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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?

CD8 cells, NK cells, ADCC (antibody-dependent cell-mediated cytotoxicity) and complement dependent.

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?

NK cells have killer cell inhibitory receptors (KIRs) that can bind MHC. This induces a nonkilling signal into the NK cell.

Explain the balance in signals that determines whether the NK cell will react.

When there is no MHC but also no activating ligands, nothing happens (erys also dont have MHC). In most cases, MHC is downregulated but not completely absent and stress signals are present. The balance determines what happens.

Which enzymes/pathways are important for NK activation/inhibition (balance)?

When the receptor binds the ligand, kinases are recruited to the receptor. The receptor is fosforylated and other proteins are recruited; pathway.
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?

Downregulation of MHC and replace this by a molecule that resembles (binds NK) but does not presentate antgen.

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.

When inhibitory receptors are knocked out, the bcell immune respons becomes too strong (increased immune respons, increased bcells, auto antibodies, hyperproliferative etc).

What do most inhibitory proteins ahve in commen (structural)?

They usually carry ITIM motifs: Immune receptor tyrosine based inhibition motif. So inhibition is tyrosine based; tyrosines on the intracellular part are defosfarylated by recruited phosphatases and therefor activation of the cell is inhibited.

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.

Left: Pathogens cause damage
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.

But when activated... the tumor an block the activated cell with PD-L1...

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?

There are a lot of immune related adverse events (side effects), since ligands are also expressed on healthy cells (especially in gut and skin; lot of antigen exposure).

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

Picture

What is the definition of inflammation? What are the characteristics of inflammation?

a protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues. The response is associated with mobilization of inflammatory cells.

Heat, red, swelling, pain, loss of function (when too much inflammation).

What is the defenition of infection?

Invasion and multiplication of micro-organisms in body tissues, especially that causing local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response.

What is systemic inflammation?

Systemic inflammation is a often used term in the literature, but is poorly defined. It generally refers to the process that inflammatory processes can be measured in the peripheral blood. These processes then can affect distant tissues not affected by the primary inflammatory response.

How does the innate respons relate to inflammation?

Inflammation mobilizes effector cells (e.g. macrophages).

Early development of innate immunity

https://www.ncbi.nlm.nih.gov/books/NBK27138/

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?

After damage, leukocytes (eosino, baso, neutro granulocytes en monocytes) migrate to the tissue.

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?

Phagocytosis:

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?

NADPH can induce mitochonrial independent 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

A potent immune respons against micro-organisms and cancer cells (with limited tissue damage and return to homeostasis) is needed, but when it escalates it can turn into a hyperactive immune respons that causes collateral damage to the tissue.

What process is induced when LPS is administrated?

LPS= PAMP in bacterial cell wall. When LPS is added in a model; acute inflammation occurs. The acute inflammation is self limiting due to the cytokine balance. In the late response, IL10 is produced, which limits inhibition.

LPS induces mobilization of "new" neutrophil phenotypes.

After multiple trauma, kinetics of neutrophils changes in time. Explain what those changes are.

Acute hyperinflammation: More eosinophils, more mature neutrphils,
<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?

When inflammation is inhibited, the host tissue is protected but there are a lot of risks.

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?

Low hygiene means more infections and more control of those infections by Tregs. High hygiene means low exposure to pathogens and therefore a weak regyulatory network. For example:
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.

Asthma:

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.

Adminstration of LPS can indeed induce innate immune tolerance (a.k.a. no chronic inflam, allergy and auto-immune). In the second visit (second time administration of LPS), inflammatory cytokines (TNFalfa, IL6) are repressed (because the immune reaction is more regulated--> tolerance for LPS).

What happens with blood leukocytes during LPS induced tolerance (=model for CARS = The Compensatory Anti-inflammatory Response syndrome ) when IFNgamma or GMCF is administrated?

GM‐CSF and IFN‐γ treatment induced a shift in granulocyte composition toward an anti‐inflammatory direction by increasing CD16bright/CD62Ldim cells or decreasing neutrophil counts, respectively.

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?

Tolerance induced by PAMPs/DAMPs. This is now used to dampen undesired immune responses in padiatric patients undergoing heart surgery ("shock"after surgery can be dangerous). This is called ischemic preconditioning; to control ischemia and reperfusion.

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Klinische I&I

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