Pattern recognition receptor
Pattern recognition receptors (PRRs)[1] play a crucial role in the proper function of the innate immune system.
Endogenous stress signals are called damage-associated molecular patterns (DAMPs) and include uric acid and extracellular ATP, among many other compounds.
Recognition of extracellular or endosomal pathogen-associated molecular patterns is mediated by transmembrane proteins known as toll-like receptors (TLRs).
[7] TLRs share a typical structural motif, the leucine rich repeats (LRR), which give them their specific appearance and are also responsible for TLR functionality.
[8] Toll-like receptors were first discovered in Drosophila and trigger the synthesis and secretion of cytokines and activation of other host defense programs that are necessary for both innate or adaptive immune responses.
In addition, many of acquired nonself surfaces e.g. carcinoembryonic/oncofetal type neoantigens carrying "internal danger source"/"self turned nonself" type pathogen pattern are also identified and destroyed (e.g. by complement fixation or other cytotoxic attacks) or sequestered (phagocytosed or ensheathed) by the immune system by virtue of the CLRs.
[20][21] It recognizes and binds to repeated mannose units on the surfaces of infectious agents and its activation triggers endocytosis and phagocytosis of the microbe via the complement system.
DC‑associated C‑type lectin 1 (Dectin1) subfamily includes dectin 1/CLEC7A, DNGR1/CLEC9A, Myeloid C‑type lectin‑like receptor (MICL) (CLEC12A), CLEC2 (also called CLEC1B)- the platelet activation receptor for podoplanin on lymphatic endothelial cells and invading front of some carcinomas, and CLEC12B; while DC immunoreceptor (DCIR) subfamily includes DCIR/CLEC4A, Dectin 2/CLEC6A, Blood DC antigen 2 (BDCA2) ( CLEC4C), and Mincle i.e. macrophage‑inducible C‑type lectin (CLEC4E).
The NOD-like receptors (NLRs) are cytoplasmic proteins, which recognize bacterial peptidoglycans and mount proinflammatory and antimicrobial immune response.
[22] Approximately 20 of these proteins have been found in the mammalian genome and include nucleotide-binding oligomerization domain (NODs), which binds nucleoside triphosphate.
When inactive, NODs are in the cytosol in a monomeric state and they undergo conformational change only after ligand recognition, which leads to their activation.
NODs signal via N-terminal CARD domains to activate downstream gene induction events, and interact with microbial molecules by means of a C-terminal leucine-rich repeat (LRR) region.
[25] Another proof of the cooperation and integration of the entire immune system has been shown in vivo, when TLR signaling was inhibited or disabled, NOD receptors took over role of TLRs.
[26] Like NODs, NLRPs contain C-terminal LRRs, which appear to act as a regulatory domain and may be involved in the recognition of microbial pathogens.
They sense the conserved microbial peptidoglycans in the cytoplasm of the cell and therefore represent another level of immune response after membrane-bound receptors such as TLRs and CLRs.
[30] Three RLR helicases have so far been described: RIG-I and MDA5 (recognizing 5'triphosphate-RNA and dsRNA, respectively), which activate antiviral signaling, and LGP2, which appears to act as a dominant-negative inhibitor.
One very important collectin is mannan-binding lectin (MBL), a major PRR of the innate immune system that binds to a wide range of bacteria, viruses, fungi and protozoa.
MBL predominantly recognizes certain sugar groups on the surface of microorganisms but also binds phospholipids, nucleic acids and non-glycosylated proteins.
Plants contain a significant number of PRRs that share remarkable structural and functional similarity with Drosophila Toll and mammalian TLRs.
The first PRR identified in plants or animals was the Xa21 protein, conferring resistance to the Gram-negative bacterial pathogen Xanthomonas oryzae pv.
[40] Plant PRRs either exist as surface-localized receptor kinases (RKs) or receptor-like proteins (RLPs) that contain multiple ligand-binding ectodomains that perceive PAMPs or DAMPs.
These data indicate that kinases associated with PRRs can largely be predicted by the lack of a single conserved residue and reveal new potential plant PRR subfamilies.
[51] Another possibility is to remove the sensor for NOD2, which has been proved efficient in murine models in the effort to suppress the symptoms of Crohn's disease.
In a healthy individual Helicobacter pylori infection is targeted by the combination of PRRs, namely TLRs, NLRs, RLRs and CLR DC-SIGN.
Since all types of PRRs play a role in the identification and eradication of the infection, their specific agonists mount a strong immune response to cancers and other PRR-related diseases.
The TLRs are expressed on most cells of the central nervous system (CNS) and they play a crucial role in sterile inflammation.
