4 th June 2024 Exam Flashcards
The innate immune system constitutes the first line of defence against pathogens. In order to
sense intruders, innate immune cells are equipped with different types of pattern recognition
receptors (PRR).
a) Give a brief overview of the most important innate immune receptor classes and their
general function. (2p)
Toll like receptors are located on the membrane and endosomes and can recognise LPS, viral RNA, flagellin etc.
Nod like receptors are cytosolic and some such as the NLRP3 can activate the inflammasome that activates caspase-1 to produce pro-inflammatory cytokines such as IL-1b.
Rig like receptors recognize viral RNA and by interferon inhibits viral reproduction.
C-type lectin receptors are membrane bound and recognize fungal and bacterial carbohydrates and causes phagocytosis and inflammation.
Phagocytic receptors recognize opsonized pathogens and intituate phagocytosis. Examples of phagocytic receptors are Fc receptors and complement receptors.
The innate immune system constitutes the first line of defence against pathogens. In order to
sense intruders, innate immune cells are equipped with different types of pattern recognition
receptors (PRR).
Mention four mechanisms for limiting innate immune responses, i.e., how innate
immunity is “turned off” after an immune response.
- Antiinflammatory cytokines such as IL-10 and TGF-B are produced by macrophages and Tregs and inhibit immune cell activation and promote tissue repair.
- Molecules such as A20 and SOCS proteins inhibit downstream signalling of PRRs which dampens cytokine production.
- The clearance of PAMPs and DAMPs by phagocytosis causes the immune activation to reduce.
- Certain innate immune cells undergo apoptosis such as neutrophils after clearing infection and macrophages phagocyte them.
T helper (Th) cells are polarized by cytokines, and act by secreting cytokines that will lead to
activation and recruitment of other effector cells. Read all sub-questions before you start to
write your answers.
a. Mention for each inflammatory subset (Th1, Th2, Th17) the differentiation-inducing
cytokines, i.e. the cytokines that induce polarization of a naïve Th cell into a Th1, Th2
or Th17 cell. (1.5p)
Th1 cells develop from IL-12 and IFN-gamma signals, Th2 cells require IL4 and Th17 TGF-B, IL-6 and IL-23.
T helper (Th) cells are polarized by cytokines, and act by secreting cytokines that will lead to
activation and recruitment of other effector cells. Mention for one subset (Th1 or Th2 or Th17) one cytokine that is typically secreted
and give examples on two effector cells that are typically affected by this cytokine.
Th1 cells secrete IFN-g and IL-2 and TFN-B activates macrophages which kills intracellular pathogens and cytotxic T cells.
Th2 cells secrete IL-4, IL-5, IL-10 and IL-13 which causes antibody production, eusoniphil production and inhibition of macrophages.
Th17 produces IL-17 targets innate immune cells and epithelial cells to produce and recruit neutrophils.
T helper (Th) cells are polarized by cytokines, and act by secreting cytokines that will lead to
activation and recruitment of other effector cells.Explain briefly how each subset (Th1, Th2, Th17) leads to elimination of different
classes of pathogens.
Th1 acts on intracellular patogens by activating macrophages that can phagocytise and cytotoxic T cells that can induce apoptosis of infected cells.
Th2 eliminates extracellular parasites through promoting IgE production of B cells, mucus secretion and eosinophil activation.
Th17 works on extracellular bacteria and fungi by recruiting neutrophils and stimulating epithelial cells to produce antimicrobal peptides.
T helper (Th) cells are polarized by cytokines, and act by secreting cytokines that will lead to
activation and recruitment of other effector cells. For one of the three Th subsets, give one example of a cytokine that would be
beneficial to block in a disease setting, and in which disease.
Th17 is asscoiated with certain autoimmune diseases for example RA. Th17 produces TNF-a which if can be blocked by drugs such as infliximab can help with RA.
How are immune complexes normally cleared from the circulation? (1p)
Immune complexes when kepts soluble due to having more antibodies then antigens create small soluble IC can then be transported on eryotrhcytes (red blood cells) to the liver where kuppfer cells which are spezialiced macrophages can phagocityze and neutrilize them.
Describe how immune complexes can lead to the destruction of tissue, how can they
be involved in the pathogenesis of autoimmune diseases?
There are two ways this can happen. Desposition is when the antibody and antigen are approximatly the same ratio which means it’s hard for the body to keep it soluble and they have a lettice formation. They can then be deposited to tissues often kidneys, joints etc where it can’t be cleared from the body since it’s not soluble and it acting pro-inflammatory to the point of tissue damage.
