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Recognition-What initiates an immune response? danger or non-self PRR:TLRs, CLRs, NLRs, RLRs

Recognition-What initiates an immune response? danger or non-self PRR:TLRs, CLRs, NLRs, RLRs Danger signals. Signal-how is the message relayed to turn on genes Toll signalling pathway -NLR and RLR signalling pathway Response-what are the effectors of the innate immune response

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Recognition-What initiates an immune response? danger or non-self PRR:TLRs, CLRs, NLRs, RLRs

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  1. Recognition-What initiates an immune response? • danger or non-self • PRR:TLRs, CLRs, NLRs, RLRs • Danger signals. • Signal-how is the message relayed to turn on genes • Toll signalling pathway • -NLR and RLR signalling pathway • Response-what are the effectors of the innate immune response • antimicrobial peptides, proinflammatory cytokines, interferon stimulated genes • RNAi

  2. Competing hypotheses for initiation of immune responses Pattern recognition Danger Heath and Carbone.2003 Nature 425:426 Janeway Matzinger

  3. Pattern recognition receptors initiate immune responses Toll-like receptors (TLRs) flagellin LPS C-type Lectin (CLRs) TLR4 TLR5 TLR2/6 Nod-like receptors (NLRs) RIG-I like receptors (RLRs) b-glucan Dectin-1 CARD NF-B TLR3/7/9 Nucleic acids Cytokines, IFN-, IFN- IRF3/5/7 endosome nuclei

  4. CLRs: MBL MBL distinguishes microbial from host cell surface carbohydrates. Mannose binding lectin is a pattern recognition molecule

  5. CLR: Macrophage pattern recognition receptors include MMR, Dectin-1, DC-SIGN

  6. CLR: Macrophage mannose receptor CRD-carbohydrate recognition domains 100-fold increase in Ag uptake, re-usable:recycles to membrane, and has broad specificity for mannosylated glycoproteins Lectin-sugar binding receptor

  7. CLR: Dectin-1 Glucan receptor on Macrophages, dendritic cells, neutrophils Zymosan receptor Interacts with T cells independent of b-glucan C-type lectin near NK cell lectins in genome S. Gordon. 2004.Mol. Immunol. 40.869

  8. The structure of fungal cell walls and beta-glucans: the cell walls of fungi S. Gordon. 2004.Mol. Immunol. 40.869

  9. Dectin-1 is the macrophage zymosan receptor Expression of Dectin-1 in the murine fibroblast cell line NIH 3T3 confers zymosan-binding ability S. Gordon. 2004.Mol. Immunol. 40.869

  10. CLR: Dectin-1 can recognize an endogenous ligand on T cells: Cell-cell interaction assay Laminarin-sugar This is independent of sugar recognition S. Gordon. 2004.Mol. Immunol. 40.869

  11. CLR: DC-SIGN is an endocytic receptor HIV hitchhikes on DC-SIGN to enter cells -travels to lymph node where it can infect other cells

  12. CLR: DC lectin immunoreceptors are endocytic receptors and can influence the type of immune response. DCIR Th2 type - MHCII CD8-DCIR+ DEC205 Th1 type CD8+DEC205+ MHCI

  13. CLRs on APC are targeted to internalize antigens and stimulate immune responses for new vaccines. Decisions About Dendritic Cells: Past, Present, and Future Ralph M. Steinman Annu. Rev. Immunol. 2012. 30:1–22 Speaker: Dr. Ralph M. Steinman, The Rockefellar University Title: "Vaccines that target dendritic cells" Time & Location: 12:00 Noon, Wednesday Jan 26, 2011 Oborowsky Degner Seminar Hall (1-040 Li Ka Shing Centre for Health Innovation)

  14. TLRs Toll pathway signals for production of antimicrobials such as Drosomycin, an anti-fungal peptide normally found in the carapace Kuby Figure 1-14 Fungus growing on a Toll deficient fly.

  15. Is dToll a pattern-recognition receptor? The Nobel Prize in Physiology or Medicine 2011 Bruce A. Beutler, Jules A. Hoffmann, Ralph M. Steinman http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/hoffmann-lecture.html Jules Hoffman, 1994 NFkB response element in gene Drosomycin-antifungal peptide

  16. What are the pattern recognition proteins upstream of dToll? Bug detectors. Kaisho and Akira, 414.701

  17. Genome-wide mutagenesis and challenge with pathogens to identify genes upstream of Toll pathway seml mutant fly rescued with wt hemolymph seml mutant does not produce Ds Immune signalling through Toll visualized with GFP-Drosomycin seml named for Semmelweis J.A. Hoffman’s lab 2001 Nature 414:756

  18. PGRP-mutant Drosophila seml belongs to a peptidoglycan recognition protein family with mammalian homologues Drosophila and human genome projects were mined. J.A. Hoffman’s lab Nature 414:756

  19. PGRPs initiate prophenoloxidase pathway, activate Toll and Imd Dziarski, 2004 Mol. Immmunol. 40:877-886

  20. Some PGRPs are amidases Neutrophils deficient in PGRP-S take up bacteria but do not kill them Lysozyme is an amidase Dziarski, 2004 Mol. Immmunol. 40:877-886

