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Antibodies from IMGENEX: Toll-like Receptors

 

The GateKeepers of Innate Immunity
Innate immunity as the first line of defense

The innate immune system is an ancient host defense mechanism found in almost every multicellular organism from plants to humans. In invertebrates it is the sole mechanism of defense against pathogens but in higher vertebrates constitutes the first line of defense. The role of the innate immune system is not an insignificant one; not only must it discriminate between self and non-self as well as distinguish between pathogenic and non-pathogenic microbes, it also plays an important role in triggering and optimizing the adaptive immune response. This remarkable system allows an immediate non-specific response against microorganisms whereas the adaptive immunity mounts a specific response against the invading pathogen during the late phase of the infection.

Pattern Recognition Receptors
The cornerstone of the innate immune system is comprised of germline-encoded receptors referred to as pattern-recognition receptors (PRRs), to which the Toll-like receptors belong.  These PRRs are activated upon recognition of “Pathogen-Associated Molecular Patterns” or PAMPs.  PAMPs are molecular patterns shared by large groups of pathogens not usually present in the host. 
 
1
. Molecular patterns system must be shared by large groups of pathogens and thus must represent general patterns rather then specific structures.
2
. They must be conserved products of microbial metabolism which are not subject to antigenic variability.  Although the immune system selects against these patterns, pathogens cannot "change" them because they are essential for the survival or pathogenicity of the microorganisms.  Any attempts to change them could be lethal to the microbe or render it nonpathogenic.
3
. The recognized structures must be absolutely distinct from self-antigens. The major consequence of this requirement is the ability of the innate immune system to discriminate between self and non-self.

Characterized PAMPS include cell wall constituents such as lipopolysaccharide (LPS), peptidoglycan (PGN), lipoteichoic acid (LTA), or lipoarabinomannan (LAM), but also include single or double and stranded RNA, as well as unmethylated CpG DNA. 


Overview of Toll-like Receptors
The TLRs owe their name to a closely related receptor called Toll, first identified in Drosophila. The first member of the Toll family was identified in Drosophila in 1988 during a screen for embryonic polarity genes. In Drosophila, Toll receptors cause an induction of innate immune responses by first linking to an adaptor tube, which is a functional homolog of mammalian MyD88. This tube binds to kinase Pelle, a homologue of IRAK, and after a cascade of reactions leads to transcription of genes that modulate and mediate activation of antimicrobial pathways that directly kill the pathogen.

Toll and its mammalian homologs are type I transmembrane proteins characterized by an extracellular leucine-rich domain and a cytoplasmic domain referred to as Toll/IL-1R domain or TIR domain because of its homology to the cytoplasmic domain of the mammalian interleukin 1 receptor (IL-1R). Upon binding of the extracellular ligand recognition domain to specific PAMPs, changes in the intracellular domain result in initiation of signaling events including translocation of transcription factors, cytokine modulation, and interferon-stimulated gene regulation leading to inflammatory responses and/or release of antimicrobial agents.

The first characterized member of the mammalian family of TLRs was TLR4 which was shown to trigger the pro-inflammatory NF-kB pathway upon binding to LPS. The completion of the human genome project led to the identification of numerous putative TLRs in the genome. These TLRs differ from each other in ligand specificities, expression patterns, and target genes they induce.

At least 11 TLRs have been identified in humans and 13 in mice. While they are expressed predominantly in antigen processing and presentation cells such as macrophages, neutrophils, and dendritic cells, TLR expression is not restricted to these cell types. Although research is ongoing, TLR expression—at least at the mRNA level—appears to be detectable in a wide range of tissues including adrenal gland, liver, lung, spinal cord, spleen, testis, thymus, and trachea suggesting that subsets of TLRs are expressed in the majority of cells in the body.


TLR Signaling
 Stimulation of TLRs by pathogens leads to expression of several genes involved in immune responses through a number of signaling pathways. Activated pathways include the NF-kB pathway (IkBa phosphorylation, translocation of NF-kB p65 to the nucleus), mitogen activated protein kinases p38, Jun-N-terminal kinase (JNK), and the interferon pathway.

