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Toll-like receptors Scavenger Receptors Part of the innate immune response

Toll-like receptors Scavenger Receptors Part of the innate immune response. Let´s talk first. Innate Immunity Pathogen recognized by receptors encoded in the germline: p attern r ecognition r eceptors

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Toll-like receptors Scavenger Receptors Part of the innate immune response

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  1. Toll-like receptors Scavenger Receptors Part of the innate immune response Let´s talk first...

  2. Innate Immunity Pathogen recognized by receptors encoded in the germline: pattern recognition receptors Receptors have broad specificity, i.e., recognize many related molecular structures called PAMPs (pathogen-associated molecular patterns) Immediate response No memory of prior exposure Adaptive Immunity Pathogen recognized by receptors generated randomly: B-cell (BCR) and T-cell (TCR) receptors for antigen Receptors have very narrow specificity; i.e., recognize a particular epitope after processing Slow (3 -5 days) response (because of the need for clones of responding cells to develop) Memory of prior exposure Innate vs. Adaptive Immunity

  3. Elements of the non-specific (innate) immune system Anatomical barriers: Skin, Intestinal movement, Oscillation of broncho-pulmonary cilia Secretory molecules: • Transferrin and lactoferrin deprive organisms of iron.  • Interferon inhibits viral replication and activates other cells which kill pathogens • Lysozyme, in serum and tears, breaks down the bacterial cell wall (peptidoglycan) • Fibronectin coats (opsonizes) bacteria and promotes their rapid phagocytosis.  • Complement components and their products cause destruction of microorganism directly or with the help of phagocytic cells. Acute phase proteins (such as CRP) interact with the complement system proteins to combat infections.  • TNF-alpha suppresses viral replication and activates phagocytes. • Antimicrobial peptides Cellular Components: • Neutrophils (polymorphonuclear: PMN), Mononuclear phagocytes (include monocytes in circulation, histiocytes in tissues, microglilal cells in the brain, Kupffer cells in the liver and macrophages in serous cavities and lymphoid organs), dendricitc cells. • NK cells are important in defense against viral infections and malignancies. • Gamma delta T cells (in epithelia) -no MHC N. B. All components of the non-specific immune system are modulated by products of the specific immune system, such as interleukins, interferon-g, antibody, etc.

  4. How does the host organism detect the presence of infectious agents and dispose of them without destroying self tissues? How non-specific is innate immunity really ? • Adaptive immunity mediated by clonally distributed T & B lymphocytes • Characterized by specificity & memory • Innate immunity has long been thought of as a non-specific immune response • Characterized by engulfment & digestion of microorganisms by macrophages & leukocytes • Now seen that innate immunity has considerable specificity • Recognizes self & non-self • Discriminates between pathogens • Innate immune response also shown to be a prerequisite for triggering acquired/adaptive immunity

  5. Innate Immune Recognition via Patterns • All multicellular organisms are able to recognize and eliminate pathogens • Despite their extreme heterogeneity, pathogens share highly conserved molecules, called “pathogen-associated molecular patterns” (PAMPs) • Host cells do not share PAMPs with pathogens • PAMPs are recognized by innate immune recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs)

  6. Pathogen-associated molecular patterns • CHALLENGE: How can the host discriminate large numbers of diverse pathogens from each other &/or from self using a restricted number of receptors? • SOLUTION:Evolve variety of receptors that recognize conserved motifs on pathogens that are not found on higher eukaryotes • Pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptors (PRRs) or molecules (PRMs) • Two categories of PRRs: • Those that mediate capture, uptake & presentation of antigen (scavenger receptors) • Those that lead to the activation of pro-inflammatory pathways (Toll-like receptors) • PRMs are soluble, secreted proteins, such as SP-A, SP-D, MBL, Ficolins, CRP.

