Inflammation part 2 Flashcards
what are the 5 steps of the inflammatory response
5 RS
recognition of injurious stimulus recruitment of leukocytes removal of the causative agent regulation of the response resolution of the response and repair
what is the first line of defence in recognising different pathogen
macrophages and dendritic cells
how many kinds of receptors do dendritic and macrophage cells have
several different types to recognise different pathogen associated molecular patterns (PAMPS)
what does PAMPS stand for
pathogen associated molecular patterns
what are TLRs
toll like receptors- a class of proteins which recognises PA,PS
what are TLRs made from
multiple leucine rich repeats
where are TLRs found
membrane associated proteins- some are found on the surface and some are endocytic vesicles
what do the endocytic TLrs detect
where they survey degraded particles of substances taken in by endocytosis
what does TLR5 recognise
flagellin- highly conserved constituent of bacterial flagella
what do bacterial genomes contain
highly methylated CPG oligonucleotides MOTIFS
what does TLR9 detect
highly methylated CPG oligonucleotides MOTIFS once it has been degraded in the lysosome
where is TLR9 found
in the endocytic vesicle
what TLRS are a dimer
TLR2 + TLR6
TLR1 +TLR2
what does TLR2 and TLR6 detect
diacylipopeptide
what do TLR1 and TLR2 detect
triacylipopeptide
what does TLR4 detect
lipopolysaccharide- found in gram -ve bacteria
where is TLR3 AND TLR7 found
inside the endocytic vesicle
what does TLR3 recognise
double stranded RNA
what does TLR7 recognise
single stranded RNA
What happens when TLR is activated
it sends a signal to the nucleus which activates transcription factors
where do viruses exist and replicate
in the cytosol
what are the two classes of receptors which recognise pathogens in the cytosol
NOD- nucleotide oligomerazation domain proteins
RNA helices domain and caspase recruitment domain- more importantly RIG-I
what does the NOD2 protein detect
bacterial proteoglycans of intracellular bacteria
what happens when the NOD2 receptor recognises its ligand
sends a signal to nucleus to activate transcription
what is the ligand of the NOD2 protein
muramyl dipeptide
what does RIG-I detect
double stranded rna which sends a signal to the nucleus
what happens when RIG-I is activated
sends a signal to the nucleus to produce type 1 interferon
what re the functions of a leukocyte
phagocytosis
secretion of microbicidal substances to remove extracellular inflammatory agent
release of extraceullar tramps eg NETosis
amplification of inflammatory response
what is NETosis
neutrophil-death through a different pathway than apoptosis or necrosis.
what can the secretion of microbicidal substances to remove extracellular inflammatory agent lead to
tissue damage
what is the key function of macrophages
to secrete pro inflammatory cytokines which then recruit further cells at the site of inflammation
what are the key players in amplification of inflammatory response
macrophages
what is NET
neutrophil extracellular traps
what is phagocytosis
recognition and attachment
engulfment
killing and degradation
what are microbes or dead cells recognised by in phagocytosis
direct or by opsonins
how does killing and degradation occur
by enzyme degradation and products of respiratory burst such as NO AND ROS
what is ROS in phagocytosis
reactive oxygen species
what is at the respiratory burst
a burst of activity where you get ROS AND NO into the intracellular space which are toxic molecules helps to kill pathogens
what is superoxide produced from
the oxidation of NADPH carried out by phagocyte oxidase
which enzyme carries out the oxidation of NADPH
phagocyte oxidase
what can superoxide be covered to
hydrogen peroxide and then hypochlorite by myeloperoxidase
what enzyme converts super chloride into hydrogen peroxide and hypochlorite
myeloperoxidase
WHERE IS MYELOPEROXIDASE FOUND
in cells with the myeloid lineage
what produces peroxynitrite
superoxide and nitric oxide
what can ROS cause
killing microbes but can also damage host cell injury
what is the pathological effects of ROS
LIPID PEROXIDATION- membrane damage
PROTEIN MODIFICATIONS- breakdown and misfolding
DNA DAMAGE leading to mutations
what enzymes are secreted from neutrophils azurophilic granules
neutrophil elastase
proteinase 3
cathespin G
