Samenvatting
CST samenvatting - minor DSDT
- Vak
- CST (CST)
- Instelling
- Universiteit Leiden (UL)
Samenvatting van de colleges van CST als onderdeel van de minor DSDT
[Meer zien]Voorbeeld 4 van de 43 pagina's
Voorbeeld 4 van de 43 pagina's
In winkelwagengesponsord bericht van onze partner
Voorbeeld van de inhoud
CytokinesCytokines and atherosclerosis
1. Bad function of the endothelial
Permeability, leukocyte migration, endothelial adhesion, leukocyte adhesion
2. Fatty streak
Adherence of white blood cells, SMC migration, Foam cell formation, T-cell
activation, platelet aggregation
3. Advanced lesion
Macrophage accumulation, Necrotic core, Cap containing fibroblasts
4. Plaque rupture
Cap thinning erosion, Platelet aggregation
Adaptive immune response in atherosclerosis: T cells
Influx of monocytes -> education of T cell -> migration of effector T cells specific for atheroma
antigens -> T-eff macrophage interaction
Intercellular signalling
Innate immune responses
o Chemokines between dendritic cells, monocytes and PMN : Disease associated
damage
Adaptive immune response
o Interleukins between macrophages, T-cells, dendritic cells and B-cells (T-cell -> B-cell)
Diseases
Atherosclerosis
Cytokine balance: pro- and anti-inflammatory
Rheumatoid arthritis
Bone erosion, swollen inflamed synovial membrane, cartilage wears away and reduced joint space
TNF-alpha, IL-1B
Multiple sclerosis
Myelin sheath, scarred myelin
TNF-alpha, IL-1B ( INF-B therapy)
Sepsis
TNF-alpha, IL-1B
Infectious diseases
TNF-alpha, IL-1B, IL-12, IL-17 and IL-10
Cancer
Immune system is not functioning appropriately ( little response on cancer cells/tissue, immune
suppression)
,IL-3 & IL-5 family
Receptors for IL3&5 and GM-CSF are heterodimers of a unique chain and the common beta chain (bc,
CD131) subunit.
IL-10 family
IL-10 family members are IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29, similarities in intron-exon
structure, types of receptors, they share common receptor subunits
IL-12 family
IL-12R consists of 2 subunits: IL-12Rb1 and IL-12Rb3
A heterodimer of IL-12Rb1 and IL-23R binds IL-23, IL-12Rb2 shows homology to the gp130 subunit of
IL-27R
Interferon family
IFN-a and IFN-b bind to the heterodimer receptor consisting of IFNAR1 and IFNAR2
IFN-b binds to IFNAR1, and IFN-g binds to the IFN-gR1 and IFN-gR2 heterodimer
Cooperation of IFN-gamma and TNF-alpha (Use distinct intracellular pathways)
Enhance each other’s cytotoxicity and induce CSF and G-CSF
Differentiation of monocytes, antiviral action, NO induction
Counteract each other’s function: brake on an inflammatory process
IL-10, IL-5, IL-13 and TGF-B (inhibitory)
Cytokines activation of cells
Binding to a specific cytokine receptor -> activation of intracellular pathways -> induces a change in
gene expression -> change in cell mobility, cytokine profile, cytotoxicity
Cooperation of JAKs 1-3, Tyk2 and STATS 1-6
JAK pathway
o Jak1 pathway
Interferons type I and II
Cytokines binding to a receptor containing gp130 (IL-6, IL-11, LIF)
Cytokines receptors containing the common receptor subunit yc (lL-2, lL-4,
lL-7,IL-9 and IL-15)
IL21R complex -> regulation of T,B and NK lymphocyte proliferation,
differentiation and survival
Jak1 deficiency -> severe neurological defects, reduction in the number of
lymphoid progenitor cells
o Jak2 pathway
EPO signaling through Jak2
Jak2 deficiency -> EPO signaling to severe, large impact on the formation of
red blood cells ( anemia, pale color)
o Jak3 pathway
Associated with the common cytokine receptor yc chain
Mutation in men results in X-linked severe combined
immunodeficiency (SCID)
Deficiency -> small thymus, no proliferation of peripheral T cells
, STAT pathway
STAT proteins are expresses ubiquitously ( large numbers throughout the body)
o Differential splicing (STAT1, STAT3, STAT4 and STAT6)
o Post-translational, proteolytic processing of the STATs (STAT5a and STAT5b)
STAT1
