Innate Immunity Flashcards
Skin barriers
Longitudinal air flow
Fatty acids
Beta-defensins
Gut barriers
Longitduainl air flow
Low pH
Pepsin
Alpha-defensins
Lung barriers
Movement of cilia Pulmonary surfactant (chemical) Alpha-defensins
Eyes/nose/oral cavity barriers
Tears/nasal cilia (mechan)
Lysozyme in tears
Beta-defensins
What do all surfaces share as a barrier?
Epithelial tight junction and normal microbia
How does lysozyme break down bacteria?
Can eat through peptidoglycan and exposes cell membrane …particularly effective for gram-positive
How do defensins work?
Electrostatically (positive charge) attracted to the membrane and brought into the lipid bilayer to form a pore
Defensins produced by
Epithelial cells and macrophages
TLRs on plasma membrane (subunits and what they recognize)
Diacyl lipopeptides (TLR2/TLR6)
Triacyl lipopeptides (TLR2/TLR1)
Flagellin (TLR-5)
LPS (TLR4)
Lipopeptides mostly be gram-positive bacteria
LPS mostly from gram-negative bacteria
Endosomal TLRs and what they recognize
dsRNA (TLR3)
ssRNA (TLR7)
ssRNA (TLR8)
CpG DNA (TLR9)
All viral except CpG which can also recognize bacteria
Plasma membrane TLR pathway
Dimers form when PAMP encountered…MyD88 binds to receptor…IRAK4 recruited (kinase that phosphorylates stuff)…NFkB activated (regulatory unit removed and complex made of p65 and p50 now free)…goes to nucleus and transcirbe cytokine genes
Which doesn’t use MyD88
TLR 3
TLR 3 pathway
Eventually uses IRF3 that induces type 1 interferon genes
All of TLR endosomal pathway except TLR 3
Uses MyD88…Activates IRF7 and goes induces type 1 interferon genes
NOD proteins
Activated when it binds to intracellular bactera…NFkB moves to nucleus and increases cytokine production
NLRP proteins
Type of NOD protein
Activated by toxins that cause efflux of potassium ions
Form inflammasome…activates caspase 1…that activates IL-1B and IL-18…these are acute phase proteins that involved in sepsis and activation of immunity
RIG-like receptors
Recognize uncapped RNA with 5’-triphosphate group…recognized by RIG or MDA-5…produce IRF-3 and NFkB activation (type 1 interferon and cytokines)
STING receptor
In ER
Recpgnizes c-di-GMP and c-di-AMP from bacteria…dowstream effect is IRF3 (type 1 interferon)
TNF source and target
Macrophages and T cells
Endothelial cells, neutrophils, hypothal (fever), fat (cachexia) and many cell types (apoptosis)
IL1 source and target
Macro, endo, some epithel
Endothel, hypothal, liver, T cells (TH17 differentiation)
IL1 activated by
Inflammasome
IL 6 source and target
Macro, endo, T cells
Liver, B cells, T cells (TH17 differenatiation)
IL 12 source and target
Macro, dendritic T cells (TH1 differentiation), NK cells and T cells (interferon gamma synthesis, increased CD8 activity)
Type 1 interferons source and target
IFN alpha and beta
source - alpha - macro, plasmacytoid dendritic cells
beta - fibroblasts
Act on - all cells (increase MHC class 1 expression for viruses ), activate NK cells
Chemokine type receptor and example
IL-8
G-protein domain
SCID mutation
X-linked mutation in gamma hematopoietin receptor
Cytokine receptors
2 chains using JAK-STAT pathway…STAT moves to nucleus to initiate gene trascription
Macrophage receptors
Mannose - bacteria
Dectin-1 - for fungal B-glucans
Fc receptors - antibodies
Phagosome binds
Lysosome or neutrophils
Macrophage and neutrophil similarities
Low pH
NO
ROS
Lysozyme
Macro and neutro differences
Macro - cathelicidins
Neutro - defensins and cathelicidins
Neutrophil have lactoferrin inhibitor and B12 binding protein
Neutrophil process of engulfment and digestion
