Toll-like Receptor
The term Toll -like receptor ( TLR short, of Engl. Toll-like receptor ) refers to a structure of the so-called innate immune system ( innate immunity ) and belongs to a group of receptors, the PRRs ( Pattern Recognition Receptors ). Toll -like receptors are used for detection of PAMPs ( Pathogen Associated Molecular Patterns ), which are structures which occur exclusively on or in pathogens, and control respective activations of genes. This activation of the " antigen-specific adaptive immune system " (antigen -specific acquired immunity ) is initiated and modulated. Through the "toll - like receptors " can the innate defense system between "self" and " non-self " distinction.
The name " Toll-like receptor" ( in German literature referred to as " signal transduction mediating PRRs " or, rarely, also known as " Toll -like receptor" ) is derived from a protein in Drosophila melanogaster, about their discovery, the research group led by Nobel laureate Christiane Nüsslein-Volhard was so excited that they called Toll. TLRs consist of proteins that are similar to Toll, ie Toll-like are.
Since the discovery of the first Toll-like Receptors mid-1990s, each year new variants have been discovered in humans and animals. TLRs are found in all vertebrates, including fish and reptiles; but also in simpler organisms, such as Drosophila melanogaster, which suggests that it is an evolutionary very old system. Most species have more than ten different (known) TLRs, with some types occur, for example, in the mouse, but not in humans.
TLRs recognize various functional components of viruses, bacteria and fungi and can trigger biochemical reaction chains in the cells which serve the defense against these pathogens.
Discovery of the TLRs
As a first time microbes have been identified as the cause of infectious diseases, it was immediately clear that multicellular organisms must be able to recognize this, and that it is necessary for this to recognize typical molecular structures of microorganisms. A large amount of literature that encompassed most of the 20th century, is dedicated to the key molecules and their receptors. More than 100 years coined Richard Pfeiffer, a student of Robert Koch, the term endotoxin, to name a substance that was produced by Gram-negative bacteria and in animal experiments led to fever and shock states. In the following decades endotoxin was chemically characterized and as lipopolysaccharide ( LPS), which is produced by most gram-negative bacteria identified. It was also shown that other molecules (bacterial lipopeptides, flagellins and non-methylated DNA ) may lead to an immune response. Logically, it was concluded that there must be receptors that are able to induce an immune response to such molecular structures. However, these were not found for many years.
In the mid-1990s has been recognized by research in the field of developmental biology of Drosophila melanogaster by chance that Toll- negative mutants are very susceptible to fungal attack. This observation initiated a targeted search for similar proteins in mammalian cells. 1994 was by Nomura and colleagues from the first human TLR are found, which could be assigned to a chromosome in 1996 by Taguchi and colleagues. This shows that it is mediated via Toll -like receptor immune response is an evolutionarily very old form, which is genetically highly conserved. As the role of TLRs in the immune response at the time was not yet known, it was assumed that TLR1 would play a role in the developmental biology of mammals. 1997 showed Charles Janeway and Ruslan Medzhitov, that a Toll-Like Receptor - when it is artificially tied to the corresponding antibody, can activate certain genes that are required for an adaptive immune response. The function of TLR4 as the LPS receptor was discovered by Bruce A. Beutler and colleagues. Over time, the ligands of other TLRs were determined. Shizuo Akira took it a central role.
Structure and ligand
The common structural features of all Toll-like receptors, the N -terminal leucine-rich LRR sequences (leucine rich repeats) and the TIR domain ( Toll/IL-1R homology domain). The different TLRs can identify each different PAMPs ( Pathogen Associated Molecular Patterns ) by direct interaction with the respective membrane surface of the pathogen.
TLR2 recognizes many components of bacteria, mycoplasma, fungi and viruses. This includes the lipoproteins of bacteria and mycoplasma. TLR2 recognizes its ligands in which it forms a heterodimer with either TLR1 or TLR6. The resulting TLR1/TLR2 and TLR6/TLR2 complexes recognize this triacyl or Diacyllipoproteine . The activation of TLR2 leads to the distribution of a number of cytokines. I interferon and usually only partially released; generally is believed that the release of IFN I on the cell type would depend. TLR 10 is similar in primary structure ( sequence identity ) TLR1 and TLR6, but the ligand is not known. TLR4 may recognize LPS (lipopolysaccharide ) on the cell surface together with MD2 ( myeloid differentiation factor 2). LPS is a substance from the outer membrane of gram-negative bacteria and can be the cause of septic shock. In the detection of LPS two TLR -4- MD2 - LPS complexes work together and form a TLR -4 homodimer.
TLR5 is mainly distributed in the lamina propria, where it recognizes bacterial flagellin. As an immune response, induced TLR5 the differentiation of B cells into IgA -producing blood cells and T cells in antigen-specific Th17 and Th1 cells. TLR11 found only in the mouse but not in humans, shows great similarities to TLR5. It recognizes a profilin - like molecule derived from intracellular protozoan Toxoplasma gondii. A number of TLRs, including TLR3, TLR7, TLR8 and TLR9 recognize derived from viral or bacterial nucleic acids. The activation of these TLRs leads to the formation of interferon and other inflammatory causing I cytokines. TLR3 detects viral double-stranded RNA in endolysosom. This prevents the dsRNA to the N -terminal and the C-terminal end of the LRR sequence. TLR3 is also in the detection of poly I: C ( polyinosinic polycytidylic acid) involved.
The intracellular signaling cascade
The Chemoattraktorproteine " C3a " and " C5a " of the complement system caused by proteolytic cleavage of the inactive precursor C3, and C5, respectively. Enables they attract macrophages and neutrophils. These phagocytic cells have receptors on their surface by TLR type. The TLRs to respond to bacterial proteoglycans or lipopolysaccharides (LPS), DNA and RNA. You solve in their support cells from a signaling cascade that ultimately leads to the stimulation of defense against infection. Signaling cascades triggered - After detecting these bacterial surface structures on the extracellular side, are intracellularly - by TLR.
The detection of PAMPs ( pathogen associated molecular patterns ) by TLRs results in an increase in the rate of transcription of specific genes, depending on the TLRs, and which cell types are involved. The difference between the activated by individual TLRs signaling cascades can be explained at least partially containing adapter molecules by the TIR domain (TIR domain-containing adapter molecules). There are here five TIR domain-containing adapter molecules, including MyD88, TRIF/TICAM-1 (TIR domain-containing adapter inducing IFN- β ), TIRAP / Mal, TRAM ( TRIF -related adapter molecule ) and SARM ( sterile - alpha and Armadillo motif-containing protein). TRL signal chains are divided, depending on the involvement of adapter molecules MyD88 and TRIF roughly into two different reaction chains.
This results in the phosphorylation and thus activation of intracellular kinases whose task is to phosphorylation of intracellular inhibitors of transcription factors. First, the adapter protein MyD88 binds to the cytoplasmic portion of TLR. As a result, the IL -1 receptor - associated kinase then binds ( IRAK ) to MyD88 and activates itself by autophosphorylation on further individual steps it comes finally to activation of the transcription factor NF -kB, which translocates then to the nucleus, where the expression of genes for TNF, IL -1, IL -12 and e-selectin regulates.
At TLRs binding drugs
The imiquimod used in various skin diseases and its successor substance Resiquimod (R 848 ) are ligands for TLR7, respectively. TLR7 and TLR 8 HEPLISAV binds to TLR9. Eritoran binds to TLR4.