Download - Innate vs. Adaptive Immunity
Innate vs. Adaptive Immunity
• 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
• Only in vertebrates• Directed towards specific
epitopes• Response is slow• Effectors are highly
specific• Memory persists• Effectors: Lymphocytes,
APCs
Innate Adaptive
Skin
Mucosae
Gastric acid, Gut motility,Mucus, Sebum
Physical features
Physical barriers
Cytokine productionreactive oxygen/nitrogen
Fluid secretion
Epithelial cells
Kupffer cellsLangerhans Cells
Dendritic CellsMacrophages
Antigen-presenting cells
PMNsMast CellsEosinophils
Granulocytes
NK cellsNK T cells
Lymphocytes
Cellular responses
Complement
FeverMalaise
Cytokines
Humoral responses(proteins, etc.)
Innate Immunity
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 N-terminal 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
MyD88} {
TLR IL-1R
IRAK
TRAF-6
NIK
IKK
NF-B
I-B
NF-B
Pi
I-B
Pi
Inflammatorygenes (chemokines,cytokines, etc)
Adaptors(Rac1, ? ceramide)
nucleus
cell membrane
p85
p110
PI 3-kinase
PI(3,4,5)-P3
Pi
Akt
NF-B
Pi
TIR domains
Erk
p38
AP-1
WM
Bay11
SB
NF-B activation shown by EMSAa)- +---++-++-+---b)020406080100120FliCcontrolFliC+coldFliC+SB
% of FliCdensity(mean±SEM)N=3---++-TimeFliC-EAECcold NF-B oligoSB-20358030 min60 min
NF-Bprobe
TLR5
FliC
PI3K
AktI-B
degradation
IL-8 transcription
NF-IL-6
AP-1
?
WM
LY(50%)
IL-8mRNA IL-8
p38
?
degradation
NF-B activation LY
IRAK/TRAF-6
Bay11
TLRs and adaptive immunity:old paradigm
Ag
macrophage/DC
B cell
T cell
mature DC
T-cell
TCR
No activation/anergy
CD28
CD80/CD86
Activationclonal proliferation
New paradigm of TLR-controlled DC activity
Ag
Immature DC
Th1 cell
IL-12TNF-IL-6
+ TLRligand
Mature DC
immature DC
clonal deletionTreg cell
No ligand
IL-10tissue lymph node
Dendritic cell subsets and theirTLRs