How is the Immune Response Initiated? What are the ligands and receptors?

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How is the Immune Response Initiated?What are
the ligands and receptors?

• Infectious-Nonself Model
• Charles Janeway Jr.
• Cold Spring Harbor Symp. Quant. Biol. (1989)
• Danger Model
• Polly Metzinger
• Ann. Rev. Immunol. (1994)
• Guard Model
• Jeffrey Dangl Jonathan Jones
• Nature (2001)

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Infectious-Nonself Model

• Detection of conserved molecular patterns
  (pathogen-associated molecular patterns, PAMPs)
  by pattern recognition receptors (PRR).
• Upon recognition of PAMPs by
• Membrane-associated PRR signaling pathways that
  induce antimicrobial effectors and inflammation
  is activated.
• Soluble PRRs pathogens bound and flagged for
  destruction by phagocytosis or the complement
  system.

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Identification of PRR in Drosophila

• Drosophila produces 7 structurally diverse,
  cationic and predominantly membrane active AMPs.
• Activity Spectra
• Fungi Drosomycins, Metchnikowin
• Gram-positive bacteria Defensin
• Gram-negative bacteria Attacins, Cecropins,
  Drosocin, Diptericins
• The promoter regions of these AMP genes contain
  nucleotide motifs similar to mammalian binding
  sites for NF-kB/Rel proteins.
• The Drosophila NF-kB/Rel ortholog is Dorsal, had
  been genetically identified as a regulator of
  dorsoventral patterning in the early embryo.
• In 1996, Hoffmanns group reported that
  loss-of-function mutations in the Toll receptor
  compromised the survival of flies faced with
  fungal infection and the challenge-dependent
  transcription of the antifungal peptide
  Drosomycin.

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Identification of PRR in mammals

• In 1994, the first mammalian TLR, TLR1 was cloned
  and was identified as a homolog of the Drosophila
  Toll DNA Res. 1, 27. It was designated as TIL
  (Toll/IL-1 receptor-like) by Taguchi et al in
  1996 Genomics 32, 486 and was suspected to have
  a developmental function as the immune function
  of Toll had not been demonstrated.
• In 1997, Janeway and Medzhitov successful cloned
  a human homologue of Drosophila Toll and showed
  this Toll-like receptor (TLR) activate NF-kB
  Nature 388, 394.
• The immune relevance of TLR was shown in 1998
  when Bruce Buetler and colleagues showed that
  defective LPS signaling in C3H/HeJ and
  C57BL/10ScCr mice was a consequence to mutation
  in Tlr4 Science 282, 2085.
• Akiras group, by means of gene targeting,
  determined the main microbial specificity of
  TLR2, TLR6 and TLR9.

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Human Toll-like Receptors
Members of the interleukin-1 receptors (IL-1Rs)
family. They share a conserved cytoplasmic region
known as the Toll/IL-1R (TIR) domain. But the
extracellular portion of the TLRs contains a
leucine-rich repeat (LRR) motif whereas that of
the IL-1Rs contains three immunoglobulin
domains.LRR domains may be directly involved in
the recognition of PAMPs.TLR7 TLR9 are in
intracellular compartments.Individual TLR can
interact with several structurally unrelated
ligands of exogenous and endogenous origin.
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TLR Ligands (origin)
TLR1 Tri-acyl lipopeptides (bacteria, mycobacteria) Soluble factors (Neisseria meningitides)
TLR2 Lipoprotein/lipopeptides (a variety of pathogens) Peptidoglycan Lipoteichoic acid (Gram bacteria) Lipoarabinomannan (mycobacteria) A phenol-soluble modulin (Staph. epidermidis) Glycoinositolphospholipids (Tryp. cruzi) Glycolipids (Trep. maltophilum) Porins (Neisseria) Zymosan (fungi) Atypical LPS (Leptospira interrogans, Porphyromonas gingivalis) HSP70 (host)
TLR3 Double-stranded RNA (virus)
TLR4 LPS (Gram-negative bacteria) Fusion protein (RSV) Envelope proteins (MMTV) HSP60 (Chlamydia pneumoniae) Taxol (plant) HSP60 HSP70 (host) Type III repeat extra domain A of fibronectin Oligosaccharides of hyaluronic acid Polysaccharide fragments of heparan sulfate Fibrinogen (host)
TLR5 Flagellin (bacteria)
TLR6 Di-acyl lipopeptides (mycoplasma)
TLR7 Imidazoquinoline Loxoribine, Bropirimine (synthetic compounds)
TLR8 ?
TLR9 CpG DNA (bacteria)
TLR10 ?
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Lipid A structure
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Effect of Lipid A Structure on TLR-mediated
Signaling
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TLR Signal Transduction pathway
All TLR signal through MyD88.Individual TLR also
induce pathogen-specific immune response.TLR2
TLR4 also signal through TIRAP/Mal.TLR3 (?TLR4)
also signal through TRIF.Induction of IFNa/b
expression through IRF3 by TLR3 TLR4 is
MyD88-ndependent.
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Defense Pathways in Drosophila
?
?
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What features distinguish Gram ve and Gram -ve
Peptidoglycan (PGN)?
Gram-positive
Gram-negative
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Recognition of PGN in Drosophila and mammals
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NOD Proteins as PRR
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The Danger Model

