Flashcards
Cytokines - the good and the bad of the immune system
Cards in this deck (47)
- 1What regulates the response of the immune system?Controlled expression of cytokines and their specific receptors
- 2What are the three things which cytokines influence?1) Innate immunity
2) Adaptive immunity
3) Haematopoiesis - 3What are the four attributes of cytokines?1) Pleiotropy - a cytokine can have multiple effects
2) Redundancy - different cytokines can do the same job
3) Synergy - cytokines act together to cause an effect
4) Antagonism - cytokines can also have opposing effects - 4What does redundancy make difficult?Targeting a specific cytokine in a disease
- 5What are chemokines?A subfamily of cytokines involved in cell movement
- 6How big are chemokines? How do they signal? What do they control? (3)1) Small polypeptides (90-130aa)
2) Signal through GPCR
3) Cell adhesion, chemotaxis, activation - 7What causes the redundancy in the chemokine system? How can viruses interfere?1) Many receptors respond to more than one chemokine
2) Some pathogens have evolved their own chemokine receptors which interferes with chemokine signaling - 8Name 3 inflammatory cytokines? What do they promote?1) IL-1, TNFa, IL6 - promote immune activity
- 9Name two anti-inflammatory cytokines - what do they promote?1) IL-10, TGF-B - primarily regulatory
- 10What initiates an inflammatory response to infected tissue?Resident tissue macrophages
- 11What drives leukocyte recruitment?Inflammatory cytokines and chemokines
- 12Which cytokines and chemokines are secreted by resident macrophages in infected tissue?TNF-a (cytokine) and CXCL8 (IL-8; chemokine)
- 13What are the stages of chemotaxis? (401) Tethering
2) Rolling and activation
3) Arrest
4) Diapedesis and migration - 14What role do cytokines play in chemotaxis - give an exampleIncrease stickiness of endothelium - i.e. through upregulation of selectins (TNF-a)
- 15What role do chemokines play in chemotaxis? (2) Give an example1) Can upregulate/activate adhesion molecules to allow arrest and influence the position of cells within tissue.
2) IL-8 for neutrophil recruitment - 16Where are adhesion molecules released from in response to TNF-a? (2)1) Either pre-made in Weibel-Palade bodies for rapid expression within minutes
2) Newly synthesised - takes longer - 17What causes a given family to particularly susceptible to developing mycobacterial infections?Mutation in macrophage cytokine receptor which prevents it from responding to IFN-y secreted by Th1.
- 18What is the collateral damage which occurs in tuberculoid leprosy?Macrophages activated by secretion of IFN-y by Th1 successfully kills the bacteria but results in collateral damage - nerve damage and consequent loss of sensation along with limb deformity.
- 19What is the bacteria which cause leprosy?Mycobacterium leporine
- 20What happens to mice which can't produce IL-10 (KO)? What happens in humans? How is this treated?1) Get spontaneously sick due to intestinal inflammation driven by gut bacteria
2) People with mutations in IL-10 receptor genes develop very severe gut inflammation very early in life
3) Bone marrow transplant - 21Which cytokines can activated endothelium secrete? (3)1) TNF-a
2) IL-1
3) IL-6 - 22What benefits does controlled widespread cytokine secretion cause? (3)1) Fever
2) Acute phase proteins - like C reactive proteins and mannose binding lectin which results in soluble pattern recognition
3) Stimulation of immune cell production in the bone marrow - 23What are the deleterious effects of uncontrolled systemic TNFa?Septic shock:
1) Loss of blood pressure
2) Fever
3) Diarrhea
4) Clotting
5) Death - 24What can cause toxic shock syndrome? (2)1) Overwhelming bacterial infection
2) Superantigens - antigens which activate many different T cells and drive the overproduction of cytokines - 25What is a cytokine storm?When cytokine production becomes uncontrolled, a potentially fatal positive feedback loop can become establish leading to a cytokine storm. I.e. cytokine stimulates immune cell, immune cell produces cytokine, feedback.
