Ch2pp26-29

Innate Immune System Receptors and Functions

• Toll-like receptors (TLRs) recognize various microbial products such as lipopeptides, peptidoglycans, bacterial LPS, flagellin, dsRNA, ssRNA, and unmethylated CpG DNA.
• TLRs specific for microbial proteins, lipids, and polysaccharides are located on cell surfaces, while those recognizing nucleic acids are in endosomes.
• There are five major families of cellular receptors in innate immunity: TLRs, C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and cytosolic DNA sensors (CDSs).
• TLR signals activate transcription factors, such as NF-κB and interferon regulatory factors (IRFs), stimulating the expression of cytokines and proteins involved in inflammation and antiviral response.
• Mutations affecting TLRs or their signaling molecules can cause rare autosomal recessive diseases characterized by recurrent infections, indicating the importance of these pathways in host defense against microbes.
• Different TLRs recognize structurally diverse products of microbes, with plasma membrane TLRs specific for bacterial cell wall components and endosomal TLRs recognizing nucleic acids.
• TLR-4 is specific for bacterial LPS and binds to MD2, while TLR-5 is specific for bacterial flagellin.
• TLRs contain a ligand-binding domain composed of leucine-rich motifs and a cytoplasmic signaling Toll-like interleukin-1 (IL-1) receptor (TIR) domain, activating signaling mechanisms that involve adaptor proteins and lead to the activation of transcription factors.
• TLR engagement by bacterial or viral molecules leads to the activation of NF-κB, which promotes the expression of cytokines, adhesion molecules, and costimulators, resulting in acute inflammation and stimulation of adaptive immunity.
• TLRs in endosomes activate transcription factors and lead to the production of interferon regulatory factors (IRFs), which stimulate the production of type 1 interferon (IFN alpha, beta) and antiviral state.
• TLR-3 mutations make individuals susceptible to herpes simplex virus infections, particularly encephalitis, while mutations in MyD88, a signal transduction adaptor protein downstream of several TLRs, make individuals susceptible to bacterial pneumonias.
• TLRs play a crucial role in host defense against microbes by recognizing a wide range of microbial products and activating signaling mechanisms that lead to inflammation, antiviral defense, and the production of antiviral cytokines.