)

Necrotic:

  • Macrophage detects necrotic cell using Fc receptors and immmunoglobulin receptors, which detect opsonins that mark out the necrosed cell
  • This leads to changes in gene expression that are more pro-inflammatory
190
Q

Compare the difference in morphology seen during apoptosis and necrosis.

A

Add more flashcards on this!

191
Q

Summarise the two main pathways of apoptosis.

A

Intrinsic pathway:

  • Non-receptor mediated: Various stimuli (e.g. DNA damage) lead to eventual release of cytochrome c from mitochondria
  • Activates caspases
  • Leads to cell death

Extrinsic pathway:

  • Receptor-mediated: Stimulation of death receptors by death receptor ligands leads to signalling cascade
  • Activates caspases
  • Leads to cell death

Think of the caspase as the common end goal of these pathways. They can either be triggered by ligands that bind to receptors, or some sort of cell damage (or other change) which lead to release of cytochrome c from mitochondria.

192
Q

What happens following necrosis?

A

There is release of inflammatory mediators, which can attract phagocytes, etc. However, these can lead to damage of surrounding tissue, so that the process is renewed and is self-reinforcing.

193
Q

Describe how TNF-α and FAS ligand can lead to apoptosis.

A

They both trigger the extrinsic apoptotic pathway:

  • Signalling via the TNF receptor and FAS receptor leads to activation of proteins with a FADD (FAS-associated death domain)
  • This FADD cleaves pro-caspase 8 into caspase 8, which in turn leaves pro-caspase 3 into caspase 3.
  • Activated caspase 3 cleaves I-CAD (the inhibitor of CAD)
  • CAD then enters the nucleus and cleaves DNA
194
Q

What is apoptosis?

A

Programmed cell death, which is controlled and done in an orderly fashion.

195
Q

What are some things that can trigger the intrinsic apoptotic pathway?

A
  • It can be developmentally programmed
  • Lack of a specific growth factor
  • Unrepaired DNA damage
196
Q

Compare apoptosis and necrosis.

A

Apoptosis:

  • Controlled
  • Cells play an active role (cell suicide)
  • Does not lead to cell lysis and release of inflammatory mediators

Necrosis:

  • Uncontrolled
  • Cells are more passive
  • Leads to cell lysis and release of inflammatory mediators
197
Q

Draw a summary of apoptotic pathways.

[EXTRA]

A

You can see how there are the extrinsic pathway (via receptor-ligand interactions) and the intrinsic pathway (via all the other number 1s). They all ultimately lead to executioner caspase activation, although these caspases can be regulated by various mitochondrial regulators. The caspases lead to DNA fragmentation, cytoskeleton breakdown, and formation of apoptotic bodies that are broken down by macrophages.

198
Q

Show some of the regulators of apoptosis.

[EXTRA]

A
199
Q

What are some things that can trigger the extrinsic apoptotic pathway?

A
  • TNF-α activating the TNF receptor
  • FAS ligand activating the FAS receptor
  • Cytotoxic T-cell granule release
200
Q

Give some clinical relevance of FAS.

[EXTRA]

A

FAS signalling explains the concept of immune privileged sites (in some cases):

  • Cells in immune-privileged sites (such as in the eye) expressed FAS ligand. This binds to the FAS receptor of any incoming T-cells, causing them to die by apoptosis.
  • Some cancers make use of this immune privilege by also expressing FAS ligand, so that T cells cannot target them
201
Q

How is apoptosis regulated?

A

The common end to the intrinsic and extrinsic pathways of apoptosis are the executioner caspases. These are under the control of various mitochondrial regulators.

202
Q

How does apoptosis actually happen (mechanistically)?

A
  • The executioner caspases lead to endonuclease activation (leading to degradation of DNA) and catabolism of the cytoskeleton.
  • DNA fragments and organelles are packed into cytoplasmic buds (blebbing), known as apoptotic bodies, which are dealt with by macrophages (without release of inflammatory mediators)
203
Q

Give some clinical relevance of a regulator of apoptosis.

