Mannose-binding lectin

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Mannose-binding lectin
Mannose-binding lectin
Ribbon model of amino acids 108-248 in the monomer of mannose-binding lectin
Properties of human protein
Mass / length primary structure 228 amino acids
Secondary to quaternary structure Oligomer from homotrimers
Cofactor Ca 2+
Identifier
Gene name MBL2
External IDs
Occurrence
Parent taxon Mammals
Orthologue
human House mouse
Entrez 4153 17195
Ensemble ENSG00000165471 ENSMUSG00000024863
UniProt P11226 P41317
Refseq (mRNA) NM_000242 NM_010776
Refseq (protein) NP_000233 NP_034906
Gene locus Chr 10: 52.76 - 52.77 Mb Chr 19: 30.23 - 30.24 Mb
PubMed search 4153 17195

The mannose-binding lectin (MBL) is a protein of the innate immune system in mammals . In humans, the protein is produced in the liver in response to infection and is released into the blood . Mutations in the MBL 2 - gene can MBL deficiency cause associated with increased susceptibility to infection.

MBL is a member of the Acute Phase Proteins and a Collectin. Collectins belong to the upper group of the C-type lectin receptors , whose task is the recognition of foreign structures as the first stage of the immune defense . MBL detects carbohydrate patterns that are on the surface of a large number of pathogenic microorganisms , including bacteria , viruses , protozoa and fungi . When the MBL binds to a microorganism, activation of the complement system follows via the lectin pathway .

structure

MBL has an oligomeric structure (400–700  kDa ) and consists of several subunits, each containing three identical peptide chains of about 32 kDa in size. Although it can form various oligomeric forms, there is evidence that dimers and trimers are not biologically active and that at least one tetrameric form is necessary to activate the complement system.

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 α-helical coiled-coil structure as a link between the carbohydrate and protein binding site and an N -terminal cysteine-rich domain. In the blood, MBL forms a protein complex with the serine proteases MASP-1 and MASP-2 (MBL-associated serine protease) . This is very similar to the C1 complex of the classical path, so that it is assumed that both have the same evolutionary origin.

Mode of action

The complement system can be activated in three different ways: the classic way, the alternative way and the lectin way. The mannose-binding lectin uses the so-called lectin path. It binds to mannose or N-acetylglucosamine on the pathogenic surface (e.g. bacterial peptidoglycan) and then activates the MBL-activated proteases MASP-1, MASP-2 and MASP-3. The MASP-2 proteins split the blood proteins C4 and C2 into two fragments each: C4a, C4b, C2a, C2b. The role of the other MASP proteins has not been finally clarified, but they seem to intensify the splitting even if they cannot initiate it themselves.

The C4b and C2b fragments then combine on the membrane surface of the pathogen and lead to the formation of a C3 convertase. The subsequent complement cascade resembles the classic way. It is catalyzed by the C3 convertase and leads to the formation of a membrane attack complex (MAC). Finally, the lysis is carried out of bound to the MBL pathogen . MBL has been shown to bind to yeasts such as Candida albicans , to viruses such as HIV and Influenza A , to many bacteria, including salmonella and streptococci, and to parasites such as leishmania .

Mutations

The MBL2 gene codes for mannose-binding lectin, which is brought into the bloodstream by the liver. Even if the concentration of MBL in human serum is relatively low (1500 micrograms / liter), MBL plays a decisive role in the innate immune system. The incidence of a mutation-related immunodeficiency that leads to a lack of mannose-binding lectin is estimated to be 5 to 10%. Such a deficiency leads to an increased risk of illness; not only the frequency but also the severity of the disease progresses. Although most people with MBL deficiency are healthy, they are more susceptible to certain diseases. The deficiency disease is particularly common in small children with recurring respiratory diseases , otitis media and chronic diarrhea . The mostly low concentration of MBL in infants with recurrent infectious diseases suggests that the mannose binding-lectin pathway plays an important role in the period between the loss of passively obtained antibodies from the mother and the formation of a mature immune system.

Although the real job of MBL is to eliminate bacteria and other pathogens, MBL deficiency also leads to autoimmune conditions such as lupus erythematosus and rheumatoid arthritis . The immune system has many superfluous reaction pathways so that it can continue to function if one of the pathways does not work. In our case, the classic, the lectin, and the alternative route lead to C3 convertase and via this common intermediate stage to the activation of the complement system. If the MB lectin pathway does not work sufficiently well due to the MBL deficiency, this is compensated by the immune system by correspondingly strengthening the other complement cascades. Particularly noteworthy is the increase in the concentration of antibodies, which are used as the starting product of the classic route. The greatly increased number of antibodies in circulation proportionally increases the risk of developing rheumatoid arthritis.

