Pathogen-binding Receptors of Innate Immunity
Pathogen-binding Receptors of Innate Immunity
- The innate immune response against the all groups of infectious agents (bacteria, fungi, viruses or protozoans) is largely dependent on primary interaction of the innate immune cells with highly conservative structural motifs of microbial cells or viruses termed as pathogen-associated molecular patterns (PAMP).
- These appeared to be quite similar among the distinct microbial groups. This type of interaction between the innate immune cells and pathogenic agents was designated as pattern-based recognition. It is essential for the innate immune response against the great variety of microbials.
- In turn, the immune system recognizes microbial pathogenic patterns by several groups of specialized receptors. These receptors are phylogenetically ancient; their structure is similar in various animal species that stay on different steps of the evolutionary ladder. They were generally entitled as pattern-recognition receptors or PRRs.
- The first representatives of PRR family were discovered in drosophila fruit flies. They have got the names of Toll receptors. In drosophila flies Toll receptors are responsible for tissue diferentiation and organ morphogenesis. Besides, they were shown to take part in defensive reactions against some infectious pathogens (e.g., fungi).
- In some time it was firmly established that similar receptors are expressed on the cells of highest animals including humans and other mammal species. According to the above mentioned case they were termed as Toll-like receptors or TLRs for short.
- In addition, the members of other families of pattern-recognizing receptors were recently discovered in humans as well.
Toll-like Receptors in Humans and Their Functions
- In humans more than 10 representatives of TLR family were described to date. They are expressed on membranes of many cells of innate immunity.
- The most significant role they play for antigen-presenting cells – dendritic cells, Langerhans cells, macrophages and others.
- TLR-1 binds to lipopeptides of various bacterial groups.
- TLR-2 recognizes the large number of pathogenic microbial patterns – lipoteichoic acids of the most of gram-positive bacteria, borrelial and treponemal lipoproteins, lipoproteins of micobacteria; cell wall structures of neisseriae, listeriae, and fungi.
- TLR-3 binds to double-stranded RNA, thus promoting antiviral immunity.
- TLR-4 interacts with lipopolysaccharides (LPS) of gram-negative bacteria (e.g., enterobacterial representatives) and with heat-shock proteins.
- TLR-5 reacts with bacterial flagellin (microbial Н-antigen).
- TLR-6 also binds to lipopeptides (e.g., in micoplasmas).
- TLR-7 interacts with single-stranded RNA of viruses.
- TLR-8 binds to single-stranded RNA of viruses and bacterial RNA.
- TLR-9 recognizes bacterial and viral DNA.
- TLR-13 reacts with the sequence of bacterial ribosomal RNA.
- Besides TLR receptor family, whose members commonly recognize pathogenic structures from the outside, other families of pattern-recognition receptors (e.g., NOD and RLR) are capable of binding microbial pathogens intracellularly after their invasion and degradation.
- The functions of receptors of TLR family are extremely meaningful in the development of innate natural immune response.
- The basic role of TLRs is the activation of the cells of innate immunity after their primaty binding to the antigens.
- Notably, antigen binding by TLRs on the membranes of dendritic antigen-presenting cells (APC) results in sharp rise of expression of co-stimulatory molecules by dendritic cells.
- This ensures further activation of antigen-specific T cells and their next proliferation. On the contrary, T cells, devoid of co-stimulation, become unresponsive to the certain antigen, falling into anergy state.
- Moreover, primary binding of microbial pathogens to various types of TLR leads to the re-direction of the antimicrobial immunity towards cell-mediated or, alternatively, humoral immune response. Such a change of the immune response depends on the different cytokine profile that is secreted by dendritic cells after alternative TLR activation.
- For instance, stimulation of APC (e.g, dendritic cells) via TLR-4 elicits the production of pro-inflammatory cytokines (IL-1, IL-12, TNF-alpha and interferons) resulting in Th0 transition into Th1 with activation of cellular immunity.
- And conversely, stimulation of APC via TLR-2 largely results in transformation of Th0 into Th2 followed by synthesis of IL-4 and IL-10 cytokines, suppression of inflammatory response and activation of humoral immunity with antibody secretion by plasma cells.
- Besides the recognition of microbial structures, pattern-recognition receptors from TLR and other familes successfuly react with the host products of cell destruction and non-microbial inflammation.
- They were generally termed as damage-associated molecular patterns (DAMPs) or alarmins. Their release is associated with the cell injury.
- The great number of intracellular molecules as well as the components of extracellular matrix can play a role of alarmins (host nucleic acids and nucleotides, hyaluronan and proteoglycan fragments, defensins from leukocytes, and many others).
- The signals from alarmins can also stimulate the cells of innate immunity resulting in inflammation.
- Sometimes pathogen-associated and damage-associated molecular patterns are combined together as danger-associated molecular patterns, which signals stress the immune system activating the innate immune response.