Читать книгу Immunology - Richard Coico - Страница 65

A major class of pattern recognition receptors is the TLRs. The Toll gene family was originally discovered via its contribution to dorsoventral patterning in Drosophila melanogaster embryos. Later, studies showed that Toll genes encode proteins that play a critical role in the fly’s innate immune response to microbial infection. Further investigation then confirmed the existence of homologous proteins in mammals (TLRs) that can activate phagocytes and DCs to respond to pathogens. TLRs make up a large family of receptors and each recognizes specific microbial molecular patterns (Figure 3.5). Activation of cells expressing TLRs following receptor ligation also facilitates initiation of adaptive immune responses due to the production of proinflammatory cytokines by these activated cells. This phenomenon illustrates, yet again, the important functional and coordinated relationship that exists between the innate and adaptive immune systems.

Toll‐like receptors are expressed as membrane‐bound or cytoplasmic receptors that recognize a remarkably large number of PAMPs expressed by viral, bacterial, fungal and parasitic pathogen. TLR1, TLR2, TLR4, TLR5, and TLR6 are primarily expressed on the plasma membrane where they sense specific molecules on the surface of microbes. In contrast, TLR3, TLR7, TLR8, and TLR9 traffic from the endoplasmic reticulum to endolysosomal compartments where they recognize RNA and DNA. TLRs initiate signaling pathways through interactions with adaptor proteins, including MyD88 and Toll/interleukin‐1 receptor domain‐containing adaptor inducing IFN‐β (TRIF). Adaptor proteins function as flexible molecular scaffolds that mediate protein–protein and protein–lipid interactions in signal transduction pathways. When specific TLRs interact with adaptor proteins, signal transduction pathways are activated resulting in generation of mitogen‐associated protein kinases (MAPKs), nuclear factor κB (NF‐κB), and transcription of interferon regulatory factor (IRF)‐responsive genes.

Figure 3.5. Pattern‐recognition receptors called TLRs binding to molecules with specific pattern motifs expressed by various pathogens.