Immune, Cellular, and Innate Inflammatory Responses

Question 1

What is the purpose of neutrophils in tissue damage?

Answer 1

They die when they come in contact with damaged cell masses which causes many more neutrophils to migrate.

Question 2

How long does it take immune cells to circulate in the body?
Where do key cell-cell interactions take place?

Answer 2

30 minutes

lymph nodes are key

Question 3

How are intravital microscopy videos made?

Answer 3

Involves taking videos in vivo so the mouse needs to be ventilated, and under anesthesia with temperature control.

Question 4

What do naive lymphocytes do before being activated?
Why?
Where do lymphocytes exit the blood stream? why?

Answer 4

Circulate between secondary and tertiary lymphoid tissues.
So they can constantly scan for Ag to respond to.
HEVs - express ligands for L-selectin adhesion which allows cells to roll down walls and stop at other interactions to then squeeze between cells.

Question 5

Which interact more with DCs, CD4 or CD8 cells?

Answer 5

CD4+ T cells
CD8s DO react much more when CD4+ T cells are present. Without, they barely react at all.
CD8s require CD4 cells to prime them.

Question 6

How do lymphocytes know where to travel through the lymph nodes?
What kind of c-c interactions do FRCs promote? Why?

Answer 6

Fibroblast reticular cells

T-DC interaction. T cells exit HEVs directly onto FRC network.

Question 7

What are the four key steps in immune cell extravasion from blood vessels into tissues?

Answer 7

Rolling
Activation - mediated by chemokines
Arrest/adhesion
Transmigration

Question 8

Where are naive lymphocytes activated?

What is responsible for the activation of naive T cells?

Answer 8

SLOs or SLtissues

DCs

Question 9

What are the phases of CD8+ T cell priming?

Answer 9

Active migration
Stable interaction (3-4 hours) and secretion of IL-2 and cytokines
T cells resume migratory behaviour and have short DC interactions afterwards.

Question 10

Which chemokine guides naive CD8+ T cells to DCs?

Answer 10

CCR5

Question 11

What are the three main viral restriction factors in the intrinsic immunity?

Answer 11

Tetherin, APOBEC, and TRIM5alpha

Question 12

List some things that may be recognized as DAMPs by the immune system?

Answer 12

Damaged cells
Host proteins under stress
Host RNA/DNA in wrong compartment
Purine metabolites (ATP/Uric acid) in extracellular space
Hyaluronan fragments

Question 13

Describe the following...
NFkB
IRFs
IFNs
Proinflammatory cytokines
ISGs

Answer 13

Transcription factor of IFN responsive genes and pro-inflammatory genes
Transcription factor for IFN responsive genes
Antiviral cytokines that elicit activation of downstream genes for pathogenic protection
Inflammatory response
Host genes for cellular protection against pathogens (includes restriction factors)

Question 14

How can innate immune sensors be grouped?

Name the groupings and the sensors in each.

Answer 14

By location of PAMP/DAMP recognition
Extracellular stimuli – TLRs and CLRs
Phagocytosed particles/molecules in endosome – TLRs
Cytoplams particles/molecules – NLRs and RLRs

Question 15

How are TLRs activated?

What do TLRs activate?

Answer 15

Ligands that bind to TLRs cause homo/heterodimer formation.

They activate IFN, ISGs and pro-inflammatory genes.

Question 16

How are RLRs activated?

What do RLRs activate?

Answer 16

Ligands that bind to RLRs cause interaction with adaptors MAVS/IPS on the mitochondria surface.
They activate IFN, ISGs and pro-inflammatory genes.

Question 17

How are NLRs activated?

What do NLRs activate?

Answer 17

NLRs need to be primed by either NOD1 or NOD2 which activate pro-inflammatory gene transcription. They are activated by NLRP3 inflammasomes.
NLRs activate Caspase-1 which converts pro-forms of IL1beta and IL18 into active forms of same.

Question 18

What are the two cellular DNA sensors?

What do they do and where do they do it?

Answer 18

DAI and AIM2 in cytoplasm
DAI activates IRF and NFkB
AIM2 activates adaptor protein ASC and drives inflammasome activation.

Question 19

What to CLR receptors bind?

