Mannan-binding lectin

• OMIM: 154545
• UniProt: p11226

The mannose - binding lectin (MBL ) is a protein of the innate immune system in mammals. In humans, the protein is produced in response to infection in the liver and secreted into the blood. Mutations in the MBL2 gene can lead to MBL deficiency, which is associated with increased susceptibility to infection.

MBL is a member of the Acute - phase proteins and a collectin. Collectins belong to the top group of the C - type lectin receptors, whose task is the recognition of foreign structures as the first stage of the immune response. MBL recognizes the carbohydrate patterns in this case, located on the surface of a large number of pathogenic microorganisms, including bacteria, viruses, protozoa and fungi. If the MBL binds to a microorganism, followed by the activation of the complement system via the lectin pathway.

Structure

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

The mannose - binding lectin in this case has all the important Sturkturmerkmale the collectin proteins: it has two to six clusters of CRDs ( carbohydrate recognition domains). In each of the clusters contains the carbohydrate binding sites in a fixed location, which is the basis for the specific detection. In addition, the protein still has a collagen triple helix as a binding site for proteins which a winding alpha-helical coiled-coil structure, the connecting piece between carbohydrate and protein binding site and an N-terminal cysteine-rich domain. In the blood MBL forms with the serine proteases MASP -1 and MASP -2 ( MBL -associated serine protease ) a protein complex. This is similar to the C1 complex of the classical pathway strongly, so it is assumed that both have the same evolutionary origin.

Operation

The complement system can be activated via three different pathways: the classical pathway, the alternative pathway and the lectin pathway. The mannose - binding lectin uses the so-called lectin pathway. It binds to mannose or N-acetyl- glucosamine on the pathogen surface (for example bacterial peptidoglycan ) and then activates the MBL -activated proteases MASP -1, MASP -2 and MASP - third The MASP -2 proteins cleave the blood proteins C4 and C2 into two fragments: C4a, C4b, C2a, C2b. The role of other MASP proteins has not been definitively clarified, but they seem to reinforce the division, even if they can not initiate itself.

The C4b and C2a fragments then link to the membrane surface of the pathogen and lead to the formation of a C3 - convertase. The subsequent complement cascade is similar to the classical pathway. It is catalyzed by the C3 convertase and leading to the formation of a membrane attack Komplexs (MAC). Finally done the lysis of MBL bound to the pathogen. MBL binds proven to yeasts, such as Candida albicans, to viruses such as HIV and influenza A, many bacteria including Salmonella and Streptococcus and to parasites such as Leishmania.

Mutations

MBL2 the gene coding for the mannose -binding lectin, is brought from the liver into the bloodstream. Even if the concentration of MBL in human serum is relatively small (1500 micrograms / liter), MBL plays a crucial role in the innate immune response. The frequency of mutation, immune defect that leads to a lack of mannose - binding lectin, is estimated at 5 to 10%. Such deficiency leads to an increased risk of disease; not only the frequency but also the severity of the progression of the disease is increasing. Although most people are healthy with MBL deficiency, they have an increased susceptibility to certain diseases. The deficiency disease is especially common in young children with recurrent respiratory illnesses, middle ear infections and chronic diarrhea. The usually low concentration of MBL in infants with repeated Infektionenskrankheien, suggests that the mannose -binding - lectin pathway in the period between the loss of passively received the mother's antibodies and the establishment of a dedicated mature immunological defense system, plays an important role.

Although the actual task of MBL is to eliminate bacteria and other pathogens, MBL deficiency can also lead to autoimmune diseases such as lupus erythematosus and rheumatoid arthritis. The immune system has many superfluous pathways so that it remains operational if one of the routes is not functioning. In our case, lead the classical, the lectin, and the alternative pathway C3 convertase and for this common intermediate for activation of the complement system. When the MB - lectin pathway is not working well enough because of MBL deficiency, this is offset by the immune system by the corresponding gain of the other Komplementkaskaden. Particularly noteworthy is the increase in the concentration of the antibodies, which are used as starting material for the classical pathway. The greatly increased number of antibodies in circulation proportional boosts risk of rheumatoid arthritis.

Treatment options

The treatment of MBL deficiency is an area of current research. This involves the intravenous infusion of pure, obtained from human blood donors with the aim of MBL to prevent or reduce infection. The MBL therapy could in future be used in three clinical situations: First of MBL replacement could the immune system be used to strengthen against diseases. Secondly, in the case of an acute infection, the MBL therapy may slow the disease process and lead to faster healing. However, show analogies with similar deficiencies that MBL replacement more harm than good could, as it leads to greater damage in the host organism. In addition, the MBL therapy to alter the course of chronic diseases could be used.