trigger 4 - sepsis Flashcards
1
Q
which 2 signalling pathways lead to activation of NF-KappaB
A
classical (canonical) pathway
alternative (non-canonical) pathway
2
Q
IkB is degraded in the proteasome enabling NF-kB transcription factor to…..
A
… translocate to the nucleus and induce gene expression
3
Q
canonical signalling pathway
A
ligand binds to cell surface receptor (e.g. TLR)
recruitment of adaptors (e.g. TRAF) to cytoplasmic domain of receptor
adaptors recruit IKK complex
phosphorylation and degradation of IkB inhibitor
4
Q
when does non-canonical signalling pathway occur
A
during the development of lymphoid organs responsible for generating B and T lymphocytes
5
Q
process of non-canonical signalling pathway
A
ligand-induced activation
NF-kB inducing kinase (NIK) phosphorylates and activates IKKa complex
IKKa complex phosphorylates p100
p52/RelB heterodimer processed and liberated
6
Q
IKK complex
A
core element of NF-kB cascade
made of two kinases and a regulatory subunit
NEMO
IKKa
IKKB
7
Q
cytokines
A
regulatory molecules that coordinate immune responses
8
Q
mechanism of JAK/STAT signalling
A
- ligand binds (e.g. cytokine)
- receptor dimerisation activates JAK phosphorylation of receptor
- STAT binds to phosphorylated receptor
- JAK phosphorylates STAT
- STAT dimer forms
- STAT dimer travels to nucleus
- STAT dimer binds DNA and changes gene expression
9
Q
binding sites for STAT proteins
A
phosphotyrosine residues on the receptor proteins
10
Q
JAK
A
JAnus Kinase
11
Q
STAT
A
Signal Transducer and Activator of Transcription
12
Q
STAT proteins are latent transcription factors
A
they are always present in the cytoplasm waiting to be activated by JAK
13
Q
STAT dimer is an active transcription factor
A
travels to nucleus and binds to specific sequences in the DNA
14
Q
JAK inhibitors
A
drugs that inhibit the kinase activity of JAK
small molecule drugs
e.g. Ruxoltinib and Tofacitinib
15
Q
what processes does JAK activation stimulate
A
cell proliferation
cell differentiation
cell migration
apoptosis
16
Q
characteristics of cardiac muscle contractions
A
rapid
short duration
17
Q
calcium-calmodulin complex
A
activates myosin light chain kinase (MLCK)
18
Q
MLCK
A
phosphorylates myosin light chains in the presence of ATP
19
Q
myosin light chains
A
20-kD regulatory subunits found on the myosin heads
20
Q
MLC phosphorylation
A
leads to cross-bridge formation between the myosin heads and the actin filaments
therefore smooth muscle contraction
21
Q
reduced phosphorylation of MLC
A
VSM relaxation
22
Q
cause of reduced MLC phosphorylation
A
- reduced release of Calcium by the SR or reduced calcium entry into the cell
- inhibition of MLCK by increased cellular concentration of cAMP
- phosphatase-activated MLC dephosphorylation
23
Q
what regulates the degree of MLC phosphorylation
A
G-protein-couple signal transduction pathways
nitric oxide activation of guanylyl cyclase and cGMP formation
24
Q
the SR re-sequesters calcium
A
using ATP-dependant calcium pump
25
why is CSF testing used
to diagnose a disease affecting the CNS
26
how is a CSF sample collected
lumbar puncture or spinal tap
27
where is CSF formed
choroid plexus
28
MenB vaccine
routinely administered to babies
protects against Meningococcal group B bacteria
infections can cause meningitis and septicaemia
vaccine used is Bexsero
29
microorganisms causing meningitis and septicaemia
```
meningococcal
pneumococcal
haemophilus influenzae type B (Hib)
group A/B streptococcal
E. COli
listeria
salmonella
tuberculosis
```
30
what ligand causes JAK/STAT signallign
cytokines e.g. IFN-y, IFN-a
| growth hormone
31
important of commensal microorganisms
out-compete pathogenic bactera
provide vitamins
colonisation resistnace
32
effects of antibiotics on commensal bacteris
reduce their diversty
33
commensal microorganisms as cause of diesease
enogenous infection