  7. Scavenger receptors • Recently, a series of genes identified in DCs & macrophages encoding lectin or lectin-like receptors • Preferentially bind to carbohydrate-bearing pathogen-derived antigens • Multifunctional: • Associated with antigen-uptake – “scavenger receptors” • Important for DC migration (role of chemokine gradient) • Play a role in DC interaction with lymphocytes

  8. Functions of membrane bound lectins produced by dendritic cells and Langerhans cells: - MMR, DEC-205 (CD205), and Dectin-2: Antigen Uptake, DC trafficking. - Dectin-1 and DC-SIGN (CD209): T-cell interaction, DC trafficking. ! C-type lectin receptors also recognize glycosylated virus envelope proteins but some viruses appear to utilize these as attachment (& entry?) receptors.

  9. Peiser Infect Immun. 2002;  70 (10): 5346–5354 FIG. 3. EM of N. meningitidis uptake. WT and SR-A-/- BMM were incubated for various times with 150 live MC58 bacteria per cell at 37°C. At various intervals, the cells were washed to remove extracellular bacteria before being processed and analyzed by EM. The fields chosen are representative of the whole M population

  10. Toll-like receptors • TLRs are transmembrane proteins • “Toll” identified as essential molecule for embryonic patterning in Drosphila • Evolutionary conserved among insects & humans • Mammalian TLRs have homology to IL-1 receptor in cytoplasmic domain (the Toll-IL1-R or TIR domain) • Extracellular domain quite different • 10 TLRs reported (1-10) • Expressed differentially on immune cells (low level) • Also expressed on other cell types (e.g., endothelial cells) • Respond to different stimuli • Expression modulated in response to stimuli – i.e., inducible

  11. TLR signaling pathways • Activation of signal transduction pathways by TLRs induces genes that function in host defense • Pro-inflammatory cytokines • Chemokines • MHC & costimulatory molecules • iNOS & antimicrobial peptides that directly destroy pathogens • TLRs have “shared” & “specific” signal transduction pathways • Shared – all TLRs & IL1R • 4 essential components – adaptor proteins MyD88, TOLLIP & TRAF6, & protein kinase IRAK • Specific – some, but not all TLRs…

  12. Involvement of TLR in Linking Innate Immunity to Adaptive Immunity Nature Immunology 2001 2:675

  13. Van Crevel, Clin Microb. Rev 15, 294-309, 2002 Phagocytosis and immune recognition of M. tuberculosis. Tailleux et al., J Exp Med. 2003;197(1):121-7. : „DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells“. Complement receptor (CR)3 and mannose receptor (MR), which are the main M. tuberculosis receptors on macrophages, appeared to play a minor role, if any, in mycobacterial binding to DCs. The mycobacteria-specific lipoglycan lipoarabinomannan (LAM) was identified as a key ligand of DC-SIGN.

  14. SUMMARY • Scavenger receptors are important for antigen uptake, trafficking, and T cell stimulation. • Toll-like receptors are a multigene family that initiate pro-inflammatory gene induction in response to bacterial products and viral products. Binding of ligands to homo- or heterodimerised TLRs activates a sequential signalling cascade involving accessory molecules. • As presented here, pattern recognition receptors/molecules support the so-called „stranger hypothesis“ (Janeway 1989). However, recent work suggests the relevance of a so-called „danger hypothesis“ according to which cellular stress resulting from infection alerts the immune system (Matzinger, Nature 425: 2003).

  15. Recommended reading: Zhang and Ghosh: Toll-like receptor-mediated NF-kB activation: a phylogenetically conserved paradigm in innate immunity J Clin Invest 107, 13-19, 2001 Thank you

  16. C-type lectins as DC antigen receptors • Membrane-associated lectins capture pathogens for intracellular destruction, degradation & antigen loading of MHC molecules • MMR constitutively internalized from cell-surface & recycled • DEC-205 & DC-SIGN internalized upon ligand binding C-type lectins in DC trafficking • MMR appears to direct DCs & macrophages to germinal centers of lymph nodes & spleen during immune response • Binds sLeX on endothelium • DC-SIGN producing DCs tether & roll on endothelium by interaction with ICAM-2 • Regulated by chemokine gradients • Facilitates endothelial transmigration in vitro

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