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