Lecture 7 & 8(Innate Immunity Lectures)

Question 1

What are the effects of PRR signalling?

Answer 1

(1) Cytokine production:
- Examples: IL-1, IL-6, IL-18, TNF- alpha, IL-12 → inflammation (pro-inflammatory cytokines)
– Type I IFN (IFN- alpha, IFN- beta) → potent antiviral effects.

Subset of cytokine production:
(2) Chemokine production (tell the cells, this way we have an infection - lead migration of cells to site of infection)
Two families:
–> CC chemokines (ec. CCL2) and CXC chemokines (ex. CXCL 8 or IL-8)
—–> Difference in their location of two cysteine residues.

(3) Increase expression of co-stimulatory molecules.
- B7.1 (CD80), B7.2 (CD86)
- These provide SIGNAL 2 to T cells in secondary lymphoid tissue
(T cells need 3 signals to get fully activated, this is the 2 signal that it receives)

(4) Enhanced migration to regional, secondary lymphoid organ
(or to site of infection)
– Upregulation of specific adhesion molecules.
(allowing for migration to happen)

Question 2

What is the primary role of Type I Interferons (IFN)?

Answer 2

They have antiviral effects.
It is an anti-viral cytokine.

Question 3

What triggers the secretion of Type I IFN?

Answer 3

Pattern Recognition Receptor (PRR) signaling.

Question 4

How does Type I IFN signal surrounding cells?

Answer 4

It binds to receptors on nearby cells.

Question 5

What happens after Type I IFN binds to its receptor?

Answer 5

It triggers signalling, leading to more transcription of antiviral genes.

Question 6

What is the effect of the antiviral genes transcribed due to IFN signalling?

Answer 6

• These genes inhibit viral replication, which can halt or slow viral infection.
• Have effect on the viral life cycle.

Question 7

What does PRR signalling trigger in dendritic cells (DCs)?

Answer 7

It triggers migration and targeting of DCs to (secondary lymphoid organ-lymph nodes) lymphoid tissue.

Question 8

What happens to costimulatory molecules after PRR signaling in DCs?

Answer 8

• There is increased expression of costimulatory molecules (CD80/CD86, aka B7.1/B7.2).
• this is signal 2 of 3 signals that T cells need to get activated and differentiated.

Question 9

What type of receptors are chemokine receptors?

Answer 9

Chemokine receptors are G-protein-coupled receptors.

(next to complex that can switch from GDP to GTP)

Question 10

How do chemokine receptors transduce signals?

Answer 10

They transduce signals via interactions with GTP/GDP-binding G proteins.

GDP removed, GTP added.

Question 11

Can chemokine receptors and chemokines bind to multiple partners?

Answer 11

Yes, many receptors can bind to more than one chemokine, and several chemokines can bind to more than one receptor.

Question 12

What is the primary function of chemokines in the immune system?

Answer 12

Chemokines direct leukocyte migration, a process called chemotaxis.

Question 13

How do chemokines influence leukocyte movement?

Answer 13

Signaling through chemokine receptors helps cells move to different areas, changing cell adhesiveness and the cell’s cytoskeleton.

Question 14

What happens to leukocytes in a chemokine concentration gradient?

Answer 14

Leukocytes are induced to move up the chemokine concentration gradient.

Question 15

You discover that a new virus blocks TLR3 signaling by preventing the nuclear translocation of the IRF3. You decide to further study this virus’ impact on TLR3 signaling. What are you most likely to find in a
monocyte infected with this virus?

Answer 15

High levels of activated IRF3 in the cytoplasm.

(to answer the question;
- Transcription factors (NF-kB, IRF3, AP-1, IRF7) in the cytoplasm
- Signaling from a PRR results in their activation
- Once transcription factors are activated, they translocate to the nucleus)

Question 16

What are the effects of PRR signalling?

Answer 16

• Cytokine and chemokine secretion
• Costimulation molecule expression
• Migration (adhesion molecule expression)
• Expression of other genes (could be a transcription factor! Ex. Type I
  IFN)

Question 17

Inflammatory responses

Answer 17

(1) Tissue damage and bacteria cause residential sentinel cells to release chemoattractants and vasoactive factors that trigger a local increase in blood floe and capillary permeability.

2) Permeable capillaries allow an influx of fluid (exudate) and cells.

3) Neutrophils and other phagocytes migrate to site of inflammation (chemotaxis)

4) Phagocytes and antibacterial substances destroy bacteria.

Question 18

How are monocytes recruited to the site of infection?

Answer 18

Monocytes are recruited via adhesion molecules.

