LECTURE 7

Question 1

result of phagocyte migration?

Answer 1

IL1! leads to fever and signals BM to make more monocytes

Question 2

2 general types of myeloid cells

Answer 2

1. circulating
2. tissue resident

Question 3

describe circulating myeloid cells

Answer 3

high turnover rate, quickly mobilized

mononuclear = monocytes/DCs
polymorphonuclear = granulocytes

Question 4

describe tissue resident myeloid cells

Answer 4

macrophages, TAMs, DCs, MDSCs

Question 5

what can monocytes become?

Answer 5

GM-CSF –> DCs
M-CSF –> Macrophages

Question 6

2 roles of monocytes

Answer 6

1. patrol for pathogens (via PRRs)
2. phagocytic/APC

Question 7

where are monocytes?

Answer 7

IN BLOOD

Question 8

differentiation of monocytes

Answer 8

highly plastic! many diff subtypes and can differentiate btwn them to change phenotype

Question 9

3 types of monocytes (2 major ones)

Answer 9

1. CD14++CD16- classical (major)
2. CD14++CD16+ intermediate
3. CD14+CD16++ non-classical (major)

Question 10

describe classical monocytes

Answer 10

CD14+CD16-
- 90% of monocytes
- CD14 helps with TLR4 signaling
- cross endothelium to enter tissues
- pro-inflammatory!
- **can differentiate into macrophages/DCs

Question 11

describe intermediate monocytes

Answer 11

CD14++CD16+
- pro-inflammatory (IL6, IL1, TNFa)
- good APC

Question 12

describe non-classical monocytes

Answer 12

CD14+CD16++
- patrolling!
- remove damaged cells / debris from blood
- promote wound healing, resolution of inflammation
- induce complement, cell adhesion, phagocytosis

Question 13

where are macrophages found?

Answer 13

in all tissues!! make up 10-15% of total cell numbers

Question 14

when does the number of macrophages increase?

Answer 14

with increased inflammatory signals from neutrophils (1st cell to move into tissue)

Question 15

4 basic functions of macrophages

Answer 15

1. phagocytosis
2. clear dead cells
3. increase immune response
4. APC

Question 16

how do macrophages increase immune response?

Answer 16

1. systemic inflammation
2. pro-inflammatory cytokines
3. activate neighbouring stromal and immune cells

Question 17

difference btwn macrophages and DCs as APC

Answer 17

macrophages can only activate effector T cells

DCs activate naive T cells

Question 18

describe activation of M1 macrophages

Answer 18

“classically activated” via IFNy

Question 19

role of M1 macrophages

Answer 19

pro-inflammatory (TNFa), phagocytosis, bacterial clearance, proteolysis

Question 20

describe activation of M2 macrophages

Answer 20

“alternatively activated” via IL4

Question 21

role of M2 macrophages

Answer 21

anti-inflammatory, wound repair/tissue remodeling, chemokines, phagocytosis

Question 22

origin of macrophages

Answer 22

before birth, macrophages from yolk sac and fetal liver become tissue resident macrophages

upon infection, HSC in BM produce monocytes that seed the blood to move to site of infection

Question 23

2 ways DCs are produced

Answer 23

1. leave BM as fully formed DC
2. leave BM as monocyte that can become DC

Question 24

are there more macrophages or DCs?

Answer 24

macrophages

Question 25

where do immature DCs become mature DCs?

Answer 25

in periphery

Question 26

describe development of immature DCs to mature DCs

Answer 26

NF-kB stimulates 1. increased number of dendrites 2. increased MHC presentation 3. increased co-stimulatory molecules then move to LN and activate naive T cells

Question 27

4 subsets of DCs1

Answer 27

1. plasmacytoid 2. DC1/CD141 3. DC2/CD1 4. MoDC

Question 28

describe plasmacytoid DCs

Answer 28

type I and III IFNs for viruses

Question 29

describe DC1/CD141

Answer 29

- make IL12 and type III IFN - cross-presentation --> present exogenous Ag to CD8 - intracellular pathogens and tumours

Question 30

describe DC2/CD1

Answer 30

- make IL23 - present exogenous Ag to CD4 - extracellular pathogens

Question 31

describe MoDCs

Answer 31

- derived from monocytes in circulation then go to tissue during infection - produce TNF, ROS

Question 32

describe origins of DC subsets

Answer 32

plasmacytoid, DC1, and DC2 leave BM as DCs MoDC leave BM as monocytes

Question 33

describe lifespan of neutrophils

Answer 33

short-lived + terminally differentiated without inflammatory stimulus --> apoptosis by macrophages (EFFEROCYTOSIS)

Question 34

where are neutrophils found?

Answer 34

abundant in blood but not in healthy tissue

Question 35

how do neutrophils move to infected tissue?

Answer 35

IL8!!!!

Question 36

why are neutrophils really good

Answer 36

highest phagocytic activity, responds fastest to infectious agents

Question 37

neutrophils in inflammation (10 stages)

Answer 37

1. patrol in blood 2. tether 3. integrins (endothelium) and selectins (cell) 4. cytoskeletal rearrangement for diapedesis 5. migration 6. phagocytosis 7. NETs 8. degranulation 9. cytokines 10. efferocytosis

Question 38

2 stages of phagocytosis by neutrophils

Answer 38

1. PHAGOSOME --> contains primary granule, DEFENSIN which disrupts membrane -fuses with- 2. LYSOSOME --> contains secondary granule, CATHELICIDIN (mostly made by neutrophils, must be activated)

Question 39

role of MDSCs

Answer 39

inhibitory --> TGFB, IL10

Question 40

when are MDSCs found?

Answer 40

when there's dysfunction --> cancer, autoimmunity, chronic infection

Question 41

2 types of MDSCs

Answer 41

1. PMN-MDSC 2. M-MDSC

Question 42

Describe PMN-MDSCs

Answer 42

phenotypically similar to neutrophils (derive from polymorphonuclear cells)

Question 43

describe M-MDSCs

Answer 43

phenotypically similar to monocytes (derive from monocytes)

Question 44

why do MDSCs develop?

Answer 44

neutrophils and monocytes get reprogrammed to be anti-inflammatory by TME and suppress nearby immune cells

Question 45

2 signals leading to MDSC development

Answer 45

1. excess expansion of myeloid cells from BM 2. cells move to TME and drive cells to become MDSCs (thru IFNy, TLR ligands, IL4, IL13, TGFB)