switch role and cause disease in weak immune system
produce metabolites used by pathogens
34
overall effect of meningitis
inflammation of lungs and subarachinoid space and psinal cord
35
types of meningitis
bacterial - most severe
viral
non-infectious
recurrent/chronic
36
symptoms of meningitis
headache
fever
rash
sepsis
seizures
37
diagnosis of meningitis
CSF analysis - lumbar puncture
- looking for increased proteins, neutrophils and leukocytes
CT scan/MRI
38
treatment for viral meningitis
none
39
treatment for bacterial meningtisis
vaccines
| treatment of assocaited disorders
40
abnormal permeabiltiy of BBB
bacteria infect meninges
| systemic inflammation
41
mechanism of meningitis
bacteria colonise and penetrate mucosal membranes
invade CNS and multiply in subarachnoid space
release pro-inflammatory cytokines
swelling and increase in intracranial pressure
oedema
42
dendritic cell function
recognises and endocytoses PAMPs
antigen-presenting cell vis MHC
allows differenatiation o Th cells via cytokine release
links innate and adaptive immune system
43
dendritic cell structure
membrane folds allow maximum interaction with other immune cells
44
co-stimulation of T cells
required for full t cell activation
co-stimulatory molecules expressed by both T cell and APC
e..g CD28 binds to CD80
45
strucutre of eosinophils
bi-lobed nucleus
| small, pink cytoplasmic granules
46
function of eosinophils
mechanisms associated with allergies and asthma
| circulate in blood and migrate to inflammatory tissues
47
what do eosinophils produce
toxic cationtic proteins by degranulation
ROS
enzymes
cytokines
48
when/where do eosinophils develo
during haematopoiesis in bone marrow
| migrate to blood
49
mechanism of eosinophils
chemotaxis
target recognition via Fc receptors
phagocytosis
release destructive enzyme and granules
50
what do neutrophils respond to
cytokines
| released by mast cells and macrophages
51
3 ways neutrophils kill invading microorganisms
phagocytosis
production of ROS
Relase of cytotoxic granules
52
how does neutrophil recruitment increase inflammation
they release cytokines and chemokines
| e.g. IL-8
53
respiratory burst
rapid release of ROS from neutrophils
54
killing mechanisms of NK cells
release of granules containing perforin granzyme
fas/fas ligand - death signal - induces apoptosis
TRAIL - TNF-related apoptosis inducing ligand
ADCC - antibody dependent cell-mediated cytotoxicity
release of cytokiens
55
missing self hypothesis
NK cells recognise cells that have dont have MHC
| caspase killing pathway activated on infected cell
56
what do NK cells respond to
recognise and respond to MHC I on infected cells
57
what do monocytes differentiate into
macrophages or myeloid lineage dendritic cells
58
what are alarmins
endogenous molecules released during infection
often debris from dying cells
e.g. DAMPs
59
what are DAMPs
danger/damage associated molecular patterns
60
what recognises alarmins
PRRs on innate immune cells
61
release of alarmins from dendritic cells
active release
62
effect of alarmins on innate immune cell
causes release of pro-inflammatory cytokines
| e.g. IFN-y, IL-6, TNF-a
63
uses of alarmins in diagnossis
biomarkers of inflammation
64
examples of alarmins
heat shock proteins
fibrinogen
own DNA
hyaluronic acid
65
6 types of vaccine
```
live attenuated
toxoid
subunit
naked dna
inactivated
conjugated
```
66
live attenuated vaccines
weakened version of the microbe
long-term immunity
not good for immunocompromised patients
67
toxoid vaccines
iactivated bacterial toxins
no risk of infection
boosters required
68
subunit vaccines
fragments e.g. antigens of pathogen
reduced side effects
boosters required
takes time to identify specific antigen
69
naked dna vaccine
pure dna injected into patient
body makes proteins after injection
doesnt work well in humans
70
inactivated