Question 18

What happens first when monocytes are recruited to the site of infection?

Answer 18

Monocytes bind to adhesion molecules on the vascular endothelium near the site of infection and receive a chemokine signal.

Question 19

What are the main families of adhesion molecules?

Answer 19

Selectins, integrins, and the immunoglobulin superfamily.

Question 19

What occurs once the monocyte reaches the site of infection?

Answer 19

The monocyte differentiates into an inflammatory monocyte at the site of infection.

Question 19

What happens after the monocytes bind to adhesion molecules?

Answer 19

The monocyte migrates into the surrounding tissue.

Question 20

How are adhesion molecules distributed across tissues?

Answer 20

They have different tissue distributions.

Question 21

Are all adhesion molecules expressed at all times?

Answer 21

No, some adhesion molecules are expressed at baseline, while others are expressed during an infection.

Question 22

What are the steps involved in leukocyte recruitment during an infection?

Answer 22

1) Cytokines produced by macrophages cause dilation of local small blood vessels. 2) Leukocytes move to the periphery of the blood vessel due to increased expression of adhesion molecules by the endothelium. 3) Leukocytes extravasate (exit the bloodstream) at the site of infection. 4) Blood clotting occurs in microvessels.

Question 23

What are the types of leukocytes recruited during an infection, and what are the signs of inflammation?

Answer 23

- Leukocytes recruited include monocytes (precursors of macrophages), neutrophils, and other leukocytes. - Signs of inflammation: heat, redness, swelling (edema), and pain. - Severe/chronic inflammation can lead to conditions like arthritis or loss of function.

Question 24

What are the steps involved in leukocyte migration, and what is diapedesis?

Answer 24

1) Rolling adhesion: Leukocytes loosely attach and roll along the vascular endothelium. 2) Tight binding: Leukocytes firmly attach to endothelial cells. 3) Diapedesis: The process by which a leukocyte crosses from the lumen of a blood vessel, between endothelial cells, and into surrounding tissue. 4) Migration: Leukocytes move in the direction of higher chemokine concentrations (chemotaxis).

Question 25

What are cytokines, and what are their general characteristics?

Answer 25

- Cytokines are small (~25kD), heterogeneous glycoproteins. - They are mostly soluble, but some have membrane-bound forms. - Their production is tightly regulated, involving post-transcription and post-translation modifications.

Question 26

What is the primary role of cytokines?

Answer 26

Cytokines provide cellular communication.

Question 27

How do cytokines affect cell behavior?

Answer 27

Cytokines affect behavior through three mechanisms: 1) Autocrine mechanism: Affecting the producing cell itself. 2) Paracrine mechanism: Affecting adjacent cells via directional release. 3) Endocrine mechanism: Affecting distant cells.

Question 28

What are the three mechanisms of cytokine action, and how do they differ?

Answer 28

1) Autocrine: Cytokines act on the cell that produces them. 2) Paracrine: Cytokines act on adjacent cells using directional release. 3) Endocrine: Cytokines act on distant cells.

Question 29

What are the five main groups of cytokines?

Answer 29

(1) Interleukins (IL): Numbered 1 to 37 so far. (2) Interferons (IFN): Type I: IFN-α, IFN-β Type II: IFN-γ (3) Tumor Necrosis Factors (TNF): TNF-α, TNF-β (4) Hematopeoitins/Growth Factors: e.g., GM-CSF, G-CSF (5) Chemokines

Question 30

What are the four ways cytokines can exert their effects?

Answer 30

1) Pleiotropy: One cytokine produces multiple effects. 2) Redundancy: More than one cytokine induces the same effect. 3) Synergy: Two (or more) cytokines work together to induce an effect. 4) Antagonism: One cytokine can inactivate the effect of another.

Question 31

What is cytokine pleiotropy?

Answer 31

Pleiotropy occurs when one cytokine produces multiple effects.

Question 32

What is cytokine redundancy?

Answer 32

Redundancy occurs when more than one cytokine induces the same effect.

Question 33

What is cytokine synergy?

Answer 33

Synergy occurs when two or more cytokines work together to induce an effect.

Question 34

What is cytokine antagonism?

Answer 34

Antagonism occurs when one cytokine inactivates the effect of another.

Question 35

Why is the cytokine network considered complex?

Answer 35

The cytokine network is complex because: - The same cytokine can be produced by multiple cells. - Each cell type can produce multiple cytokines. - There is a network of complex interactions among cytokines. - Specific cytokines are produced at different times in different locations.

Question 36

Can the same cytokine be produced by more than one cell type?

Answer 36

Yes, the same cytokine can be produced by multiple cells.

