Innate Immunity

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Toll-like receptors Scavenger Receptors Part
of the innate immune response
Lets talk first...
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Innate vs. Adaptive Immunity

• 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

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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.

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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

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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)

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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.

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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

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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.
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Peiser Infect Immun. 2002  70 (10) 53465354
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 37C. 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
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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

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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

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Involvement of TLR in Linking Innate Immunity to
Adaptive Immunity

Nature Immunology 2001 2675
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Van Crevel, Clin Microb. Rev 15, 294-309, 2002
Phagocytosis and immune recognition of M.
tuberculosis.
Tailleux et al., J Exp Med. 2003197(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.
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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).

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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
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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