Therapy options

The treatment of MBL deficiency is an area of ​​current research. This involves the intravenous infusion of pure MBL obtained from human donor blood with the aim of preventing or reducing infections. In the future, MBL therapy could be used in three clinical situations: First, the MBL replacement could be used to strengthen the immune defense against diseases. Second, in the case of an acute infection , MBL therapy could weaken the course of the disease and lead to faster healing. However, analogies with similar deficiency symptoms show that the MBL replacement could do more harm than good, since it leads to greater damage in the host organism. In addition, MBL therapy could be used to change the course of chronic diseases .

Individual evidence

  1. ↑ Orthologist at OMA
  2. ↑ E. Tutdibi, A. Black, D. Monz, G. Dockter, L. Gortner: surfactant protein D and mannan-binding lectin in the serum of patients with CF and chronic Pseudomonas aeruginosa infection. In: Z Obstetrics Neonatol. Volume 213, 2009. doi : 10.1055 / s-0029-1223124 .
  3. ↑ UniProt P11226
  4. ↑ IP Fraser, H. Koziel, RA Ezekowitz: The serum mannose-binding protein and the macrophage mannose receptor are pattern recognition molecules that link innate and adaptive immunity. . In: Semin. Immunol. . 10, No. 5, 1998, pp. 363-72. doi : 10.1006 / smim.1998.0141 . PMID 9799711 .
  5. ↑ Worthley DL, Bardy PG, Mullighan CG: Mannose-binding lectin: biology and clinical implications. . In: Internal medicine journal . 35, No. 9, 2005, pp. 548-55. doi : 10.1111 / j.1445-5994.2005.00908.x . PMID 16105157 .
  6. ↑ Worthley DL, Bardy PG, DL Gordon, Mullighan CG: Mannose-binding lectin and maladies of the bowel and liver . In: World J. Gastroenterol. . 12, No. 40, October 2006, pp. 6420-8. PMID 17072973 .
  7. ↑ S. Sheriff, CY Chang, RA Ezekowitz: Human mannose-binding protein carbohydrate recognition domain trimerizes through a triple alpha-helical coiled-coil . In: Nat. Struct. Biol . 1, No. 11, November 1994, pp. 789-94. doi : 10.1038 / nsb1194-789 . PMID 7634089 .
  8. ↑ Janeway et al .: Immunobiology. Garland Science, New York, NY. 2005, pp. 54-55.
  9. ↑ Misao Matsushita et al .: Proteolytic activities of two types of mannose-binding lectin-associated serine protease. In: The Journal of Immunology. Volume 165, 2000, pp. 2637-2642.
  10. ↑ Janeway et al .: Immunobiology. Garland Science, New York, NY. 2005, pp. 66-67.
  11. ↑ Lauren Sompayrac: How the Immune System Works. Blackwell Science, Malden, MA. 1999, pp. 17-19.
  12. ↑ Janeway et al .: Immunobiology. Garland Science, New York, NY. 2005, p. 66.
  13. ^ MA de Jong, LE Vriend, B. Theelen, ME Taylor, D. Fluitsma, T. Boekhout, TB Geijtenbeek: C-type lectin Langerin is a beta-glucan receptor on human Langerhans cells that recognizes opportunistic and pathogenic fungi . In: Mol. Immunol. . 47, No. 6, March 2010, pp. 1216-1225. doi : 10.1016 / j.molimm.2009.12.016 . PMID 20097424 . PMC 2837148 (free full text).
  14. ↑ X. Ji, H. Gewurz, GT Spear: Mannose binding lectin (MBL) and HIV . In: Mol. Immunol. . 42, No. 2, February 2005, pp. 145-152. doi : 10.1016 / j.molimm.2004.06.015 . PMID 15488604 .
  15. ↑ Lauren Sompayrac: How the Immune System Works. Blackwell Science, Malden, MA. 1999, pp. 17-19.
  16. ^ MW Turner: Mannose-binding lectin (MBL) in health and disease. In: Immunobiology. Volume 199. No. 2, 1998, pp. 327-339.
  17. ^ MW Turner: Deficiency of mannan binding protein - a new complement deficiency syndrome. In: Clin Exp Immunology Volume 86, 1991, pp. 53-56.
  18. ↑ Flemming et al .: Disease-associated mutations in human mannose-binding lectin compromise oligomerization and activity of the final protein. In: Journal of Biological Chemistry . Volume 279, 2004, pp. 21302-21311.
  19. ↑ Summerfield et al .: Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series. In: British Medical Journal Volume 314, 1997, pp. 1229-1231.
  20. ^ S. Jacobsen et al .: The influence of mannose binding lectin polymorphisms on disease outcome in early polyarthritis. In: The Journal of Rheumatology . Volume 28, No. 5, 2001, pp. 935-942.
  21. ↑ JA Summerfiled: Clinical potential of mannose-binding lectin-replacement therapy. In: Biochemical Society Transactions . Aug. 2003, pp. 770-773.

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