[EXTRA]

A
  • Bcl-2 is an inhibitory regulator of the caspase cascade in apoptosis
  • Thus, when it is upregulated, it can lead to development of cancers
204
Q

Summarise the mechanism of pyroptosis.

[IMPORTANT]

A
  • TLR and TNF receptor activation leads to increased transcription of pro-IL-1β, pro-IL-18 and inflammasome components.
  • The presence of PAMPs and DAMPs (e.g. in internalisation of pathogens) and mitochondrial dysfunction leads to the assembly and activation of the inflammasome
  • The inflammasome produces caspase-1, which cleaves the pro-IL-1β and pro-IL-18 into their active forms
  • Caspase-1, along with caspases 4 and 5, also cleaves gasdermin D
  • The cleaved gasdermin D can now form a pore through which the inflammatory cytokines and DAMPs can leave, leading to inflammation
205
Q

What changes does the caspase cascade lead to in apoptosis?

[EXTRA]

A
  • Activation of multiple proteolytic pathways.
  • Cytoskeletal changes -> Forming apoptotic bodies.
  • Chromatin is broken down into 180-200bp fragments.
  • Cleavage of enzymes involved in DNA repair and replication.
206
Q

What are some of the roles of apoptosis?

[IMPORTANT]

A
  • Normal tissue homeostasis
  • Embryonic morphogenesis
  • Deletion of self-reactive lymphocytes
207
Q

What is NETosis?

A
  • NETosis is a slow form of apoptosis seen in neutrophils.
  • It is characterized by the release of decondensed chromatin and granular contents to the extracellular space, forming a NET.
208
Q

What triggers NET formation?

A

NET formation is triggered by innate immune receptors acting through intracellular mediators that include reactive oxygen species (ROS) produced by NADPH oxidase or mitochondria, which activate myeloperoxidase (MPO), neutrophil elastase (NE) and protein-arginine deiminase type 4 (PAD4) to promote chromatin decondensation.

209
Q

What are some functions of NETs?

A
  • Capture pathogens
  • Degrade bacterial toxic factors
  • Kill bacteria
  • Prime other immune cells to induce inflammation
  • Occlude the vasculature by promoting thrombosis and obstruct important organ areas
210
Q

What is pyroptosis?

[IMPORTANT]

A

A controlled form of cell necrosis that is highly inflammatory, since it releases cytokines and DAMPs.

211
Q

How does pyroptosis differ from necrosis?

A
  • Necrosis is caused by physical or mechanical tissue injury -> It is not controlled.
  • Pyroptosis is carried out in a deliberate and highly self-programmed process that generally involves innate immune cells and activation of inflammasomes.
212
Q

What are the roles of pyroptosis?

A

Death of bacterially infected cells and the bacteria they contain.

213
Q

What is cellular senescence?

A
  • Cellular Senescence is a ‘permanent’ arrest of the cell division cycle.
  • It is associated with hyperactivated secretion of pro-inflammatory factors that affect a range of patho-physiological processes such as impaired wound healing, cancer and aging.
  • This behaviour of aging cells has been referred to as senescence-associated secretory phenotype (SASP).
214
Q

What are the cytokines and pathogenic products that activate macrophages?

[IMPORTANT]

A

Classic activation:

  • IFN-γ (in CLASSIC activation)
  • Endotoxins (LPS)

Alternative activation:

  • IL-4
  • IL-13
215
Q

What are interferons and what is their function? What are the different types?

A
  • Interferons (IFN) are cytokines that are released primarily in respones to viral infection (and tumours)
  • Thus they mostly activate the innate immune system -> In particular, macrophages
  • The two types:
    • Type 1 interferons -> IFN-α and IFN-β
    • Type 2 interferons -> IFN-γ
216
Q

What cytokines do macrophages secrete?

[IMPORTANT]

A

Pro-inflammatory:

  • TNF-α
  • IL-1
  • IL-6

Anti-inflammatory:

  • IL-10
  • IL-12

They also produce IFN-α and IFN-β according to the spec

217
Q

Do macrophages secrete complement components?

A

Yes

218
Q

When do macrophages play a pathogenic role?

A

In chronic inflammation.

YEAR 2 - Principles of Pathology (18 decks)

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