Transcript Toll-like receptor structure - University of British Columbia

Innate vs. Adaptive Immunity
Innate
• Primitive (found in all
multicellular organisms)
• Directed towards types of
molecules
• Effectors are broadly
reactive
• Response is immediate
• No anamnestic responses
• Effectors: epithelial cells,
phagocytes, endothelial
cells, fibroblasts
Adaptive
• Only in vertebrates
• Directed towards specific
epitopes
• Response is slow
• Effectors are highly
specific
• Memory persists
• Effectors: Lymphocytes,
APCs
Innate Immunity
Physical barriers
Skin
Cellular responses
Epithelial cells
Mucosae
Physical features
Gastric acid, Gut motility,
Mucus, Sebum
Humoral responses
(proteins, etc.)
Complement
Cytokines
Cytokine production
reactive oxygen/nitrogen
Fluid secretion
Fever
Malaise
Antigen-presenting cells
Kupffer cells
Langerhans Cells
Dendritic Cells
Macrophages
Granulocytes
PMNs
Mast Cells
Eosinophils
Lymphocytes
NK cells
NK T cells
Adaptive
Immunity
Defects in Innate Immunity
• Chronic granulomatous disease--CGD (pyogenic
infections, Aspergillus)
• Burns/chemotherapy: Loss of barrier integrity
(bacteria, yeasts)
• Neutropenia (bacteria, yeasts, molds)
• Rare specific defects in cytokines/receptors
(susceptibility to particular infections)
• Complement deficiencies (meningococcus)
• Corticosteroids (Aspergillus, Candida,
herpesviruses)
Defects in Adaptive Immunity
• SCID--no T or B cells (severe, fatal infections)
• AIDS--loss of CD4+ T cells (Intracellular
pathogens, fungi, viruses, pyogenic infections,
etc.)
• Transplant--immunsuppression of T cells (viral,
fungal)
• Common Variable Immunodeficiency (decreased
IgG)--generally mild increase in sinopulmonary
bacterial infections
• Asplenia--encapsulated bacteria
• Corticosteroids
Molecular features of Innate
Immunity
• Certain proteins are vital to functioning of
the innate immune system
• Both natural and acquired defects in these
proteins give clues to their roles in defense.
• These proteins are present in a wide variety
of species
Normal fruit fly
Fruit fly lacking Toll
Toll-like receptor structure
Pattern recognition receptors
Newly described PRRs
• TLR11--identifies uropathogenic E. coli in
humans (not clear what molecule yet)
• Nod1--intracellular receptor with Nterminal CARD domain and C-terminal
LRRs. Recognizes intracellular Shigella
flexneri
• Nod2--similar to Nod1. Ligand not known,
but is associated with Crohn’s disease
TLRs and their ligands
Interaction between TLRs and ligands
IRAK interactions and TLR signalling
TLR
IL-1R
cell membrane
p85
WM
TIR domains
p110
PI 3-kinase
PI(3,4,5)P3
}
Adaptors
(Rac1,
? ceramide)
{
MyD88
IRAK
Pi
TRAF-6
NIK
Akt
Pi
Erk
Pi
Bay11
IKK
Pi
I-kB
NF-kB
NF-kB
I-kB
p38
AP-1
Inflammatory
genes (chemokines,
cytokines, etc)
NF-kB
nucleus
SB
NF-kB activation shown by
EMSA
a)
NF-kB
probe
FliC-EAEC
cold NF-kB oligo
SB-203580
Time
- + + +
- - + - - - +
- + +
- - - - +
30 min
60 min
FliC
TLR5
PI3K
IRAK/TRAF-6
WM
Bay11
Akt
I-kB
degradation
?
p38
?
NF-IL-6
NF-kB activation
LY
AP-1
IL-8 transcription
degradation
IL-8
mRNA
(50%)
LY
IL-8
TLRs and adaptive immunity:
old paradigm
Ag
T cell
macrophage/DC
B cell
mature DC
CD80/CD86
CD28
TCR
No activation/
anergy
T-cell
Activation
clonal proliferation
New paradigm of TLR-controlled
DC activity
tissue
lymph node
IL-10
No
ligand
immature DC
Ag
Immature DC
clonal deletion
Treg cell
+ TLR
ligand
IL-12
TNF-
IL-6
Mature DC
Th1 cell
Dendritic cell subsets and their
TLRs