Lecture 7 & 8(Innate Immunity Lectures) Flashcards
What are the effects of PRR signalling?
(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)
What is the primary role of Type I Interferons (IFN)?
They have antiviral effects.
It is an anti-viral cytokine.
What triggers the secretion of Type I IFN?
Pattern Recognition Receptor (PRR) signaling.
How does Type I IFN signal surrounding cells?
It binds to receptors on nearby cells.
What happens after Type I IFN binds to its receptor?
It triggers signalling, leading to more transcription of antiviral genes.
What is the effect of the antiviral genes transcribed due to IFN signalling?
- These genes inhibit viral replication, which can halt or slow viral infection.
- Have effect on the viral life cycle.
What does PRR signalling trigger in dendritic cells (DCs)?
It triggers migration and targeting of DCs to (secondary lymphoid organ-lymph nodes) lymphoid tissue.
What happens to costimulatory molecules after PRR signaling in DCs?
- 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.
What type of receptors are chemokine receptors?
Chemokine receptors are G-protein-coupled receptors.
(next to complex that can switch from GDP to GTP)
How do chemokine receptors transduce signals?
They transduce signals via interactions with GTP/GDP-binding G proteins.
GDP removed, GTP added.
Can chemokine receptors and chemokines bind to multiple partners?
Yes, many receptors can bind to more than one chemokine, and several chemokines can bind to more than one receptor.
What is the primary function of chemokines in the immune system?
Chemokines direct leukocyte migration, a process called chemotaxis.
How do chemokines influence leukocyte movement?
Signaling through chemokine receptors helps cells move to different areas, changing cell adhesiveness and the cell’s cytoskeleton.
What happens to leukocytes in a chemokine concentration gradient?
Leukocytes are induced to move up the chemokine concentration gradient.
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?
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)
What are the effects of PRR signalling?
- Cytokine and chemokine secretion
- Costimulation molecule expression
- Migration (adhesion molecule expression)
- Expression of other genes (could be a transcription factor! Ex. Type I
IFN)
Inflammatory responses
(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.
How are monocytes recruited to the site of infection?
Monocytes are recruited via adhesion molecules.
What happens first when monocytes are recruited to the site of infection?
Monocytes bind to adhesion molecules on the vascular endothelium near the site of infection and receive a chemokine signal.
What are the main families of adhesion molecules?
Selectins, integrins, and the immunoglobulin superfamily.
What occurs once the monocyte reaches the site of infection?
The monocyte differentiates into an inflammatory monocyte at the site of infection.
What happens after the monocytes bind to adhesion molecules?
The monocyte migrates into the surrounding tissue.
How are adhesion molecules distributed across tissues?
They have different tissue distributions.
Are all adhesion molecules expressed at all times?
No, some adhesion molecules are expressed at baseline, while others are expressed during an infection.
What are the steps involved in leukocyte recruitment during an infection?
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.
What are the types of leukocytes recruited during an infection, and what are the signs of inflammation?
- 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.
What are the steps involved in leukocyte migration, and what is diapedesis?
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).
What are cytokines, and what are their general characteristics?
- 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.
What is the primary role of cytokines?
Cytokines provide cellular communication.
How do cytokines affect cell behavior?
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.
What are the three mechanisms of cytokine action, and how do they differ?
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.
What are the five main groups of cytokines?
(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
What are the four ways cytokines can exert their effects?
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.
What is cytokine pleiotropy?
Pleiotropy occurs when one cytokine produces multiple effects.
What is cytokine redundancy?
Redundancy occurs when more than one cytokine induces the same effect.
What is cytokine synergy?
Synergy occurs when two or more cytokines work together to induce an effect.
What is cytokine antagonism?
Antagonism occurs when one cytokine inactivates the effect of another.
Why is the cytokine network considered complex?
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.
Can the same cytokine be produced by more than one cell type?
Yes, the same cytokine can be produced by multiple cells.
Can one cell type produce more than one cytokine?
Yes, each cell type can produce multiple cytokines.
Are cytokines produced uniformly across time and location?
No, specific cytokines are produced at different times and in different locations.
What effect can different cytokines have on cell differentiation?
Different cytokines can induce the differentiation of different cell types.
What do differentiated cell types do in the cytokine network?
Different cell types produce different cytokines, contributing to the cytokine network.
How does the cytokine environment influence adaptive immune responses?
- 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.
What is cell-mediated immunity, and what does it target?
Cell-mediated immunity is mostly directed toward:
- Viral infections
- Intracellular pathogens
- Some extracellular pathogens
What are the key features of cell-mediated immunity?
- T helper cells: Activate innate immune cells.
- Cytotoxic T lymphocytes (CTLs): Directly kill infected cells.
What is humoral immunity, and what does it target?
Humoral immunity is mostly directed toward:
- Extracellular bacteria
- Extracellular pathogens
What are the key features of humoral immunity?
1) B cell activation
2) Antibody production
What is TNF-alpha, and which cells secrete it?
- TNF-alpha is a proinflammatory cytokine.
- It is secreted by macrophages.
What are the main functions of TNF-alpha?
1) Stimulates migration of innate immune cells.
2) Dilates blood vessels and increases clotting to prevent pathogens from entering the bloodstream.
What role does TNF-alpha play in autoimmune diseases?
TNF-alpha is involved in many autoimmune diseases.
Therapies targeting TNF-alpha are used to treat:
1) Rheumatoid Arthritis
2) Crohn’s Disease
What is the difference between local and systemic effects of TNF-alpha?
1) Local TNF-alpha: Causes local inflammation.
2) Systemic TNF-alpha: Leads to systemic effects.
What is sepsis, and how does it relate to TNF-alpha?
- Sepsis is a systemic infection and inflammation.
- In sepsis, systemic TNF-alpha is involved, leading to widespread systemic effects.
What is the Acute Phase Response?
The Acute Phase Response is a change in the proteins present in the blood that occurs during the early phases of an infection.
What induces the Acute Phase Response?
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.
What are some key components involved in the Acute Phase Response?
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)
What is the role of C-reactive protein (CRP) in the Acute Phase Response?
C-reactive protein (CRP) can:
1) Opsonize bacteria (enhance phagocytosis).
2) Trigger the classical complement cascade by binding to C1q.
How do liver acute phase proteins contribute to pathogen elimination?
Liver-produced acute phase proteins activate other processes that help eliminate pathogens.
What are the key pro-inflammatory cytokines?
The key pro-inflammatory cytokines are:
- IL-1beta
- IL-6
- TNF-alpha
What effects do inflammatory cytokines like IL-1beta, IL-6, and TNF-alpha have on tissues and cell types?
Inflammatory cytokines have many effects, including:
1) Acute-phase response
2) Mobilizing cells
3) Fever
How do IL-1beta, IL-6, and TNF-alpha contribute to the response against pathogens?
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.
How do inflammatory cytokines cause fever?
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.