- 26Give three examples of viral infection which can cause cytokine storms.1) Ebola
2) SARS
3) Bird flu - 27What happened in the TGN1412 drug trial at Northwick Park in March 2006? What is TGN1412?1) Six volunteers, induced a cytokine storm, caused systemic inflammation and organ failure. Somehow caused massive activation of the effector cell population.
2) Costimulatory Ab at CD28, superagonist, preclinical studies had suggested that it selectively activated regulatory cells. Thought it could potentially be useful for the treatment of rheumatoid arthritis. - 28What three things cause type I hypersensitivity?Il-4, Th2 and IgE.
- 29What underlies allergies?Possible increased Th2 system and increased levels of IgE in response to allergen. IgE is then bound to allergen. IgE binds to mast cells. When the allergen is encountered again this results in mass degranulation
- 30What underlies Crohn's disease?Overproduction of Th1 cytokines (IFN-y, TNFa) leads to chronic inflammation & activation of innate immune cells resulting in tissue damage.
- 31With reference to Crohn's disease, give a reason why the increase in diseases caused by overactivity of the immune system is thought to be due to an environmental, not genetic, factor.Children of immigrants to areas with a high incidence of Crohn's disease have the same likelihood of developing the disease as the native population.
- 32What was studied by Stein et al 2016?Looked at prevalence of allergies and asthma in the amish and hutterite populations (genetically very similar). Asthma/allergy prevalence in the amish was 6-8X lower. Altered innate immune cell population and expression.
- 33What were the features of household dust in the amish community? (3)1) Endotoxin levels were 7X higher
2) Distinct microbes
3) Inhibits asthma in mouse model - 34How does bacterial exposure relate to cancer prognosis?How well cancer patients respond to checkpoint drugs depends on their bacterial exposure and immune activity.
- 35What are the major challenges regarding the administration of cytokines in the clinic? (2)1) Short half-lives in vivo
2) Attaining the correct effective dose - 36What is the half-life for IL-2 in vivo?7-10 minutes
- 37Give two examples of cytokines which are used in the clinic.1) IFN-a: Roferon, used in treatment of Hep B infection and some cancers
2) GM-CSF: Leukine, used to stimulate production of myeloid cells after bone marrow transplantation - 38What are the antiviral actions of IFN-a and IFN-B? (3)1) Increase MHC expression
2) Activate NK cells
3) Induce a resistant state in adjacent cells - 39What stimulates the production of IFNs in response to viruses?Engagement of PRRs - plasmacytoid DC are particularly good at this
- 40What are the two different ways in which cytokines can be blocked in vivo? Give an example for each1) Monoclonal antibodies - Anti-TNF-a; infliximab
2) Soluble receptors - TNF-a receptor; Etanercept - 41What are the different suffixes of monoclonal antibodies used to block cytokines? (4)1) -omab is mouse
2) -ximab has a mouse sequence in the variable region
3) -zumab has mouse complementary determining regions
4) -umab is human - 42What does the complementary determining region determine?Antigen binding
- 43What is infliximab used to treat? (3)Crohn's disease, rheumatoid arthritis, psoriasis
- 44What are the different patient responses to infliximab/cytokine therapies? (3)1) Some patients don't respond
2) Some lose response
3) Potential complications with infection and malignancy - 45What are fistulae?Essentially tracts of inflammation which from from the inflamed gut to the skin
- 46What may underlie loss of response?Cytokine redundancy
- 471. Cytokines facilitate communication in the immune system 2. Local, controlled production of a small amount of cytokine is good 3. Uncontrolled, overproduction of large amounts of cytokine can be very bad 4. Diseases of excessive immune activity & cytokine production are a feature of the modern world 5. In the clinic, cytokines can be administered or their activities targeted in vivo. 6. Anti-TNFα therapy has been very successful in a number of inflammatory conditionsX