CYTOKINES - THE GOOD AND THE BAD OF THE IMMUNE SYSTEM Flashcards
how do cytokines work (basic overview)
cytokines are soluble signals between cells
- cytokine producing cell gets induced stimulus
- produces cytokines
- gets released
- binds to cytokine receptor of target cell
- signalling cascade inside cell
- biological effects
what are cytokines?
which internal body systems do they regulate? (3)
- small proteins or glycoproteins
- act via specific receptors
- some are called interleukins (IL1-IL37)
- some are not (TNFa)
- *- influence innate immunity, adaptive immunity and haemotopoeisis**
what does it mean that cytokines have following charact.?
a) pleoitropy?
b) redudancy?
c) synergy?
d) antagonism?
with regards to distance - how can they work?
a) pleoitropy: a cytokine can have multiple effects
b) redudancy: different cytokines can do the same job
c) synergy: cytokines act together to cause an effect
d) antagonism: cytokines can have opposing effecrs
- can work autocrinally (self signalling), paracrinally (local siganlling) or endocrinally
what do the subfamily of cytokines, chemokines, involved specifically in/
- *involved in cell movement:**
- migration along a chemokine concetration gradients provide a directional movement (can be agaisnt or with gradient)
- signal using GPCR: can bind to multiple different chemokines
- small polypeptides
- control adhesion, chemotaxis and activation
how can cytokines promote or limit immune responses?
- can be inflammatory (IL-1, TNFa) or anti-inflam (IL-10, TGFb)
- good immune response will have an appopriate balance of these
explain the role of cytokines in acute inflammation
- damage and infection stimulates inflammation
- resident macrophages and injured tissues initiate inflam. response
- inflam cytokines and chemokines drive leukocyte recruitment
-neutrophils and moncytes come in and fight infection - T and B cells come in later
how do cytokines drive the recruitment of immune cells (when endothelium is damaged)? (3)
what do TNFa and chemokines do specifically?
-
tethering: cytokines make the lining the BV more sticky
* *2. rolling and activation:** chemokines activated adhesion molecules and allow rolling arrest
* *3 diapedesis & migraton:** cause cells to flow in to cells within tissues
- *TNFa**: increaes stickiness of endothelium by increasing expression of adhesion molecules:
- rapid release from Weibal-Palade bodies (WP) (adhesion molecules)
- new synthesis of TNF molecules
- *Chemokines:** activate adhesion molecules to increase binding
- causes rearangement of adhesion molecules on surface of cell, to bind more strongly to vessel wall.
how do cytokines work in T cells clonal expansion
- cytokine activation causes both production of IL-2 and expression of a high-affinity IL-2 receptor
- example of autocrine cytokine signalling
- IL-2 on T-cell receptor drives cell proliferation / clonal expansion
how do cytokines influence differentation of CD4+ T cells ?
how do cytokines made by t cells w?
- cytokines influence niave CD4+ cell (Th0) -> Th1 (due to IL-12) or Th2 (IL-4)
- Helper t cells make many cytokines that affect other cells:
- Th1 cells produce IFNy which activates macrophages (after binding with affected cell) to kill intracellular bacteria like Mycobacterium tubercolis
people with non-functional IFNy receptor are highly suscepitble to ?
mycobacterial infections
how do cytokines from T cells help B cells make antibodies?
- *- cytokines from T cells help B cells make antibodies:**
- provide signals from helper T cell, to make the differentation of B-cell -> Plasma cell
- cytokines from helper T cell also influence class switching (change on antibody production) (e.g IL-4 increases IgE).
how does the differential production of cytokines during leprosy infection influence the type of disease that develops?