Question 37

Can one cell type produce more than one cytokine?

Answer 37

Yes, each cell type can produce multiple cytokines.

Question 38

Are cytokines produced uniformly across time and location?

Answer 38

No, specific cytokines are produced at different times and in different locations.

Question 39

What effect can different cytokines have on cell differentiation?

Answer 39

Different cytokines can induce the differentiation of different cell types.

Question 40

What do differentiated cell types do in the cytokine network?

Answer 40

Different cell types produce different cytokines, contributing to the cytokine network.

Question 41

How does the cytokine environment influence adaptive immune responses?

Answer 41

- The cytokine environment imprints adaptive immune responses. - While there is normally a mix of responses, one response can dominate. - Cytokines determine the type of adaptive immune response: cell-mediated or humoral immunity.

Question 42

What is cell-mediated immunity, and what does it target?

Answer 42

Cell-mediated immunity is mostly directed toward: - Viral infections - Intracellular pathogens - Some extracellular pathogens

Question 43

What are the key features of cell-mediated immunity?

Answer 43

- T helper cells: Activate innate immune cells. - Cytotoxic T lymphocytes (CTLs): Directly kill infected cells.

Question 44

What is humoral immunity, and what does it target?

Answer 44

Humoral immunity is mostly directed toward: - Extracellular bacteria - Extracellular pathogens

Question 45

What are the key features of humoral immunity?

Answer 45

1) B cell activation 2) Antibody production

Question 46

What is TNF-alpha, and which cells secrete it?

Answer 46

- TNF-alpha is a proinflammatory cytokine. - It is secreted by macrophages.

Question 47

What are the main functions of TNF-alpha?

Answer 47

1) Stimulates migration of innate immune cells. 2) Dilates blood vessels and increases clotting to prevent pathogens from entering the bloodstream.

Question 48

What role does TNF-alpha play in autoimmune diseases?

Answer 48

TNF-alpha is involved in many autoimmune diseases. Therapies targeting TNF-alpha are used to treat: 1) Rheumatoid Arthritis 2) Crohn’s Disease

Question 49

What is the difference between local and systemic effects of TNF-alpha?

Answer 49

1) Local TNF-alpha: Causes local inflammation. 2) Systemic TNF-alpha: Leads to systemic effects.

Question 50

What is sepsis, and how does it relate to TNF-alpha?

Answer 50

- Sepsis is a systemic infection and inflammation. - In sepsis, systemic TNF-alpha is involved, leading to widespread systemic effects.

Question 51

What is the Acute Phase Response?

Answer 51

The Acute Phase Response is a change in the proteins present in the blood that occurs during the early phases of an infection.

Question 52

What induces the Acute Phase Response?

Answer 52

The Acute Phase Response is induced by proinflammatory cytokines such as: 1) IL-1 2) TNF-α 3) IL-6 These are typically released by macrophages.

Question 53

What are some key components involved in the Acute Phase Response?

Answer 53

The Acute Phase Response involves: 1) Increased synthesis/secretion of antimicrobial proteins (acute phase proteins) by the liver. 2) Examples of acute phase proteins: - Mannose-binding lectin (MBL) - Complement components - C-reactive protein (CRP)

Question 54

What is the role of C-reactive protein (CRP) in the Acute Phase Response?

Answer 54

C-reactive protein (CRP) can: 1) Opsonize bacteria (enhance phagocytosis). 2) Trigger the classical complement cascade by binding to C1q.

Question 55

How do liver acute phase proteins contribute to pathogen elimination?

Answer 55

Liver-produced acute phase proteins activate other processes that help eliminate pathogens.

Question 56

What are the key pro-inflammatory cytokines?

Answer 56

The key pro-inflammatory cytokines are: - IL-1beta - IL-6 - TNF-alpha

Question 57

What effects do inflammatory cytokines like IL-1beta, IL-6, and TNF-alpha have on tissues and cell types?

Answer 57

Inflammatory cytokines have many effects, including: 1) Acute-phase response 2) Mobilizing cells 3) Fever

Question 58

How do IL-1beta, IL-6, and TNF-alpha contribute to the response against pathogens?

Answer 58

IL-1beta, IL-6, and TNF-alpha contribute to the immune response by: 1) Triggering the acute-phase response. 2) Mobilizing immune cells to fight infection. 3) Inducing fever to enhance the immune response.

Question 59

How do inflammatory cytokines cause fever?

Answer 59

Fever is caused by IL-1beta, IL-6, and TNF-alpha, which: 1) Signal a cascade that leads to a signal to the hypothalamus. 2) The hypothalamus then increases body temperature.