-
physical findings at 4 levels in which inflammation encompasses
- 1) clinical
- 2) physiological
- 3) cellular
- 4) molecular
-
clinical level of inflammation
- redness and swelling with heat and pain
- +loss of function
-
consists of T & B cells which recognize antigen and produce killer cells & antibodies
adaptive immune system
-
consists of everything other than T/B cells and includes cells that mediate inflammation
innate immune system
-
type of information inflammatory cells provide to T cells
antigenic information
-
function of immune cells
provide essential signals to inflammatory cells
-
what is inflammation mediated by
by cells of the innate immune system
-
Janeway's definition of the immune system
ancient pathogenic molecules that are conserved are the driving force behind inflammation
-
PAMPs
- pathogen associated molecular patters
- associated with Janeway's definition
-
Matzinger's definition of the immune system
- Danger Model
- the immune system (and cells that mediate inflammation) is concerned primarily with danger signals rather than issues of self and non-self
-
in which model would it be as likely that a damaged tissue would elicit inflammation as an infection?
Matzinger's
-
discovery of the inflammasome and its ability to illicit pro-inflammatory cytokine secretion supports which model?
Matzinger's
-
central to autoimmune disease such as type 1 diabetes
self antigens
-
useful for explaining how infection is handled
PAMP danger signals
-
useful for explaining how inflammation underlies non-immunological diseases such as atherosclerosis and type 2 diabetes
danger signals
-
3 issues sufficient to elicit an inflammatory response
- 1) infection
- 2) trauma
- 3) toxicity
-
detected via pattern recognition receptors that recognize Janeway's PAMPs and by antigens recognized by T cells
infection
-
sentinel cells
dendritic cells, macrophages
-
results in overt tissue damage including the rupture of blood vessels that exposes basement membrane
trauma
-
binds to components of the basement membrane and begin to form a clot and secrete inflammatory mediators
platelets
-
intracellular components released during necrosis that act as inflammatory signals (2)
-
buildup of ROS intermediates in the cell leads to activation of an intracellular receptor called the ___.
inflammasome
-
initiates a signal transduction process that results in the secretion of inflammatory mediators
inflammasome
-
cytokine inflammatory mediators (4)
- IL-1
- IL-6
- IL-8
- TNF
-
4 types of inflammatory mediators
- 1) cytokines
- 2) chemokines
- 3) growth factors
- 4) autacoids
-
signaling molecules that recruit inflammatory cells and provide a "bread crumb" trail back to the site of injury
inflammatory mediators
-
how inflammatory mediators prepare for incoming inflammatory cells (3)
- 1) slow blood flow in the area (relax vascular smooth muscle)
- 2) decrease integrity of vessel walls to allow fluid/cells to move in (edema)
- 3) degrade ECM to allow access
-
means "local hormone"
autacoid
-
family of molecules that provide inflammatory signals in a local area
autacoids
-
8 types of autacoids
- 1) prostaglandins
- 2) thromboxanes
- 3) leukotrienes
- 4) histamine
- 5) serotonin
- 6) bradykinin
- 7) platelet activating factor (PAF)
- 8) NO
-
expressed on the surface of the vessel wall to which circulating inflammatory cells bind during the vascular response
CAMs - cell adhesion molecules
-
secreted to break down collagen during the vascular response
matrix metalloproteinases
-
takes place later in the vascular response if there is damaged tissue that needs to be repaired
angiogenesis
-
produce the sensation of pain associated with inflammation when released during the neurogenic response (2)
- 1) substance P
- 2) CGRP (calcitonin gene related peptide)
-
can induce vascular leakage in the absence of infection or trauma
neurogenic inflammation
-
circulating cells that adhere to regions expressing CAMs
neutrophils and monocytes
-
differentiate into macrophages during extravasation
monocytes
-
extravasation/diapedesis
neuts/monos squeeze through holes between vascular endothelial cells and follow the chemokine gradient leading to the site of damage
-
process during which phagocytic cells become 10x better at engulfing