Lepropsy exists as a disease spectrum: same bacteria that infects, but due to different cytokines produced, determines different outcomes
- one end = Tuberculoud leprosy, other end = Lepromatous leprosy
- *Tuberculoud leprosy:** Th1 (IFNy)
- macrophages activated, bacteria killed
- but, collateral damage occurs: nerve damage and loss of sensation,
- limb deformity
- *Lepromatous leprosy:** Th2 (IL-4)
- lots of antibodies; bacteria multiply
- massive bacterial load in tissues
what happens if anti-inflam IL-10 doesnt work? :(
IL-10 knock-out get intestinal inflammation due to gut bacteria: if receptors damaged may need bone transplantation
describe difference between local bacterial and widespread bacterial infection with regards to no. of cytokines produced
- *local bacterial infection:
- **local, controlled: production of TNF-a, IL-1 and IL-6 is GOOD
- causes fever, bone marrrow production of immune cells
- limited stimulation
- *widespread bacterial infection (sepsis)**
- ‘overstiumulation’ and septic shock of TNFa, IL-1 and IL-6 is BAD
- also can occur from superantigens: toxic shock syndrome
what is a cytokine storm?
which diseases does it occur in?
cytokine production becomes uncontrolled to a potentially fatal positive feedback loop:
- *- cytokine stimulates immune cell
- immune cell produces cytokine**
occurs in:
- ebola, SARs, bird flu, covid
how did TGN1412 @ Northwick park cause cytokine storm?
drug: TGN1412 - superagonist to CD28:
- idea was that would enhance regulatory T cell activity
- instead: caused massive activation of effector T cells: cytokine release and storm
what is difference between immune reponse in normal v asthma / allergy ?
normal:
- niave CD4+ T cell in presence of IL-4 = Th2 cell
- Th2 cell produces more IL-4, which induces B cell to class swich to make IgE
- IgE binds to mast cells, which, if comes into contact with antigen that induced B cells, causes degranulation
asthma:
- overproduction of IL-4 -> drives allergies and asthma
- its the release of the degranulation by mast cells that causes response
- if have an allergy: subsequent exposure are rapidly released (why get really quick response)
what causes chronic inflammation? e.g. in crohns disease?
chronic recruitment & activation of innate immune cells: Tissue damage
In Crohn’s disease:
- overprodution of IL-12 & IL-23: **amplified Th1 Cell
- causes increases ofIFNy and INFa**
= tissue damage
whats world population of incidence of immune disorders like?
e.g. Crohns disease?
worldwide increase in immune disorders
due to environment:
- children of immigrants have high Crohns disease (developing countries have low incidence, but developed has high incidence of Crohns)
what is hygiene hypothesis?
- David Strachan
- *-** being more hygienic may reduce protective exposures
- old friends, rather than pathogens may be critical
what is difference between amish and hutterite with hygiene H
- *Amish:**
- asthma and allergy prevalence 6-8 x lower
- altered innate immune cell populations and gene expression
- household dust: endotoxin levels 7x higher = PROTEC (in mouse model)
- *Hutterite:**
- NOT ABOVE
what are major challenges of administering cytokines in the clinic?
how are Interferon a and GM-CSF used?
- short half life - hard to attain an effective dose
- *Examples:
- **Interferon a: (aka Roferon); used for Hep B infection
- GM-CSF: (aka Leukine): used to stimulate production of myeloid cells after bone marrow transplantation
cytokines in the clinic:
- how do IFNa and IFNb work for anti-viral action?
2 administration of agents to block cytokines in vivo (e.g. agaisnt inflam. diseases)?
IFNa and IFNb work for anti-viral action:
- engagement of PRRs by viruses stimulates production of IFNs (IFNa & IFNb)
- IFNs induce a resistant state in adjacent cells
- Also increase MHC expression, activate NK cells etc
administration of agents to block cytokines in vivo (e.g. agaisnt inflam. diseases)
- can use monoclonal antibodies
- soluble receptors
- BUT redudancy is a major challenge when targeting many cytokines
what does anti-TNF therapy Infliximab treat?
complications with this?
Anti-TNFa (Infliximab therapy):
- major impact on treatment of Crohn’s disease, RA, psoriasis
- some patients dont respond
- some lose response
- potential complications with infections
