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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

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Innate vs. Adaptive Immunity

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  1. 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 vs. Adaptive Immunity Adaptive Innate

  2. Adaptive Immunity

  3. 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)

  4. 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

  5. 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

  6. Normal fruit fly Fruit fly lacking Toll

  7. Toll-like receptor structure

  8. Pattern recognition receptors

  9. 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

  10. TLRs and their ligands

  11. Interaction between TLRs and ligands

  12. IRAK interactions and TLR signalling

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

  14. NF-B activation shown by EMSA

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

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

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

  18. 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

  19. Dendritic cell subsets and their TLRs

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