Mannose-binding Lectin Deficiency Offers Protection From Acute Graft Rejection After Heart Transplantation James E. Fildes, PhD, Steven M. Shaw, MRCP, Antony H. Walker, MD, Michael McAlindon, MBChB, Simon G. Williams, MD, Brian G. Keevil, MSc, and Nizar Yonan, MD Mannose-binding lectin (MBL) deficiency (or the common opsonic defect) has been reported as a risk factor for several immunologically controlled conditions, including infection and graft rejection. However, the effects of MBL deficiency on acute rejection after heart transplantation are unknown. Ninety heart transplant recipients were included in this study. Plasma MBL quantification was performed using a commercially available enzyme-linked immunoassay (ELISA). Acute rejection was diagnosed via endomyocardial biopsy and histologic assessment. MBL concentration was controlled for demographics, immunosuppression and anti-viral therapy. Individuals with dysfunctional MBL had significantly fewer rejection episodes (6.3  3.8%) than those with functional MBL (12.9  11.6%) (p = 0.016). We found no significant difference between MBL concentrations among those with (1,232  58 ng/ml) and those without (1,216  161 ng/ml) GCAD (p = 0.841). There was also no significant difference between the incidence of GCAD in those with “normal” concentrations (p = 0.782). Heart transplant recipients with MBL deficiency had fewer acute graft rejection episodes compared to patients with functional MBL. This suggests the lectin pathway of complement activation is an important process in graft rejection. Furthermore, functional MBL may indicate a greater likelihood of rejection. J Heart Lung Transplant 2008;27:1353– 6. Copyright © 2008 by the International Society for Heart and Lung Transplantation. Historically, the pathogenesis of graft rejection after organ transplantation was believed to occur predomi- nantly via adaptive immune responses. More recently, cells of the innate immune system have been shown to play key roles in the orchestration of events that lead to graft rejection. 1,2 This has led to a resurgence in studies exploring the roles of innate components in graft rejection, including the complement cascade. 3 Complement is essential for the rapid recognition of pathogens, yet its role after organ transplantation re- mains unclear. Complement activation has the potential to initiate a series of complex immune processes, which have the capacity to destroy graft cells. 3,4 Animal work has provided preliminary evidence that comple- ment blockade prevents graft rejection and graft loss. 5 This phenomenon has also been translated into human transplantation, with reports suggesting that the initia- tor protein of the lectin pathway, mannose-binding lectin (MBL), is essential for successful complement activation. 6 MBL is a C-type lectin that specifically binds carbohydrate residues (mannose, glucose, fucose and N-acetylglucosamine). 7 After ligand binding, MBL com- mits the generation of C3 convertase by cleaving C4 and C2, which ultimately leads to the formation of the lipophilic membrane attack complex (MAC). MAC for- mation induces rapid target cell death, as large pores are formed on the target cell surface. This disrupts the intracellular environment and necrosis occurs. A series of mutations exist in exon 1 of the MBL- encoding gene, MBL2, which are responsible for a defect in the MBL binding site. 8 These mutations pre- vent MBL binding to its ligands and cause MBL serum deficiency in humans. 9 The most severe genetic defect results in dysfunctional high-molecular-weight MBL, which theoretically disables the lectin pathway of com- plement activation. Detection of dysfunctional MBL can be easily achieved using an enzyme-linked immunoas- say (ELISA), where antibody binding does not occur as a result of the mutation. This technique has been reported to be more relevant in assessing patients with MBL deficiency than in determining MBL genotype. 10 MBL deficiency has been associated with an increased susceptibility to bacterial and viral infection (termed the common opsonic defect) and, more recently, to chronic rejection after transplantation. 11 However, the role of MBL and MBL deficiency in the pathogenesis of acute rejection remains unclear, as there have been conflicting reports. This study was designed to assess the effects of MBL functionality in a heart transplant cohort, in an attempt to delineate the role of MBL and, ultimately, lectin-dependent complement activation in acute graft rejection. From the Transplant Centre, University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK. Submitted April 3, 2008; revised June 17, 2008; accepted August 26, 2008. Reprint requests: James E. Fildes, PhD, Transplant Centre, Univer- sity Hospital of South Manchester NHS Foundation Trust, Manchester M23 9LT, UK. Telephone: +44-161-291-5023. Fax: +44-161-291- 5024. E-mail: james.fildes@manchester.ac.uk Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.08.011 1353