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Toll- like receptors - encoded by germline genes, unlike antigen receptors on B and T cells - recognize more than one

Toll- like receptors - encoded by germline genes, unlike antigen receptors on B and T cells - recognize more than one type of ligands through extracellular leucine-rich repeat domains - interact with intracellular signaling components through Toll/IL-1 receptor (TIR) domain Ligands

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Toll- like receptors - encoded by germline genes, unlike antigen receptors on B and T cells - recognize more than one

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  1. Toll- like receptors - encoded by germline genes, unlike antigen receptors on B and T cells - recognize more than one type of ligands through extracellular leucine-rich repeat domains - interact with intracellular signaling components through Toll/IL-1 receptor (TIR) domain Ligands - from microbes; bacteria, viruses, protozoan, but not in host - essential for survival of microbes; thus conserved structure - not specific to pathogens

  2. (Toll/IL-1 receptor) TIR domain in host-defence pathways

  3. Ligand specificities of mammalian TLRs

  4. Mammalian Toll-like Receptor signalling pathways TLR 4 TLR3 IFN-a, b TNF-a, IL-1, IL-6, IL-12

  5. Toll signalling pathways in Drosophila

  6. Innate immune receptors trigger a variety of responses: (1) internalization of the microbe by phagocytic cells; (2) antimicrobial killing mechanisms, such as production of NO and bactericidal peptides (3) production of inflammatory cytokines and chemokines that recruit and activate other immune cells (4) maturation of antigen presenting cells; increased expression of CD80/86, MHCII

  7. Toll-like receptors on adaptive immunity

  8. Expression of TLRs in human B cells

  9. Differential responses of various B cell stages to TLR ligands

  10. CFSE assay for cell division 1st division 2nd division

  11. No anti-IgM plus anti-IgM No anti-IgM IgM memory Switch memory

  12. Antigen-receptor signaling and cytokines prime B cells for bacterial DNA recognition TLR 9 Antigen +IL2 + DNA Human naïve B cell No response DNA TLR’s TLR’s Human memory B cell DNA Blood. 2003 Jun 1;101(11):4500-4

  13. Non-microbial (endogenous) ligands for TLR

  14. TLR3-mediated activation of NF-{kappa}B and IL-8 secretion by mRNA in TLR3-293 cells Kariko, K. et al. J. Biol. Chem. 2004;279:12542-12550

  15. Activation of TLR9 by DNA (endogenous?) Leadbetter et al, 2002 Viglianti et al, 2003 Nucleosome/ chromatin Proliferation and differentiation no response

  16. Model for activation of TLR9 by DNA (endogenous?) Leadbetter et al, 2002, Nature Viglianti et al, 2003, Immunity Activation signal Internalization Delivery of antigen TLR9 TLR9

  17. TLR9 KO/MRL-lpr mice (Christensen et al, 2005) Figure 1

  18. FITC Secondary Ab Serum antibody antigen Indirect immunofluorescence

  19. Figure 2

  20. Figure 3

  21. Figure 4

  22. Figure 5

  23. Figure 6

  24. Figure 7

  25. TLR9 KO/MRL/lpr mice - conclusion - TLR 9 is critical for production of anti-dsDNA antibodies - Lack of anti-dsDNA antibodies has no apparent effect on manifestation of autoimmune phenotype in lpr mice

  26. Suppression of CpG-mediated activation in anergic cells CpG Rui et al, 2003, Nat. Immunol. Activation signal CpG Binds TLR9 TLR9 TLR9

  27. Complement pathways

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