Innate Immunity Activation Lecture Flashcards
Innate defensive components:
Anatomic & physical barriers
effectors: skin, mucous membranes, temperature, acidic pH, lactic acid, chemical mediators
Innate defensive components:
Immune cells
effectors Granulocytes: phagocytosis, release of mediators. macrophages: phagocytosis, release of mediators, Ag presentation
Innate defensive components:
Inflammatory mediators
effectors: complement, cytokines, lysozyme, acute-phase proteins, leukotrienes and prostaglandins
function: lysis of pathogens, activation of immune cells
bacterial cells wall destruction
mediation of reponse
vasodilation, vascular perm.
Skin: mechanical/Chemical/Microbiological roles
M: flow of fluid, perspiration, sloughing off skin
C: Sebum (contains fatty acids, lactic acid, lysozyme)
M: normal flora of the skin
Gastrointestinal tract: mechanical/Chemical/Microbiological roles
M: Flow of fluid, mucus, food and saliva
C: acidity, protease enzymes
M: normal flora of the GI
Resp. Tract: mech/chem/micrbio roles
M: flow of fluid, mucus, cilia by air flow
C: lysozyme in nasal secretions
M: normal flora of rest t.
Urogenital tract
M: flow of fluid, urine, mucus, sperm
C: acidity in vaginal secretions/sperm
M: normal flora
Eyes
M: flow of fluid
C: lysozyme in tears
M: normal flora of the eyes
“natural immunity” is associated with which aspect of the immune system?
innate
What does “PRP” represent for innate immunity?
Phagocytosis
Recruitment
Presentation
Neutrophils: high lighted points
1) first cells to arrive at site of tissue damage
2) activation leads to respiratory burst and release of granules to control bacterial growth
Macrophages: high lighted points
Engulf organisms
Release inflammatory mediators
THEY DO NOT LEAVE THE TISSUES
Eosinophils: high lighted points
contain cationic granules (basic protein, peroxidases, antimicrobial proteins)
fight HELMINTHES and multicellular parasites
NK cells: high lighted points
large, granular lymphocytes that kill infected host cells by cytolytic mediator perforin
Neutrophils and Monocytes
Where they arive, how they get to sites of inflammation/infection
they arise in bone marrow
they are ready to be activated, and do not require activation
How do neuts and monocytes physically access tissues where they are recruited?
they are recruited through post-capillary venules EXCEPT for parenchymal tissues like lungs, liver, kidneys
where all WBCs enter through capillaries
name the 3 functions of myeloid leukocytes
elimination of infectious pathogens
clear dead tissues
repair the damage
“how neutrophils come into the tissues”
inflammation activated endothelial cells express which selectins? and in response to what?
E and P selectin
P selectin arises in response to histamine
E selectin arises in response to IL-1 and TNF from Macrophages
both P and E are used by monocytes and neutrophils
“how neutrophils come into the tissues”
Chemotaxis the 4 general steps
1) Neutrophils “slow down and roll” along endothelium
i. selectin-selectin co receptor interactions
2) tight binding
i. integrins (on leukocytes) and integrin ligands (on
endothelia)
3) Diapedesis
i. transmigration through endothelium
4) Chemoattractant controls migration (IL-8 controls neutrophil migration to inflammatory sites)
LFA-1
What is it?
What is its receptor?
neutrophil integrin (low affinity integrin-1)
its affinity for its ligand increases as chemokine IL-8 binds to chemoattractant receptor on cell
ICAM-I is LFA-1’s receptor
ICAM-1
neutrophil integrin LFA-1’s endothelia receptor
Transmigration of Leukocytes “big” picture steps
1) capture: mediated by selectin
2) rolling: mediated by selectin
3) activation: IL-8 (neutrophils), MCP-1 (monocytes)
4) arrest: VCAM-1 (Baso/Eosino/Mono), ICAM-1 (neutro)
5) firm adhesion VCAM-1, ICAM-!