activation
-
process during which the MHC is upregulated
activation
-
holds onto peptides to present to T cells as antigens
MHC
-
process during which complement proteins are expressed and secreted
activation
-
process during which enzymes which generate reactive molecules (peroxides) are expressed and release said reactive molecules
activation
-
activated by a cascade of protein cleavage events where the cleaved protein fragments assemble to form the MAC
complement system
-
4 purposes of the complement system
- 1) drill holes in the cell walls of pathogens/transformed cells
- 2) coat pathogens to increase adhesiveness for phagocytosis
- 3) serve as chemokines
- 4) assist in the removal of dead blood cells
-
3 systemic responses of inflammatory mediators to inflammation
- 1) travel to liver to promote expression of acute phase proteins
- 2) travel to bone marrow to increase rate of production of inflam. cells
- 3) travel to brain to induce fever, activate hypothalamus to induce cortisol secretion
-
negative regulator of inflammation
cortisol
-
4 types of granulocytes
- 1) neutrophils
- 2) eosinophils
- 3) mast cells
- 4) basophils
-
granulocytes with multilobed nucleus
neutrophils
-
granulocytes with bilobed nucleus
eosinophils
-
granulocytes (2 types) with lobed nucleus and heavily granulated cytoplasm
mast cells and basophils
-
most common granulocytes & percentage of WBCs
-
phagocytic granulocytes
neutrophils, eosinophils
-
secondary function of granulocytes
release of pyrogens to raise body T/cause fever
-
first of granulocytes to respond/arrive at the site of infection
neutrophils
-
leukocytosis
presence of an increased number of neutrophils
-
length of time neutrophils reside in a tissue
~1 day
-
major role of eosinophils
fight against parasitic organisms - granules damage parasite membrane
-
major roles of basophils
- fight helminth infections
- certain allergic reactions
-
what do basophil granules contain?
- heparin
- histamine
- serotonin
-
type of granulocyte that does not circulate in the blood
mast cells
-
major roles of mast cells
- important mediators of allergy
- fighting pathogens (viruses, bacteria, parasites)
- tissue remodeling, wound healing, angiogenesis
-
characteristics that distinguish tissue macrophages from monocytes
- -10x larger
- -increased phagocytic capacity
- -increased number/complexity of intracellular organelles
- -produce higher levels of hydrolytic enzymes
- -secrete soluble factors
-
histiocyte
connective tissue specific macrophage
-
Kupffer cell
liver specific macrophage
-
mesangial cell
kidney specific macrophage
-
microglial cell
brain specific macrophage
-
macrophages express _____ which bind to _____.
-
M1
classically activated macrophages
-
M2
alternatively activated macrophages
-
implications of the presence of M2-like macrophages in cancer
poor prognosis prediction
-
factors in platelets that promote clotting/wound healing (4)
- 1) serotonin
- 2) epinephrine
- 3) fibrinogen
- 4) PDGF (platelet derived GF)
-
how platelets are activated
by contact with tissue collagen, air, or foreign surfaces
-
4 major types of dendritic cells (DC)
- 1) LangerhansÂ
- 2) interstitial
- 3) monocyte-derived
- 4) plasmacytoid-derived
-
general role of DCs
gather info and transport it where it is needed (encoded as an antigen)
-
DC that resides in epidermal layers of the skin, shuttles to lymph nodes
Langerhans DC
-
DC found in the interstitial spaces of almost all internal organs (except brain)
interstitial DC
-
highly mobile DC
monocyte-derived DC
-
DC that plays roles in innate response and as APCs
plasmacytoid-derived DC
-
virtually all genes related to the inflammatory response are targets for this TF
NF- B
-
NF- B mechanism of action
bound inhibitor I BÂ phosphorylated by IKK & becomes ubiquitinated -> degraded by proteasome to expose nuclear localization signal -> translocated to nucleus & activates genes involved in inflammation/immune response
-
how glucocorticoids inhibit inflammation
transcriptional repression
-
process in which glucocorticoid receptor binds to other proteins that had themselves bound to DNA, in order to repress NF- B
transrepression
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