WHAT EXTRACELLULAR ACTIVITY CAN OCCUR
Secretion of microbicidal substances: Secretion of enzymes release of lysosomal enzymes secretion of chemokines and cytokines NETosis
what is NETosis
the generation of neutrophil extracellular traps
what is NETosis stimulated by
microbes and inflammatory signals
what are the traps made from
nucleosomal DNA complex with histones which extrudes and produces a dense net of fibres which helps trap pathogens and materials
what does the trap also contain
lots of degrataive proteins such as myeloperoxidase cathepsin G elastase and LL37 Proteinase 3
what can end up happening to the neutrophil once they have released the trap
they die in the process
how does NETosis occur
- neutrophil is stimulated and results in the formation of NADPH oxidase and ROS production
- PAD4 is activated and the nuclear chromatin decondenses and the nuclear envelope loses its integrity
- NUCLEAR MATERIAL FILLS THE CELL AND MIXES WITH GRANULE CONTENT
- the plasma membrane ruptures and the nuclear chromatin associated with proteinases and histones is released into the extracellular space
what is PAD4
peptidyl arginine deiminase 4
what is responsible for the decondensation of the nuclear chromatin
PAD4- as it alters arginine AA in our histone complexes and changes them into another amino acid- citrulline
where has large quantities of NET been found
in purulent GCF exudate in periodontitis
what charge does arginine have
+vely charged AA
how does PAD4 alter the histone complex
as it alters arginine AA in our histone complexes and changes them into another amino acid- citrulline
what charge does citrulline have
neutral charge- change of electrostatic charges leads to the decondensation of nuclear chromatin
what enzyme degrades the NET
Serum nucleases
how is the net degredades
by serum nucleases and then macrophages dispose of the remaining net fragments
how do auto antibodies form
when all the net hasn’t been degraded which can eked to auto immune diseases such as RA
what are cell derived chemical mediators of inflammation
vasoactive amines arachidonic metabolites cytokines and chemokine lysosomal enzymes NO ROS
what are included in vasoactive amines
such as histamine/ seratonin which is found in granules
what does histamine do
vasodilation and vascular permeability
what are included in arachidonic metabolites
prostaglandins and leukotrienes
what are included in cytokines and chemonkines
TNF
IL1
IL6
CXCL8
what do arachidonic metabolites
vascular reactions and chemotaxis
what do cytokines and chemokine
leukocyte recruitment
give examples of lysosomal enzymes
Neutrophril elastase
Protinase 3
Collagensae
CG
what do lysosomal enzymes do
microbicidal and tissue injury
what are plasma protein derived chemical mediators of inflammation
complement proteins
coagulation proteins
kinins
what are coagulation proteins triggered by
activated factor XII
what is factor XII also known as
Hageman factor
how are plasma protein derived species released
they are released as zymogens and then are proteolytically cleaved to release the activated form when closer to the site
how are ROS removed
by anti oxidant molecules
which molecules induce the acute phase response
IL-1 beta
IL6
tnf alpha
what is a common blood test to see if people have an infection
is to check their serum CRP level
what molecules initiate the acute phase response WHICH HAVE SYSTEMIC EFFECTS
TNF
IL6
IL1
what do TNF, IL1.IL6 activate in the liver
acute phase proteins such as C reactive proteins
mannose binding lectin
what does the activation of C reactive protein and mannose binding lectin lead to
activation of complement opsonisation
what do TNF, IL1.IL6 activate in the bone marrow endothelium
neutrophil mobilisation
what does the activation of neutrophil mobilisation
phagocytosis
what do TNF, IL1.IL6 activate in the hypothalamus
increased body temp
what does increased body temp lead to
decreased viral and bacterial replication
increased antigen processing
increased specific immune response
what do TNF, IL1.IL6 activate in the fat muscle
protein and energy mobilisation to allow the increased body temperature
what do TNF, IL1.IL6 activate in the dendritic cells
TNF alpha stimulates migration to the lymph nodes to maturation
describe the CRP molecule
it is a pentraxin molecule and is a 5 sided shape
acts as an opsonin and activates complement