Answer 19

carbohydrates

Question 20

Name some ways that pathogens can evade the immune system?

Answer 20

Degradation of key proteins
Sequestration of key proteins
Interruption of protein-protein interactions
Modulating post-translational modifications

Question 21

What is tetherin’s function?

Which virus commonly counteracts tetherin?

Answer 21

Viral restriction factor that binds to RT virions and blocks release from cell surface. Activates innate immune response.
HIV

Question 22

What can trigger inflammation?
What can the function of inflammation be?
What are the pathological consequences of inflammation?

Answer 22

Infection, tissue injury, tissue stress/malfunction
Host defense, tissue repair, adaption to stress and restoration of homeostasis
Autoimmunity, tissue damage, sepsis, fibrosis, metaplasia, tumour growth, shift in homeostasis set points and the development of disease and autoimmunity.

Question 23

What does inflammation do in the tissues?

Answer 23

Promotes scar formation, impairs wound healing, induce expression of proteases, can be associated with malignant progression.

Question 24

Describe IFN alpha/beta/gamma and what trigger them.

Answer 24

They elicit an anti-viral state with first and second wave cell signalling and induce hundreds of ISGs
They are triggered by innate responses to infection, damage, and harmful substances just like pro-inflammatory cytokines.

Question 25

Describe pro-inflammatory cytokines and what trigger them.

Answer 25

They increase vascular permeability and recruit neutrophils and other leukocytes to the site of damage. They help with tissue remodeling and repair. Triggered by innate responses to infection and damage just like IFNs

Question 26

Briefly describe first and second wave anti-viral signalling cascades.

Answer 26

1. PRRs recognize PAMPs/DAMPs and initiate IRF3 which induces IFNbeta. 2. IFNbeta signals auto/paracrine and induces ISGs in a positive amplification loop.

Question 27

Describe the steps to the self-amplifying nature of type I IFN signalling.

Answer 27

pDCs are the main secretors of IFN IFN tivates APCs IFNs enhance CD8+ T cell cytotoxic activity which leads to more cell debris to be picked up and recognized by DCs which then secrete more IFN.

Question 28

Briefly describe the types of anatomical barriers to infection. What are the purposes of these barriers?

Answer 28

Physical and chemical barriers prevent infection. | They help prevent infection as well as mediate defense mechanisms - recognition, progression, and resolution.

Question 29

Briefly describe inflammation at the cite of tissue damage.

Answer 29

Damage and bacteria cause resident sentinel cells to release chemoattractants. Permeable capillaries allow influx of fluid and cells. Neutrophils and other phagocytes migrate to inflammation. Phagocytes and antibacterial substances destroy bacteria.

Question 30

What are irritants that may cause inflammation? | What happens if they are not removed?

Answer 30

Infections, toxins, drugs, trauma, recurrent inflammation. | They will continue to cause inflammation and lead to fibrosis, etc.

Question 31

What is the purpose of phagocytosis? | Briefly describe phagocytosis.

Answer 31

Bacterial clearance/destruction. Bacterium attaches to evaginations/pseudopodia. Bacterium is ingested in phagosome. Phagosome fuses with lysosome. Bacterium is killed by lysosomal enzymes. Digestion products released from cell.

Question 32

What kind of phenotypes can macrophages exhibit? What is the function of each? When are each present in inflammation? What do they each secrete?

Answer 32

M1: first to site of injury -- pro-inflammation, anti-microbial, matrix degradation, tissue destruction. Present in initiation phase. TNFalpha, IFNgamma, IL-1, IL-12 M2: anti-inflammatory for tissue repair -- anti-inflammation, angiogenesis, matrix synthesis, tissue remodeling. Present in resolution phase. IL-10, VEGF, TGFbeta

Question 33

What could be the consequences of PRR defects and defects in signalling pathways?

Answer 33

Susceptibility to infections

Question 34

How are inflammatory responses regulated?

Answer 34

Both positive and negative feedback mechanisms.

Question 35

What is the main link between the innate and adaptive immune systems? What is the function of this with the innate immune system? What is the function of this with the adaptive immune system?

Answer 35

DCs are a key bridge with constant interplay. Innate: drives strong responses. Adaptive: directs coordinated activation of system.