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• _5 value "All living organisms are exposed constantly to microorganisms that are present in the environment and need to cope with invasion of these organisms into the body. The vertebrate immune response can be divided into innate and acquired immunity, with innate immunity being the first line of defence against pathogens. By contrast, acquired immune responses are slower processes, which are mediated by T and B cells, both of which express highly diverse antigen receptors that are generated through DNA rearrangement and are thereby able to respond to a wide range of potential antigens. This highly sophisticated system of antigen detection is found only in vertebrates and has been the subject of considerable research. Far less attention has been directed towards innate immunity, as it has been regarded as a relatively nonspecific system, with its main roles being to destroy pathogens and to present antigen to the cells involved in acquired immunity. However, recent studies have shown that the innate immune system has a greater degree of specificity than was previously thought and that it is highly developed in its ability to discriminate between self and foreign pathogens1. This discrimination relies, to a great extent, on a family of evolutionarily conserved receptors, known as the Toll-like receptors (TLRs), which have a crucial role in early host defence against invading pathogens1, 2. Furthermore, accumulating evidence indicates that activation of the innate immune system is a prerequisite for the induction of acquired immunity, particularly for the induction of a T helper 1 (TH1)-cell response3, 4. This marked shift in our thinking has changed our ideas about the pathogenesis and treatment of cancers, and infectious, immune and allergic diseases. In the past few years, our knowledge of TLR signalling and the responses these receptors control has greatly increased. In this review, we discuss the TLRs, focusing on their signalling pathways. TLR/IL-1R superfamily: structure and function The discovery of the TLR family began with the identification of Toll, a receptor that is expressed by insects and was found to be essential for establishing dorsoventral polarity during embryogenesis5. Subsequent studies revealed that Toll also has an essential role in the insect innate immune response against fungal infection6. Homologues of Toll were identified through database searches, and so far, 11 members of the TLR family have been identified in mammals. The TLRs are type I integral membrane glycoproteins, and on the basis of considerable homology in the cytoplasmic region, they are members of a larger superfamily that includes the interleukin-1 receptors (IL-1Rs). By contrast, the extracellular region of the TLRs and IL-1Rs differs markedly: the extracellular region of TLRs contains leucine-rich repeat (LRR) motifs, whereas the extracellular region of IL-1Rs contains three immunoglobulin-like domains (Fig. 1a). Figure 1 | TLR structure and signalling. a | Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) have a conserved cytoplasmic domain, that is known as the Toll/IL-1R (TIR) domain. The TIR domain is characterized by the presence of three highly homologous regions (known as boxes 1, 2 and 3). Despite the similarity of the cytoplasmic domains of these molecules, their extracellular regions differ markedly: TLRs have tandem repeats of leucine-rich regions (known as leucine rich repeats, LRR), whereas IL-1Rs have three immunoglobulin (Ig)-like domains. b | Stimulation of TLRs triggers the association of MyD88 (myeloid differentiation primary-response protein 88), which in turn recruits IRAK4 (IL-1R-associated kinase 4), thereby allowing the association of IRAK1. IRAK4 then induces the phosphorylation of IRAK1. TRAF6 (tumour-necrosis-factor-receptor-associated factor 6) is also recruited to the receptor complex, by associating with phosphorylated IRAK1. Phosphorylated ..." provenance.