Caput 1. Checkpoints and inflammation
36 important questions on Caput 1. Checkpoints and inflammation
How are virus infected cells and tumor cells cleared by the immune system? Which cell types are involved?
Picture is really old, there are now more mechanisms known.
How does a NK cell know which cell to kill?
- No expression of MHC
- Stress factors
This mechanism is very general: specific for tumorcells, but multiple NK cells are activated by lots of factors.
Why do NK cells do not kill autologous cells? How does this mechanism works?
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Explain the balance in signals that determines whether the NK cell will react.
Which enzymes/pathways are important for NK activation/inhibition (balance)?
When the receptor binds ligand and MHC is also present, defosforylating enzymes are also recruited.
Balance fosfatase/kinase!
How can tumorcells prevent activation of MHC and CD8?
Besides KIRs, a lot of inhibitory receptors are known that regulate the immune respons. Explain the effect of knock out of inhibitory b cell receptors.
What do most inhibitory proteins ahve in commen (structural)?
For example: BCR is regulated by SHP/SHIP.
SHP = SH2 domain containing phosphatase dephosphorylates tyrosines (in i.e. ITAMs).
SHIP = SH2 domain containing inositol 5’ - phosphatase hydrolyzes PIP3 into PIP2 : release of PH domain containing proteins from the membrane.
Both inducing block of activation.
Explain the role of immune checkpoints in the balance between damage en resistance.
The immune respons fights against this pathogen caused damage. Immune checkpoints can here inhibit the immune respons and cause resistance (=no more reaction on pathogens). This can be important to protect from móre damages due to immune respons.
Right: Immune checkpoints can inhibit a response against healthy substances (and therefore induce tolerance for bacteria that protect the host).
Disease tolerance = defense strategy against móre damage.
Summarize the importance of inhibitory immune receptors
- Prevention of auto-immunity
- Prevention of virus-induced pathology (damage?)
- As a immune escape mechanism for pathogens and tumors.
Summarize the main functions of inhibitory immune receptors /immunological checkpoints.
- Higher treshhold for immune activation
- Multiple inhibitory receptors expressed by multiple cells (for different phase and place of the respons
- Important for prevention of autoimmunity, inflammation and damage.
Which two pathways can block T cells (activation)?
- CTLA-4 pathway: CTLA-4 binds CD80 as a inhibitory signal for tcel activation and expansion.
- PD-L1 pathway: PD-L1 can block tcells that are already activated (blocks effector tcells; prevents killing by tcell).
Tumorcells use this; upregulate ligands for inhibitory receptors like PD1.
How can knowledge about T cell inhibition by tumor cells contribute to new therapies?
- Ipilimumab: CTLA-4 inhibitors --> more tcell activation by DC's --> more tcells --> stronger tumor respons.
- Combined with Nivolumab: PD-L1 blockers --> activated tcells are not inhibited by the tumor.
This way, two checkpoints are blocked.
Why are more and/or better immune blockers needed?
- Rash
- Liver toxicity
- Diarhea
- Hypophysitis
But those disease are generally mild, wane after therapy (afnemen), can be easily treated with immune supressors etc.
When combination therapy is applied, side effects are worst. Immune checkpoint blockers can increase severity of pre-existing auto-immunity.
Therapeutic intervention via immune inhibitory
What is the definition of inflammation? What are the characteristics of inflammation?
Heat, red, swelling, pain, loss of function (when too much inflammation).
What is the defenition of infection?
What is systemic inflammation?
How does the innate respons relate to inflammation?
Early development of innate immunity
What are the four important functions of the innate immune respons?
- Protection by barriers
- Identification and elimination of pathogens
- Mobilzation of effector cells (inflammation)
- Production of cytokines - communication with adaptive respons.
What are the two major characteristics of PAMPS (MAMPS)?
- Conserved molecular patterns that are not present in the host
- Essential for microbe survival (otherwise evolution would release pamps...)
Explain what happens to the leukocytes after tissue damage?
- Neutrophiles adhese to the vessel wall and migrate to the site of damage/infection (extravasation). Neutrophils kill intracellular
- Eosinophils kill parasites extracellular.
How is killing of microbe acheived by the innate immune cells?
- Phagosome; membrane bound vesicle that becomes acidified (aangezuurd).
- Lysozome with granules with enzymes (lysozyme dissoles cell wall, acid hydrolase digest bacteria), proteins (lactoferrin binds Fe needed for bacterial growth, vitamin B bindig protein) and peptides (defensins an cationic proteins act directly against microbials) that can kill pathogens "melts" with phagosome.
How does the NADPH oxidase enzyme complex contribute to microbe killing?
Which enzyme reactions are important for respiratory burst?
O2 (+NADPH) -> 2O2- (superoxide, reactive oxygen) and H2O and is converted into H2O2 by superoxide dismutase
To combat infections, immune cells use NADPH oxidase to reduce O2 to oxygen free radical and then H2O2. Neutrophils (PMN) and monocytes (MQ) utilizemyeloperoxidase to further combine H2O2 with Cl− to produce hypochlorite, which plays a role in destroying bacteria.
Explain the "immunde defense vs. immunopathology" dilemma
What process is induced when LPS is administrated?
LPS induces mobilization of "new" neutrophil phenotypes.
After multiple trauma, kinetics of neutrophils changes in time. Explain what those changes are.
<12 hrs: active cells (mature cells, high cdl26).
6-10 days: more hypersegmented "trojan horse" neutrophils CD16bright cd62 dim.
So, there is a shift from a pro-inflammatory state towards an antinflammatory stage (back to normal homeostasis).
What causes inflammatory disease?
When there is imbalance after inflammation, pro-inflammation prolonges and chronic inflammatory disease, autoimmune diseases and allergy can occur.
How can inflammation be inhibited (in inflammatory disease)? What are the pro's and cons of these methods?
- Inhibition of pro-inflammatotion: corticosteroids are anti-inflammatory agents; attacks different parts of the immune system. Therefore, lots of side effects.
- Activation of anti-inflammation:
- Single mediator antagonists: anti tnf? risk; lymfoma. COPD treatment with anti TNF often causes cancer (ór the COPD causes like smoking cause cancer....)
What are the geneal pros and cons of inhibition of inflammation?
- Risk of infection
- Risk of impaired tissue repair (verzwakt)
- Risk of colonization of bacteria
- Schadelijk effect on microbioom and vaccination.
Explain how controlled inflammation can be used as a therapy for inflammatory disease?
Helminth infection initially induce a Th2 respons, and contemporary Tregs are activated to control this respons. This Treg activation induced by helminth infection can control the autoimmune disease/allergy/chronic inflammation (asthma).
http://science.sciencemag.org/content/296/5567/490.full
Summarize the research on hookworm infection to cure asthma/celiac disease.
- Biological entry route (through the skin)
- No significant effects
- People felt better and wanted to keep the hookworm
Celiac disease: picture. Is is shown that the immune system is indeed affected, but the symptoms are still there....
Future research and alternatives needed.
Since we know that infection with a helminth can cause a controlled inflammation that can be helpfull in inflammatory disease. It is also possible to use inflammatory molecules like LPS to modulate inflammation. Explain how this works.
What happens with blood leukocytes during LPS induced tolerance (=model for CARS = The Compensatory Anti-inflammatory Response syndrome ) when IFNgamma or GMCF is administrated?
https://jlb.onlinelibrary.wiley.com/doi/full/10.1189/jlb.0213066
What is a alternative for LPS induced tolerance? In which clinical procedures is this method tested nowadays?
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