Activated by large number of cytokines:
interferons, IL-5, IL-6 and IL-10, growth factors EGF, PDGF and
insulin
STAT2
Involved in type I interferon signal transduction
STAT3
Activated by cytokines and has a role outside of the immune system
Deficiency -> neutrophils & macrophages do not respond properly to
IL-10, also deficient wound healing
STAT4
Activation by IL-12, expressed in myeloid cells, thymus and testis
Deficiency -> not able to build up high IFN-gamma levels in response
to IL-12 -> deficient activation of Th1 cells
STAT5a & 5b
Activated by IL-2 family members
Single deficiency -> defects in immune system ( deficiency in IL-2
induction of IL-2Ra expression)
STAT6
Activated in response to IL-4 & IL-13 (IL-4 receptor a chain: multiple
binding sites for STAT6)
Deficiency -> No Th2 differentiation, lower B cell responses
SOCS
Suppressor of cytokine signaling, SHUT down the immune response (comparable to IL-10)
o SOCS-1 inhibits the signal transduction by binding directly to JAK
o SOCS-3 inhibits the function of JAK by binding to the Src homology phosphatase-2
(SHP-2)- binding domain of gp130 (and the EPORs)
SOCS1
Inhibits IL-4, IL-6 and IFNs induced activation -> binds to JAK2
Deficiency -> marked growth retardation, fatty liver,
lymphocytopenia, organ failure with inflammation
SOCS2
Interaction with the activated IGF-1 receptor
Bind to the SHP-2 binding site of activated GH receptors -> Inhibit
the activation of STAT5b induced by GH
Deficiency -> Interference with the action of growth hormones GH
and IGF-1 leading to gigantism, collagen deposition in the lungs
SOCS3
Inhibits the action of JAK in the presence of receptors gp130
Deficiency -> contradictory results
, Signaling by kinases/phosphatases
Phosphatases effect the interaction, which is important for signaling, regulates localization which
effects the interaction were it will bind -> effects its functionality, structure and activity
Two types of protein phosphorylating kinases: Serine/threonine and tyrosine kinases
Tyrosine-specific protein kinases
RTKs
o EGFR: Epidermal growth factor
o PDGF: Platelet derived growth factor
o C-MET: Hepatocyte growth factor
o IGF1R: Insulin-like growth factor
Non-RTKs
o c-Src
o Lck, Fyn: Src family members
o FAK: focal adhesion kinase
They have an extracellular domain to receive signals from growth factors or bacteria to interact with
receptor or another cell. They have all a different motive for their specificity. Inside they have a
kinase domain, there are differences in the part which are not kinase, to know how to interact.
Three layers in signal transduction:
- Input layer Ligands and receptors
- Signaling processing layer Kinases, substrates, adaptors, transcription factors
- Output layer Cell biological consequences
EGFR (ErbB1) tyrosine kinase receptor
N-terminal ectodomain binds EGF
Transmembrane domain
Cytoplasmic domain with Src homology region
C-terminal tail
EGFR has 4 family members and form dimers (homo & hetero), ErbB3 binds a neuroligand and has no
kinase domain, it will combine with others for ligand specificity, ErB2 is often overexpressed in breast
cancer. The main pathway which are activated are the MAPK-ERK and PI3K/AKT pathway
EGFR signaling in cancer
1. Increased expression of EGFR protein
2. Ligand/autocrine loop which produce EGF
3. Heterodimerization and crosstalk -> ErbB3 result in more effectiveness
4. Decreased phosphatase -> no inactivation possible
5. Mutant EGFR, selection for mutation to be independent on EGF -> easier activated
Normal: Ligand dependent firing, Mutation: Ligand independent firing
EGF stimulation results in internalization of EGFR, it moves into the cell and leads to endocytosis
Internalization brings it to the proteasome for lysosomal EGFR degradation. The dimers will bind tight
together if they bind EGF, more EGFR will be phosphorylated and lead to phosphorylated AKT & ERK
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