6) transmigration
IL-8
mast cell released chemoattractant for neutrophils
ICAM-1
endothelial neutrophil integrin receptor (LFA-1)
LFA-1
neutrophil integrin
VCAM-1
integrin receptor for lymphocytes, baso/eosino/monocytes
MCP-1
monocyte chemoattractant, secreted by macrophages apparently
neutrophil/monocyte capture is regulated by
selectins
neuto
neutrophil rolling is regulated by
selectins
neutrophil activation is regulated by
chemokines IL-8 for neuts and MCP-1 for monocytes
neutrophil/monocyte arrest
achieved by integrin/receptor interactions
integrins are on the neuts/monos, receptors like ICAM-1 and VCAM-1 are on the endothelia
Cathepsin G
released by neutrophils
cationic protein, a serine protease that digests collagen and proteoglycans
Lysozyme
released by neutrophils
splits mucopeptide in bacterial cell wall
Lactoferrin
released by neutrophils
bacteriostatic protein
complexs with iron
Defensins
released by neutrophils
cationic (rich in Arg): antibiotic peptides
- inserts into microbial membranes –> destabilizes ion channels
what pathogens are defensins good against?
gram +/- pathogens, fungi, enveloped viruses
BPI
bacterial permeability increasing protein
released by neutrophils
Transmigration of MONOCYTES (not neutrophils)
rolling, adhesion, and diapedesis (steps 1-3) are the same for monocytes as for neuts
chemoattractants for monocytes are
Macrophage inflammatory protein-1alpha/beta (MIPs)
Monocyte chemoattractant protein-1 (MCPs)
what do monocytes do after entering tissues?
they mature into tissue macrophages
M1
what, what do they do
classical macs: activated by IFN-gamma to destroy pathogens
secrete cytokines IL-1, 12, 23 (inflammation)
Possess intracellular microbicidal actions (ROS, NO etc)
M2
Anti-inflammatory macs
secrete IL-10 and TGE-beta to prevent the effects of IL-1 and IL-12 and IL-23 chemokines from initiating inflammation
prolines, polyamines, TGF-beta for wound repair, fibrosis)
what chemokines are responsible for inflammation in M1s? how are they suppressed?
IL-1, 12, and 23
by IL-10 from M2s
TGF-beta
M2
suppresses the effects of M1’s cytokine output (IL-1, 12, 23) and initiated wound repair by attracting fibroblasts
what cytokines induce M2?
IL-4 and IL-13
what induces M1?
TLRs and IFN-gamma
PRR triggered responses in neutrophils and MO
what is a substrate present in prokaryotes that aren’t in eukaryotes
fMet
N-formylmethionyl peptide
who recognizes fMet and what do they do
polymorphonuclear cells, they initiated phagocytosis
what is the functional outcome of fMet recognition
cytokins/chemokines signal to the endothelia for recruitment, then migration
Mannose receptor results in
both phagocytosis and cytokine production
Ligands/functions/PRRs
C type lectin (protein family)
mannose receptor on mac, phag
Scavenger receptors: name two and their ligands
SR-AI, SR AII
bind to anionic polymers
macs, phag
TLRs (again) 5 goes to…..
bacterial flaggela
for whom are PRRs the most important? neutrophils or macs?
Macs
NK cells: direct and indirect involvement
directly kill after recognition, indirectly kill by activating macs with IFN-gamma
what activates NK cells?
IL-12
NK cells: how they find their targets
two receptors, activating and inhibitory receptors
Inhibitory receptor on NK cells: how
inhibitory receptor is composed of two signals = normal expression of MHC 1 + “activating ligand for NK cell”
if there’s a change in MHC I, the activation signal is left to activate the NK cell
ADCC
antibody dependent cellular cytotoxicity
Healthy cell activating receptors on NK cells
reduce this fucker to its simplest explanation
recognize ligands on target cells which activate the protein tyrosine kinase (PTK)
PTK is inhibited by inhibitory receptors that recognie class MHC molecules and activate protein tyrosine phosphatase (PTP)
the inhibitory signals cause PTP to DE-phosphorylate PTK, which prevents PTV from sending the activation signal from its extracellular ligand
PTP and PTK
PTP prevents PTK from sending a signal inside natural killer cells
PTK
sends activating signals inside the cell
what happens in virus infected cells?
the inhibitory signal sent by MHC isn’t send, and the NK is activated
