Pattern Recognition Receptors

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As Pattern Recognition Receptors (PRRs, dt. Approximately, pattern recognition receptors') is a variety of different proteins , the pathogens on the basis of characteristic patterns - the PAMPs - recognize designated. As the trigger of a complex signal cascade , the PRR play a key role in initiating an immune response . Often they are also called Pathogen Recognition Receptors or Primitive Pattern Recognition Receptorsbecause these innate defense mechanisms were used long before the emergence of adaptive immune defense. Most PRR are bound to the surface / to the cell membrane of immune cells or are located inside their cells. Only a few PRRs are freely soluble in the blood. Due to structural similarities, the cell-bound PRRs are divided into several receptor families.

Classification in the immune system

Inflammation is a protective measure of human and animal tissue to protect against pathogens and, if necessary, to initiate the healing process of the damaged tissue. The innate immune system as the most important participant plays a key role here; The main task is to detect and combat harmful intruders without the organism necessarily having to have had contact with the pathogen. If a microorganism manages to overcome the epithelial barrier, the innate immune system intervenes in the form of macrophages, natural killer cells and neutrophils.

However, before the innate immune system can work effectively, the foreign structure must first be recognized by germline-encoded receptors. These receptors are summarized under the generic term Pattern Recognition Receptors (PRR). Detection is only made possible by pathogen-associated molecular patterns (PAMPs). These are specific patterns and codes that are absolutely necessary for the survival or function of the pathogen, so that changing these structures is almost impossible. PRRs on the cell surface can enable the phagocytosis of pathogens or transmit activating signals into the cell. Activation of immune cells is also the main function of all intracellular PRRs. Immune cells can react to this activation in a variety of ways, for example by releasing soluble defense molecules, by killing infected cells or by improving the ability to present antigens .

However, there are also other ways of determining structures that are not the body's own. For example, most of the body's own cells can be distinguished from foreign structures by the major histocompatibility complex (MHC).

Soluble PRRs

A well-studied soluble PRR is mannose-binding lectin . This plasma protein binds to bacterial membrane surfaces, which have a specific spatial arrangement and a specific distance between the mannose and fucose residues . This binding triggers the complement cascade ; the bacteria are more susceptible to phagocytosis . The wetting of the membrane surface of bacteria with proteins that facilitate their phagocytosis is called opsonization .

MBL is part of the collectin proteins. These contain both a collagen-like and a lectin-like domain. Other members of this family are the SP-A (surfacant protein A) and SP-D (surfacant protein D), which are located in the liquid environment of the epithelial cells of the lung. The mannose-binding lectin has all the important structural features of the collectin proteins: It has two to six clusters with CRDs (carbohydrate recognition domains). In each of the clusters, the carbohydrate binding sites are located at a fixed location, which is the basis for the specific recognition. In addition, the protein has a collagen triple helix as a binding site for proteins, a twisted alpha-helical coiled-coil structure, as a link between the carbohydrate and protein binding site and an N-terminal cysteine-rich domain.

Surface PRRs

Scavenger receptors

The scavenger receptors (engl. Scavenger , street sweeper ') allow phagocytes phagocytosis of pathogens. A total of at least nine different receptors were detected, which are divided into different classes (SR-A, -B, -C etc.) based on structural features. SR-A1 occurs mainly in macrophages and binds to a wide variety of polyanionic ligands, which u. a. allows the uptake of bacteria (both gram positive and negative) and dead cells. The importance of this receptor is underlined by the fact that, at least in mice, certain bacteria can no longer be effectively repelled in the absence of SR-A.

C-type lectin receptors

These receptors are also involved in the phagocytosis of pathogens. The binding to various pathogens such as bacteria, viruses, fungi and parasites takes place via a calcium-dependent recognition of typical sugar compounds, so C-type lectin receptors are glycoreceptors. The macrophages' mannose receptor, which recognizes pathogens in a similar way to mannose-binding lectin, is one of the ten different members of this family .