pathogens grown in culture then killed by heating or exposure to chemicals
e..g formaldehyde
requires multiple doses
71
conjugated vaccines
the outer polysaccharide coat of bacterium
effective aganist coated antigens
no risk of infection
expensive to produce
72
challenges to vaccine production
antigenic variation
inadequate access - some countries are poor
high costs of vaccine development
risk safety - working with pathogens
73
antibiotic definition
chemical compound that targets essential growth processes against bacteria
74
when is a broad spectrum antibiotic useful
if you dont know the disease causing bacteria
| works against many bacteria
75
when is a narrow spectrum antibiotic useful
works well against specific bacteria
76
effects of bacteriostatic antibotics
total cell count plateaus
no cell growth
no cell death
77
bacteriocidal effecs
cell death
no cell lysis
total cell count remains the same
viable cell count decreases
78
bacteriolytic
cell death and cell lysis
| total cell count plummits
79
types of antibiotic
```
b-lactam
tetracyclin
sulfonamide
quinolone
macrolide
aminoglycoside
```
80
immediate treatment of sepsis/septic shock
antibiotics given intravenously
81
role of NF-kappaB
transcription factor that acts during infection to produce different cytokines
cytokines inititate inflammation and recruit immune cells
82
NF-kappaB held inactive by
IkB in cytoplasm
83
effect of intracellular ROS on NF-kappaB
causes upregulation of NF-kappaB and IKK
84
what are pro-inflammatory cytokines
signalling molecules released from immune cells during infection
secreted in response to PAMPs binding to PRRS
85
function of pr-inflammatory cytokines
activate T cells
antibody production
make diseases worse - inflammation, fever, tissue destruction
86
types of pro-inflammatory cytokines
interleukins
interferons
chemokines
87
what secretes IL-1B
Monocytes and macrophages in injured epithelial/fibroblasts
88
effects of IL-1B
fever
pain
inflammation
89
effects of INF-y
results in complement
| activates macrophages and phagocytosis
90
what secretes INF-y
lymphocytes
91
effects of IL-6
makes acute phase proteins from liver
| causes fever
92
effects of TNF-a
activates NF-kappaB
| activates macrophages
93
role of JAK-STAT
extracellular to intracellular signalling pathway
| leads to production of transcription factors
94
what is a tyrosine kinase
enzyme that can transfer a phosphate group from ATP to a protein in a cell
95
mutations in RTKs
means they can be activated without a ligand
| causes uncontrolled cell growth
96
what allows amplification of signals
kinase phosphorylation cascades
| e.g. MAPK, PIP3
97
2 biomarkers of inflammation
CRP and complement pathway
| ESR - erythrocyte sedimentation rate
98
CRP as a marker of inflammation
test blood plasma
levels rapidly increase after 2 hours - peak at 48 hours
levels increase following IL-6 secretion
normal crp < 1mg/L
99
what is CRP
c-reactive protein
produced by liver
found in blood plasma
100
what is ESR
erythrocyte sedimentation rate
| how fast RBC fall through column of blood
101
ESR as a biomarker
```
slow rate of ESR suggests inflammation
clumping seen if increased fibrinogen
sensitive test
non-specific
levels of fibrinogen may remain high for several days
```
102
normal ESR
men - 3 mm/h
| women 7 mm/h
103
what regulates smooth muscle contraction
autonomic NS (para and symp)
hormones
stretching
104
how is contraction transmitted from cell to cell in SM
via gap junctions
| they are low resistance and allow coordinated contraction
105
characteristics of SM contraction
Ca2+ binds to calmodulin instead of troponin
| MLCK is activated and phosphorylates light chain on myosin head
106
cross-bridge formation
myosin light chain is phosphorylated and binds to actin
107
sliding filament theory
myosin head (bound to actin) moves forward
new ATP molecules (ahead) binds to myosin head
old cross-bridge detaches
