Mannose-binding protein (MBP) is a C-type lectin which recognizes mannose or N-acetylglucosamine. It has collagen-like regions and the Ca2+ dependent carbohydrate recognition domain (CRD) and belongs to the "collectin" family. Serum MBP plays a crucial role in host defence against certain microorganisms bearing appropriate carbohydrates. It acts as an opsonin through binding to the collectin receptor on phagocytes and also activates the complement system, leading to the direct killing of pathogens. MBP-mediated complement activation was first described by Ikeda and colleagues in 1987, who demonstrated that yeast mannan-coated erythrocytes beating rat serum MBP were susceptible to haemolysis by guinea pig serum and that C4 was required for this haemolysis. Since then, bacteria, vires and agalactosyl IgG bearing mannose or N-acetylglucosamine have also been reported to activate complement through the binding of MBP. The MBP-mediated complement cascade is nowadays considered a novel activation pathway designated the "lectin pathway" which differs from the classical and alternative pathways of complement activation.
The lectin pathway is very similar to the classical pathway. It is initiated by the binding of mannose-binding lectin (MBL) to bacterial surfaces with mannose-containing polysaccharides (mannans). Binding of MBL to a pathogen results in the association of two serine proteases, MASP-1 and MASP-2 (MBL-associated serine proteases). MASP-1 and MASP-2 are similar to C1r and C1s, respectively and MBL is similar to C1q. Formation of the MBL/MASP-1/MASP-2 tri-molecular complex results in the activation of the MASPs and subsequent cleavage of C4 into C4a and C4b. The C4b fragment binds to the membrane and the C4a fragment is released into the microenvironment. Activated MASPs also cleave C2 into C2a and C2b. C2a binds to the membrane in association with C4b and C2b is released into the microenvironment. The resulting C4bC2a complex is a C3 convertase, which cleaves C3 into C3a and C3b. C3b binds to the membrane in association with C4b and C2a and C3a is released into the microenvironment. The resulting C4bC2aC3b is a C5 convertase. The generation of C5 convertase is the end of the lectin pathway. The biological activities and the regulatory proteins of the lectin pathway are the same as those of the classical pathway.
Forty years after the proposal of the alternative pathway, the MBL (mannose-binding lectin)/MASP (MBL-associated serine protease) pathway was discovered. This pathway was characterised by using proteins isolated from rabbit liver and serum, but its function remained unclear initially. Two forms of MBL (MBL-A and -C) are present in rodents compared to a single form in the humans. Studies linking the deficiency of MBL protein to immunodeficiencies in children led to its recognition as an important activator of the complement system. The initiating molecules for this pathway are collectins (MBL and ficolin), which are multimeric lectin complexes. These bind to specific carbohydrate patterns uncommon in the host, leading to activation of the pathway through enzymatic activity of MASP. There are structural similarities shared between MBL and C1 complexes (MBL- with C1q-associated serine proteases, MASP-1 and MASP-2 with C1r and C1s, respectively), leading to the belief that complement activation by MBL and C1 complexes are similar. MASP-2 cleaves C4 and C2 to form C3 convertase, while MASP-1 may cleave C3 directly bypassing the C4b2a complex, albeit at a very slow rate. Another serine protease, MASP-3 was shown to down-regulate the C4 and C2 cleaving activity of MASP-2. Following the initial characterisation of MBL, 3 other lectins (known as ficolins) have been shown to interact with MASP: ficolin-1 (or M-ficolin), ficolin-2 (or L-ficolin) and ficolin-3 (or H-ficolin or Hakata antigen). The ficolins activate the lectin pathway by forming active complexes with MASP. More recently, a new C-type lectin (CL-11) was shown to interact with MASP-1 and/or MASP-3 and could activate the lectin pathway.
Mannose-binding lectin (MBL), also known as mannan-binding protein (MBP), is a protein that is involved in complement activation via the lectin pathway. The complement system provides immediate defense against infection and has proinflammatory effects.
MBL deficiency has been variously defined as a serum levels either <100 or <500 ng/mL. It is a laboratory finding that does not necessarily equate to a clinical disorder. Numerous case-control studies with widely varying methodologies have reported that MBL deficiency is associated with a large and heterogeneous group of disease processes. However, subnormal levels are also found in healthy people. To date, there is no consensus on the clinical relevance of MBL deficiency or its treatment.
This topic reviews the genetics, epidemiology, diagnosis, and management of MBL deficiency and also reviews diseases associated with both low and high levels of MBL. Genetic defects and polymorphisms of the MBL2 gene, the function of the MBL protein, and other disorders of the complement system are discussed separately.
1. Thurman J M, et al. (2006). The central role of the alternative complement pathway in human disease. The Journal of Immunology, 176(3), 1305-1310.
2. Turner M W. (2003). The role of mannose-binding lectin in health and disease. Molecular immunology, 40(7), 423-429.