The antibody and antigen can also meet at sites of tissues such as the joints and there form an insoluble IC that the body can’t remove and cause excessive inflammation.
Describe two possible ways of therapeutically targeting mechanisms mediated via
immune complex-Fc receptor interactions to improve autoimmune diseases. The
treatments do not necessarily need to be available or approved yet.
We can use monoclonal antibodies targeted to the specific disease promoting FC receptor and block the receptor so it can’t activate immune cells and cause a pro-inflammatory response. This is used for example with RA.
Small molecule inhibitors is another pathway Fostamatinib inhibits spleen tyrosine kinase (SYK) which is a key enzyme for FC receptor signalling and B cell activation and is currently being investigated for the use in RA.
There are several ways in which the immune system can be modulated in the treatment of
autoimmune diseases like rheumatoid arthritis.
Describe briefly 1) the presumed main mechanism, 2) why these drugs lead to improvement
and 3) one principal side-effect for the following biological drugs:
a) Rituximab (monoclonal antibody directed against CD20)
As rituximab targets CD20 which is found only on site of mature B cellls it leads to B cell depletion through antibody-dependent cytotoxicity and complement dependent cyttotoxicty inhibtion. RA is often driven by autoantibodies and pro-inflammatory cytokines produces by B cells. Depleting these CD20 B cells is reduces the formation of pathogenic autoantibodies and lowers inflammation by limiting B-cell activation of T cells and other immune pathways. It does however lead to the patient being immuno compromised and being more suspectible for infections.
There are several ways in which the immune system can be modulated in the treatment of
autoimmune diseases like rheumatoid arthritis.
Describe briefly 1) the presumed main mechanism, 2) why these drugs lead to improvement
and 3) one principal side-effect for the following biological drugs: Anakinra (IL-1 receptor antagonist)
It blocks the IL-1 receptor on immune cells which inhibits IL-1 mediated pro-inflammatory signalling. In RA IL-1 is a major driver of joint damage and inhibiting this pro-inflammatorey response improves the disease. However IL-1 is also important for the innate immune responses so it also makes the patient immuno compromised.
Which is the most abundant immune cell in the brain and what functions does it have under
basal states and during inflammation?
Microglia is the most abundant immune cells in the brain. During basal states it prunes the synapses, phagocytes cellular debris, takes up amolyid monomers and oligomers, enhances learning and memory etc. During inflammation however is can cause amyloid plaque formation, derscrution of viable cells and synapses, and causes impaired learning and memory.
Oral tolerance mechanisms regulate mucosal immune responses. Palforzia was recently
approved as a medicine for treating peanut allergy in children from 4 to 17 years of age and
patients who become adults whilst on treatment. After treatment, some patients tolerate a
small amount of peanuts with only mild symptoms. Palforzia contains peanut powder and
should be taken in gradually increasing doses mixed into food, first under medical
supervision. After about six months with increasing dose levels, patients then continue with
a daily maintenance dose. Explain at a molecular and cellular level how oral immunotherapy
can reduce symptoms of peanut allergy.
In allergic indeviduals the dendritic cells present peanut antigens to naive Th cells and polarize them into Th2 cells that releases cytokines such as IL-4,5 and 13 that promotes IgE production by B cells isotype switching, recruitment of mast cells and eosinophils and the IgE binds to certain FC receptors on mast cells to sensitize them further to peanuts. Re exposure triggers mast cell degrnulation, release of histamine etc causing allergic symptoms.
When repetadly being exposed to the allergen the Treg gets activated and secrete IL-10 and TGF-B suporessing the Th2 driven inflammation and supressed the previously stated allergy driven responses. It also promotes IgG4 production instead of IgE which inhibits the IgE interaction and mast cell activation.
Antibodies of the IgA class play a central role in mucosal immune defenses. Explain how IgA
is transferred across mucosal membranes and what consequences this has for the structure
and function of IgA
IgA is important for mucosal immunity
They are first produced by antibodies as monomers, single units but become monomers when passing the mucosal tissues to work more efficiently called dimers
To get across the mucosal lining IgA binds to a receptor called pIgR found on the cells lining the tissue. They are then transported as a complex through the cells to the surface where the receptor is cut and the secretory component stays attached to IgA.
The secretory component protects IgA from being degraded and allows it to work in harsh environments like the gut.
When they form dimers they can attach better to harmful microbes and blocking these pathogens help maintain balance in gut microbiome.