In the Ebola virus , the glycoreceptor " liver and lymph node sinusoidal endothelial cell C - type lectin " (LSECtin) plays an essential role in the effect of the viral surface glycoprotein (GP).

Toll-like receptors (TLRs)

TLRs recognize different components of bacteria, viruses, fungi and protozoa and trigger a strong activation of the immune cells, u. a. via the transcription factor NF-κB . All eleven members of this family are membrane-bound receptors. Some of them are on the cell membrane, others are in intracellular organelles.

Intracellular PRRs

NOD-like receptors (NLRs)

Of the more than 23 variants in the human genome, only a few have been well studied. These recognize bacteria and activate the immune cells by mobilizing the transcription factor NF-kB and the interleukin-1 -activating enzyme caspase-1. This family of receptors has structural similarities to a class of antibodies in plants, the R proteins.

RIG-I-like proteins (RLRs)

The three previously known members of the family are the eponymous RIG-I , MDA5 ( melanoma differentiation-associated protein 5 ) and LGP2. The typical structural elements are the two N-terminal CARD domains ( caspase recruitment domains ), the central DEAD-box helicase with ATPase activity and a C-terminal regulatory domain. In contrast to the TLRs, the RLRs are located in the cytoplasm and can detect double-stranded RNA (dsRNA). Thus you are able to find dsRNA viruses and ssRNA viruses in which dsRNA is produced as an intermediate product of replication. RIG-I recognizes v. a. the Paramyxoviridae such. B. Newcastle disease or parainfluenza . Also Hepatitis C can be found. MDA5 enables a rapid immune response to the Picornaviridae group , as well as the Mengovirus and EMCV. Some flaviviruses , such as dengue fever and West Nile virus, can be detected by both MDA5 and RIG-I.

In contrast to MDA5, RIG-I detects relatively short dsRNA (up to 1000 bp). The presence of a triphosphate at the 5 'end increases the IFN-inducing effect. Technically synthesized ssRNA with a 5'-terminal triphosphate group has no influence on the release of interfron, whereby it was found that double-stranded RNA is necessary for activation of RIG-I. Even dsRNA with only one monophosphate group or without a phosphate group leads to a corresponding, albeit weaker, immune response than with triphosphates. It is not yet known whether special RNA sequences are required for recognition by RIG-I.

literature

  • Charles A. Janeway, Paul Travers, Mark Walport: Immunobiology .6. Edition. B&T, 2005, ISBN 0-8153-4101-6
  • L. Peiser et al .: Scavenger receptors in innate immunity . In: Curr Opin Immunol . Vol. 14, No. 1, 2002, pp. 123-128, PMID 11790542
  • EP McGreal et al .: Ligand recognition by antigen-presenting cell C-type lectin receptors . In: Curr Opin Immunol . Vol. 17, No. 1, 2005, pp. 18-24, PMID 15653305
  • EM Creagh et al .: TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity . In: Trends Immunol . Vol. 27, No. 8, 2006, pp. 352-357, PMID 16807108
  • F. Martinon et al .: NLRs join TLRs as innate sensors of pathogens . In: Trends Immunol . Vol. 26, No. 8, 2005, pp. 447-454, PMID 15967716
  • E. Meylan et al .: Intracellular pattern recognition receptors in the host response . In: Nature . Vol. 442, No. 7098, 2006, pp. 39-44, PMID 16823444

Individual evidence

  1. Iwasaki A, Medzhitov R: Regulation of adaptive immunity by the innate immune system . In: Science . 327, No. 5963, January 2010, pp. 291-5. doi : 10.1126 / science.1183021 . PMID 20075244 .
  2. Jos Tilmann Wolf Gebhard: RT - PCR diagnostics of nosocomially transmitted hemorrhagic fever viruses , pp. 21 and 24, Inaugural - Dissertation, 2013 (PDF)