fMLF receptor activates Rac2…eventually NADPH oxidase gets ROS in phagolysosome…influx of ions and breakdown bacteria
Dying neutrophils form
Extracellular traps that trap bacteria and prevent them from moving
Cytokine effect in blood vessels
Causes dilation and upregulation of adhesion molecules…blood clotting takes place and prevents movement of infection
Monocyte binds to
Integrin on the vascular endothelium and pulled in to become macrophage
Sepsis summary
TNF-alpha secreted into the bloodstream and there is systemic edema…leads ot decreased blood volume and collapse of blood vessels
IL-1B/IL-6 and TNF-alpha act on
Liver, bone marrow, hypothal, fat/muscle, dendritic cells
IL-6 effect on liver
Acute phase proteins including CRP and MBL
CRP opsonizes
MBL activates complement cascade
IFN-alpha and Beta
Interferons
Increase MHC class 1 expression
Activate dendritic cells and macophages
Activate NK cells to kill viral cells
Induce chemokines to recruit lymphocytes
NK cells induced by what and produce what
Induced by IL12
Produce interferon gamma, perforin, granzyme
Time of onset after viral infection
Quickly - interferons, TNF alpha and IL12
Later - NK mediated killing (3 days)
Latest - T cell killing (7 days)
MHC class 1 mechanism
MHC 1 receptor is on all cells and inhibitory for NK cell…when infected, will not express…NK cell will come and kill by 1 of 2 methods
Granzyme and perforin
NK cell TRAIL binds to DR4 and DR5 and activates caspase 8 for apoptosis
Chediak-Higashi dz
Recurrent infections and pigmentation defects…bleeding
Lymphocyte proliferation…fever, liver nad spleen enlargement, reduced WBC, platelets and RBC (pancytpenia)
Caused by defect in intracell vesicle causes failure of phagosome to fuse with lysosome…inability of vesicle for melanocyte and nervous system cell function as well
Chronic granulomatous dz
Frequent infections during 1st year of like (aspergillus, staph, klebsiella, E coli)…pneumonia, lymph node infection, absecesses
Mutation in NADPH oxidase complex
LAD
Recurrent infection and gingivitis
Neutrophils and monocytes trappen in blood stream
Deficiency of CD18…common B chain of LFA-1(CR3), Mac1, and gp150,95 (CR4)
Neutropenia
Recurrent and severe bacterial infection
Brought on by immunosuppression
IRAK4 def
Recurrent pyogenic bacteria
Intermediate in TLR and IL1R signaling
Nucleic acid PAMPs
ssRNA - virus
dsRNA - virus
CpG - virus, bactera
Protein PAMPS
Pilin and flagellin - bacteria
Cell wall lipid PAMPS
LPS - gram -
Lipoteichoic - gram +
Carb PAMPS
Mannan - fungi and bacteria
Glucans - fungi
NOD protein pathway starts with
NLRP proteins
What activates STING pathway?
dsDNA from viruses or bacteria
IL-8 major function
Chemoattractant of neutrophils
Hematopoietin receptor subfamily with gammac chain and why its important
IL-2, 7, and 15 which are important for lympho development…x-lined SCID is caused by mutation in this
IL-1 local vs. systemic
Local - vascular endothelium, activates lymphocytes, local tissue destruction
Systemic - fever and production of IL-6
TNF-alpha local vs system
Local - vascular endothelium and permeability
Systemic - fever, mobilize metabolites, shock
IL-6 local vs system
Local - lympho act and increased antibody production
Systemic - fever and acute-phase proteins
Hoqw does neutrophil work?
Produce phagosome that fuse with granules and dump contents that kill organisms
Sepsis common in
Gram-negative bacteria
How does MBL start complement pathway?
Binds C1q
What do NK cells recognize?
When MHC class 1 is down-regulated, will kill
Neutrophil numbers high in
Chronic granulomatous dz
CD18 is common chain for
CR3 and CR4