While TLR-mediated signaling pathways are still being elucidated, a number of specific molecules are known to be involved. These include adapter molecules such as MyD88, MyD88 adapter-like (Mal), also known as Toll/IL-1R (TIR) domain containing adaptor protein (TIRAP), and TIR domain-containing adapter inducing interferon (TRIF), also known as TICAM1. Other key signaling proteins include IL-1 receptor associated kinases (IRAKs) such as IRAK1, 2, and 4, transforming growth factor kinase (TAK-1), IkB kinases (IKKs), and TRAFs (TNF receptor associated factors).
 


Summary of Toll-like Receptors & their Ligands

  Receptor

Bacteria Viruses Fungi Parasites Small/Synthetic Molecules Endogenous Ligands
  TLR1/TLR2
Triacyl lipopeptides lipoarabinomannan (LAM) from mycobacterium
 
 
Yeast/ Zymosan
 

Glycosylphosphatidyl inositol linked proteins,
T. cruzi
 
   
  TLR2/TLR2 (?) Published literature suggests the existence of TLR2 homo-dimers, though specific ligands have yet to be identified.
  TLR2/TLR6
diacyl lipopeptides,  LTA peptidoglycan

 
 
Yeast/ Zymosan
 

Glycosylphosphatidyl inositol linked proteins,
T. cruzi
 
   
  TLR3   dsRNA        
  TLR4 LPS       (Mouse TLR4),
Taxol

Hsp60, Hsp70?, Hyaluronic Acid? Heparan Sulfate? Fibrinogen?
 
  TLR5 Flagellin          
  TLR7   ssRNA    
Imidazoquinolines (Mouse TLR7), Loxoribine
 
 
  TLR8 ssRNA       (Human TLR8) Imidazoquinolines  
  TLR9
Bacterial CpG
 
 Viral CpG        
  TLR10 Unknown ligand(s)
  TLR11
(Mouse TLR11) Uropathogenic Bacteria
 
    (Mouse TLR11)
T. gondii profilin, apicomplexan profilins?
   
  TLR12

Unknown ligand(s)

  TLR13
Unknown ligand(s)
 
 
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Found 268 results, displaying 1 to 50 | Show all
 