what are acute phase protein examples
CRP
mannose binding lectin
how are acute phase proteins released by the liver in relation to C reactive protein
- bacteria induce macrophages to produce IL6 which acts on hepatocytes to induce synthesis of APP
THIS CAN LEAD TO
C reactive proteins binds phosphocholine on bacterial surfaces acting as opsonin and activating complement
how are acute phase proteins released by the liver relating to mannose binding lectin
binds to mannose residues on bacterial surfaces acting as opsonins
what is involved in the family of leukotrienes
leukotriene A4
Leukotriene C4
leukotriene D4
leukotriene E4
what do Leukotriene C4, leukotriene D4, leukotriene E4 cause
brochospasm
and increased vascular permeability
what does prostacyclin PGI2 cause
Vasodilation and inhibit platelet aggregation increases fever and pain
what does thromboxane TXA2 cause
vasoCONSTRICTION and promotes platelet aggregation
what does cyclooxrgenase branch off into
prostaglandin G2—-> Prostagladin H2——> then to prostacyclin and thromboxane
where does the leukotriene family start from
arachidonic acid metabolising into 5 lipoxygenase
what are the two major branches of arachidonic acid metabolism
cyclooxygenases eg COX1 + COX2
5 lipoxygenase
what is the key pathway for arachidonic acid metabolism in neutrophils
the 5 lipoxygenase pathway
how are lipoxins A4 AND b4 formed
from the metabolism of 5 lipooxygenase into 12 lipoxygenase which then branches off into lipoxin A4 and lipoxin B4
what does Lipoxin A4 AND B4 DO
inhibits neutrophil adhesion and chemotaxis
what is the cyclooxygenases pathway inhibited by
anti inflammatory drugs non steroidal such as aspirin ibuprofen
how did we think that the resolution of the response and repair occurs
due to the loss of mediators and the signal switches off for inflammation but we NOW KNOW THIS IS NOT ENOUGH
what type of reaction is the resolution of inflammation
active regulated process
how does a tissue return to health state of homeostasis
a programme of initiation must be activated
what re the mediator molecules in acute inflammation
pro inflammatory cytokines and chemokine histamin prostaglandin leukotrienes thromboxane
what are the mediators in resolution
immunoresolvent such as IL10 Resolvins lipoxins protectins maresins
what is chronic inflammation
refers to an inflammatory response of prolonged duration, in which the following proceed simultaneously:
continuing inflammation
tissue injury caused by WBC
attempts at repair (often by fibrosis and angiogenesis)
what is fibrosis
the formation fibroblast cells in damaged tissue which generate connective tissue
what are the damaged specialised cells replaced with
non specialised cells so it can change the function of the tissue which is not a good thing
why might chronic inflammation occur
persistent infections
immune mediated inflammatory disease
prolonged exposure to toxic agents
key characteristics of chronic inflammation
Mononuclear cell infiltrate- macrophages
Tissue destruction
Granulomatous tissue
Fibrosis
what are the key features of acute inflammation
predominately neutrophils
what [athology might be present in dental abscesses
both chronic and acute inflammation
can chronic inflammation be present from the outset
yes for example RA where people have genetic predisposition for it
how are macrophages split up
they can be pro or anti inflammatory depending on how they are activated aka classically activated macrophage or alternatively activated macrophage RETROSPECTIVELY
what is IFN- gamma produced by
TH1C4 cell
how is the macrophage activated in the presence of IFN- gamma and microbes
classically activated macrophage M1
how is the macrophage activated in the presence of IL13 AND IL4
ALTERNATIVELY activated macrophage M2
what does the M1 macrophage release
leading to microbicidal actions: ros no lysosomal enzymes IL1 IL2 IL23 chemokines
what is IL13 AND IL4 produced by
TH2 cell
what does the M2 macrophage produce
growth factors and TGF beta
and IL10
what does TGF beta do
anti inflammatory effects and tissue repair
what type of action occurs between the lymphocytes and macrophages
bidirectional
what are the links between periodontitis and other diseases
athersclerosis
diabetes
RA
inflammation induced pregnancy complication
what does P gingivalis have
a PAD enzyme leading to citrullinated histone complexes