• The immune system is activated in response to
  substances that cause damage, rather than those
  that are simply foreign. These alarm/danger
  signals are molecules or molecular structures,
  released or produced by cells undergoing stress
  or abnormal death. These signals are perceived
  by resting APCs.
• The alarm signals can be either endogenous or
  exogenous, intracellular or extracellular/secreted
  . They may function as primal initiators or
  simply give positive-feedback to enhance or
  modify an ongoing response.

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Empirical Support for the Danger Model

• Resting DCs are activated by cells killed by
  acute necrotic death but no by cells dying of
  physiological apoptotic death Nat. Med. 5, 1249
  (99) J. Exp. Med. 191,423 (00). Signals
  produced by necrotic cells are heat shock
  proteins gp96 and hsp70 Int. Immunol. 12, 1539
  (00).
• Crystalline, but not soluble, uric acid can
  activate DCs Nature 425, 516 (03).

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Gene-for-Gene Hypothesis by H.H. Flor
Disease resistance in plants requires two
complementary genes an avirulence (Avr) gene in
the pathogen and a matching, resistance (R) gene
in the host.Suggests a receptor-ligand model in
which R-protein-mediated recognition of the
pathogen-derived Avr products leads to
hypersensitive response (HR) in plant.
This hypothesis has led to the identification of
many R-Avr protein pairs from plants and
pathogens. However, with the exception of the in
vitro interaction between Pi-ta (a rice R
protein) and AvrPita from the fungal pathogen
Magnaporthe grisea, no direct interactions
between Avr and R protein has been demonstrated.
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Identification of R genes in Plants

• Prior to results obtained in animals, in 1993,
  Greg Martin cloned the Pto gene in tomato confers
  resistance to races of Pseudomonas syringae pv.
  tomato that carry the avirulence gene avrPto.
• In 1994, the Ausubel and Staskawicz groups clones
  the resistance gene RPS2 from Arabidopsis
  Science 265, 1856 Cell 78, 1089. In the same
  year, Barbara Bakers group cloned the N gene
  from tobacco Cell, 78, 1101.
• The N and RPS2 proteins, like Toll and TLRs has
  the LRR and TIR domains. They define a large
  group of cytoplasmic R proteins called the
  NBS-LRRs. They contain a central nucleotide
  binding site and a C-terminal LRRs called the
  NBS-LRR.
• A third class of R genes are membrane-anchored
  glycoprotein with extracytoplasmic LRRs.

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Plant, Drosophila and Mammalian PRRs
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Recognition of AvrPto by tomato NB-LRR protein
(Prf) is mediated by Pto
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The Guard Model

• R proteins associate physically and specifically
  with cellular targets (or guardee) of bacterial
  type III effectors (Avr). The interaction between
  guardee and Avr is recognized by the R protein,
  which is thus activated to initiate disease
  resistance. Guardees are likely to be plant
  defense components or host proteins whose
  function is modified to nourish the extracellular
  bacterial pathogen. In the absence of a specific
  R protein, the host target is not guarded from
  the virulence function of Avr, and disease ensues.

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Evidence Supporting the Guard HypothesisCell
108, 743 (02) 112, 369 (03) 112, 379 (03)
AvrRpt2 is a Cysteine Protease Mol. Micro.
49,1537 (03)