  21. Phylogenetic tree of insect and mammalian PGRPs and known and deduced functions PGRP-SA is only in insects. R. Dziarski. Mol. Immunol. 2004. 40.877

  22. Are pattern recognition receptors upstream of TLRs? Bug detectors. Kaisho and Akira, 2003 Nature 414.701

  23. Mammalian Toll receptors signal presence of pathogens Akira, S. 2003, 15:5-11.

  24. Pattern recognition proteins upstream of mammalian TLRs The extracellular matrix protein mindin is a pattern-recognition molecule for microbial pathogens He, Y. et al. Nature Immunology5, 88 - 97 (2004) Mindin Expressed in hematopoetic tissues Mindin-/- mice are poor responders to LPS, and cannot clear bacteria in lungs

  25. Functions of the extracellular matrix protein mindin in the immune response Mindin recognizes sugars in bacterial cell wall, promotes opsonization, phagocytosis, and connects to signalling molecules (TLRs?) Mindin the fort, Nature Immunology5, 16 - 18 (2004)

  26. TLRs, NLRs and RLRs TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity  • Trends in Immunology, Volume 27, Issue 8, August 2006, Pages 352-357 Emma M. Creagh and Luke A.J. O’Neill

  27. NLRs: Intracellular sensors of bacteria, viruses and danger signals NOD-like receptors (NLRs) are characterized by three distinct domains: the putative ligand-sensing leucine-rich repeats (LRRs); the NACHT domain, which mediates oligomerization; and an effector domain, which can be a pyrin domain (PYD), a CARD (caspase recruitment domain) or a BIR (baculovirus IAP repeat) domain. Most of the NLRs also contain a NACHT-associated domain (NAD). RIG-like helicases (RLHs) contain a helicase and two CARD domains.

  28. NLRs: NOD2 and NALP3 cytoplasmic recognition of petidoglycan Model for the activation of the inflammasome by PGN. When bacteria are phagocytosed, PGN present in the bacterial wall is degraded to produce muropeptides, which are similar to MDP. Subsequent translocation of MDP into the cytoplasm (by an enigmatic mechanism) leads to the direct or indirect activation of NOD2, which results in NOD2–RIP2 complex formation. The resulting RIP2 activation leads to NF-kb activation and proIL-1bsynthesis. Release of MDP also triggers NALP3 (Cryopyrin) activation, which results in the formation of the inflammasome complex (NALP3, cardinal, ASC and caspase-1). Caspase-1 activation then induces cleavage and maturation of IL-1b Abbreviations: FIIND, function to find; NAD, NACHT-associated domain. Martinon F. and J. Tschopp. 2005. NLRs join TLRs as innate sensors of pathogens. Trends in Immunology 26:447.

  29. RLRs: RIG-I and MDA5 Tokai and Akira, J. Biochem. Dec. 2006 RIG-I detects 5’ phosphate group on ssRNA like influenza MDA5 detects dsRNA (poly IC) and poliovirus

  30. Innate immune receptor multiplicity in the sea urchin genome . Rast J. et al., 2006 Science 314:952

  31. Infectious non-self (INS) stimulates an immune response Recognition requires two signals-MHC and co-stimulation Medzhitov and Janeway. Science 2002. 296:298

  32. ‘Danger’ is required to initiate an immune response The Danger Model: a renewed sense of self. Matzinger, P. 2002 Science 296: 301

  33. What can signal “danger”? • Pre-packaged signal-from cells that are killed immediately, such as by a stab wound. Necrotic death only that releases bits of the internal part of the cell. • DNA, RNA, • mannose on nascent glycoproteins, • the mitochondria (endosymbiont) • Pattern recognition receptors • inducible- • heat-shock proteins (chaperones induced in cells under stress) • type 1 interferons (IFN-a and b)

  34. Necrotic but not apoptotic cell death leads to release of heat shock proteins From lab of P.K. Srivastava. International Immunology 12:1539

  35. Nature. 2009 Apr 16;458(7240):899-903. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Sancho D, Joffre OP, Keller AM, Rogers NC, Martínez D, Hernanz-Falcón P, Rosewell I, Reis e Sousa C. CLEC9a detects a signal released by necrotic cells Untreated or UVC-treated MEFs were cultured with BWZ cells expressing CLEC9A–CD3 or DECTIN-1–CD3. Where indicated, Fab fragments of control (ctrl), anti-mCLEC9A or anti-hCLEC9A antibodies were added. Reporter activity in BWZ cells was measured Ligand is unknown, but is a protein

  36. Crystalline uric acid is a potent stimulator of DCs CD86 expression Unstimulated DC CD86 is a co-stimulatory molecule on DCs Allopurinol-structurally similar to uric acid BCP-basic calcium phosphate Alum-particles of aluminum hydroxide MSU-monosodium urate (crystalline uric acid) Rock, KL 2003 Nature 425:516

  37. Excess uric acid causes inflammation. gout Uric acid is detected by NALP3 Natural adjuvants as vaccine components.

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