Cat.No Description Format Species Clone Application Publications
IMG-579A TLR4/CD284 Purified H, M N/A Flow (CS), IHC (frozen), IHC (p), WB pricing
IMG-5031C TLR4/CD284 FITC H, M, R 76B357.1 Flow (CS), Flow (I) pricing
IMG-305A TLR9/CD289 Purified D, Hs, H, M, R, RH 26C593.2 CM, Flow (CS), Flow (I), IF/ICC, IHC (frozen), IHC (p), WB pricing
IMG-6795A 14-3-3 Purified H, Mq, RH N/A WB pricing
IMG-6796A 14-3-3 Purified Ca, Ch, Cha, D, H, Mq, M, O, Or, P, Pi, P, R, RH N/A WB pricing
IMG-6640A 4933415F23Rik protein Purified M N/A WB pricing
IMG-6801A AIMP1 Purified Ca, Cha, C, D, G, Hs, H, Mr, M, Mk, O, Or, P, Pi, RH, W N/A pricing
IMG-6802A AIMP1 Purified Chp, Cha, C, Ele, G, Hs, H, Mr, M, Or, Pi, R, RH, W N/A WB pricing
IMG-6800A AIMP2 Purified Chp, H, Mq, Or, RH, W N/A WB pricing
IMG-6721A AP3 Purified C, Ch, Cha, C, D, Hs, H N/A IHC (p), WB pricing
IMG-6730A AP3 Delta (AP3D1) Purified Chp, H, Mk, Or, RH N/A IHC (p), WB pricing
IMX-6734 AP3B1 Purified Chp, Cha, C, D, Ele, Fr, Hs, H, Mq, M, Mk, O, Or, P, Pi, P, Ra, R, RH N/A Peptide ELISA pricing
IMG-6265A AXL/UFON Purified, Peptide Affinity H, M, R N/A WB pricing
IMX-6254 AXL/UFON Sera D, Hs, H, M, O, R N/A Peptide ELISA pricing
IMG-6731A BST2 Purified A, Chp, H, Mq, M, R N/A IHC (p), WB pricing
IMG-6850A BST2 Purified H N/A WB pricing
IMG-6714A Cactin Purified Chp, C, D, H, O, RH, W N/A IHC (p), WB pricing
IMG-31225 CD11A / integrin alpha L Purified, Peptide Affinity H N/A IHC-P, Peptide ELISA pricing
IMG-6806A DC-SIGN Purified A, H, M, Or N/A WB pricing
IMG-6682A Dectin-2 Purified Chp, H, M, Or, R IMG3D1 Flow (CS), IHC (p), WB pricing
IMG-6682AF647 Dectin-2 Alexa Fluor® 647 Chp, H, M, Or, R IMG3D1 Flow (CS) pricing
IMG-6450A DUBA Purified Chp, H, M, R N/A IHC (p), WB pricing
IMG-90190-1 EGFR (Ser1070) Purified, Peptide Affinity H, M, R N/A IHC (p), WB pricing
IMG-6884A EPS8 Purified H IMG18F1F2 IHC (p), WB pricing
IMG-6527A FLII Purified, Peptide Affinity Chp, Hs, H, M, R, RH N/A IHC (p) pricing
IMG-30307 FOXO1A Purified, Peptide Affinity H N/A WB pricing
IMG-5950A FOXO1A Purified, Peptide Affinity Chp, C, D, H, M, Mk, R N/A WB pricing
IMG-6354A GARP/LRRC32 Purified H, Mk, M, R N/A Flow (CS), WB pricing
IMG-6752A GBP1 Purified H, M N/A IHC (p), WB pricing
IMG-6656A GMCSF2/CSF2 Purified Chp, H N/A WB pricing
IMG-6813A GNLY Purified Chp, H N/A WB pricing
IMG-6655A HMGB1 Purified Ch, C, H, M, Mk, R N/A Flow (I), IHC (p), WB pricing
IMG-6666A HMGB1 Purified Ch, H, M, Mk, R N/A WB pricing
IMG-6738A HMGB1 Purified H, M IMG19N10B7 Flow (I), IHC (p), WB pricing
IMG-6739A HMGB1 Purified H, M IMG19N15F4 Flow (I), IHC (p), WB pricing
IMG-6740A HMGB1 Purified H, M IMG19N12A1 WB pricing
IMG-6739AF647-25 HMGB1 Alexa Fluor® 647 H, M IMG19N15F4 Flow (I) pricing
IMG-6670A Ifi202b (p202) Purified M N/A WB pricing
IMG-6671A Ifi204 Purified M N/A IHC (p), WB pricing
IMG-6844A IFIT2 Purified H, M N/A WB pricing
IMG-6750A Iigp1 Purified M, R N/A WB pricing
IMG-6572A LRRFIP1 Purified H, M N/A WB pricing
IMG-6601A LRRFIP2 Purified Hs, H, Mk N/A IHC (p) pricing
IMG-6302A MERTK Purified Chp, H, M N/A WB pricing
IMG-6495A MyD88 Purified H, M N/A WB pricing
IMG-6668A NALP3 Purified H, M, Mk, R N/A WB pricing
IMG-6763A NALP3 (NOD Domain) Purified M IMG25N10E9 WB pricing
IMG-6764A NALP3 (Pyrin Domain) Purified H, M IMG8N8E9 WB pricing
IMX-6336 NALP5 Sera H N/A Peptide ELISA pricing
IMG-6357A NALP7 Purified, Peptide Affinity H, RH N/A IHC (p), WB pricing
 

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