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

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

} { AP-1 SB TLR IL-1R WM Erk Bay11 p38 Inflammatory genes (chemokines, cell membrane p85 TIR domains } { WM p110 MyD88 Adaptors (Rac1, ? ceramide) PI 3-kinase IRAK Pi PI(3,4,5)- P3 TRAF-6 NIK Akt Erk Bay11 Pi Pi IKK Pi I-kB I-kB NF-kB NF-kB p38 AP-1 Inflammatory genes (chemokines, cytokines, etc) SB NF-kB nucleus

NF-B activation shown by EMSA

TLR5 IL-8 transcription PI3K WM Bay11 Akt ? p38 ? LY LY IL-8 mRNA IL-8 FliC TLR5 PI3K IRAK/TRAF-6 WM Akt Bay11 ? I-B degradation p38 ? NF-B activation LY NF-IL-6 AP-1 (50%) IL-8 transcription LY IL-8 mRNA degradation IL-8

TLRs and adaptive immunity: old paradigm Ag macrophage/DC B cell T cell

mature DC T-cell TCR CD28 CD80/CD86 No activation/ anergy Activation clonal proliferation

New paradigm of TLR-controlled DC activity tissue lymph node IL-10 No ligand clonal deletion Treg cell immature DC Ag + TLR ligand Immature DC IL-12 TNF- IL-6 Th1 cell Mature DC

Dendritic cell subsets and their TLRs