DOI: 10.1097/TP.0b013e3181abbe6e

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PMID: 19623008

Issn Print: 0041-1337

Publication Date: 2009/07/27


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Mannose-Binding Lectin; the Sugary-Sticky Side of Transplantation

Rob Higgins; Dan Mitchell

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Author Information: Transplant Unit, University Hospitals Coventry and Warwickshire, Coventry, West Midlands, United Kingdom.

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Excerpt

In this issue of Transplantation, Iberon et al. describe an association between low levels of mannose-binding lectin (MBL) in pretransplant serum and the subsequent risk of developing new onset diabetes after renal transplantation (1). This extends previous work in subjects without renal failure, in whom the risk of developing type 2 diabetes was associated with low levels of MBL. Additionally, MBL has been reported to play an important role in autoimmune diseases and infectious responses. There are now a handful of other publications on MBL in transplanted subjects, and this molecule would seem to have an interesting and potentially important role in transplantation at several levels.
MBL is the best studied and probably the most important component of the secretory arm of the innate immune response (2). It is a circulating protein whose primary function is to bind to carbohydrate structures. These structures are those containing principally mannose, N-acetylglucosamine, and fucose residues found on bacteria and fungi, though MBL will also bind to specific self oligosaccharides, such as those found on apoptotic cells and immune complexes. MBL in the blood circulates in complex with the enzyme, MBL-associated serine protease-2 (MASP-2), that cleaves C4 into C4a and C4b, thus activating the complement system through the lectin pathway. Opsonization by macrophages and other leukocytes is also promoted. The lectin pathway of complement activation can also be triggered by other defense collagens, namely L-ficolin, H-ficolin, and M-ficolin.
Polymorphisms in the promoter and structural regions of the MBL gene determine the serum concentration of MBL. A number of studies both of the genetic polymorphisms and the serum concentrations of MBL in subjects without renal failure have indicated associations with infectious, autoimmune, neoplastic, metabolic, and cardiovascular diseases.
Why might low serum levels of MBL be associated with the risk of type 2 diabetes? Subjects with low MBL levels also have higher levels of inflammatory markers and tumor necrosis factor-α, and it is hypothesized that low grade infections because of reduced immune potential result in increased inflammation, and this promotes insulin resistance. This hypothesis is plausible but unproven. Paradoxically, other studies have shown in type 1 diabetes that higher levels of MBL are associated with the development of vascular disease, the hypothesis being that MBL may enhance endothelial damage by binding to abnormal cells.
Low MBL levels may be associated with increased risk of infections after renal and liver transplantation. However, the findings in different studies have not been entirely consistent, with the risk of CMV infection associated with MBL levels in one study but not another, and not associated with MBL but with lower MASP-2 levels in a third study. After liver transplantation, MBL levels were associated with the donor genotype because MBL is synthesized in the liver, and low levels were associated with approximately a threefold increase in an index of combined viral and bacterial infections.
What is the role of MBL in alloimmunity? This has been addressed in a small number of studies. There was an association between serum MBL levels pretransplant and long-term renal graft survival in one retrospective study, with a relative risk of graft loss of 2.7 in subjects with high MBL levels (3). In a study of renal transplant biopsies, MBL staining was not associated with rejection, but there was an association between C4d staining and H-ficolin staining. A number of these grafts were ABO incompatible, raising the possibility of lectin involvement in complement activation in this clinical setting (4). Whether lectins could bind preferentially, or in an antibody-independent manner, to incompatible ABO carbohydrates (rich in fucose) on a graft is worthy of further investigation.
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