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Gastroenterology 09/2011; 141(5):e3-4. · 11.68 Impact Factor
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Bert-Jan F de Rooij,
Bart van Hoek,
W Rogier ten Hove,
Anja Roos, Lee H Bouwman,
Alexander F Schaapherder,
Robert J Porte,
Mohamed R Daha,
Johan J van der Reijden,
Minneke J Coenraad,
Jan Ringers,
Andrzej G Baranski,
Bouke G Hepkema,
Daniel W Hommes,
Hein W Verspaget
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ABSTRACT: Infectious complications after orthotopic liver transplantation (OLT) are a major clinical problem. The lectin pathway of complement activation is liver-derived and a crucial effector of the innate immune defense against pathogens. Polymorphisms in lectin pathway genes determine their functional activity. We assessed the relationship between these polymorphic genes and clinically significant bacterial infections, i.e., sepsis, pneumonia, and intra-abdominal infection, and mortality within the first year after OLT, in relation to major risk factors in two cohorts from different transplant centers. Single-nucleotide polymorphisms in the mannose-binding lectin gene (MBL2), the ficolin-2 gene (FCN2), and the MBL-associated serine protease gene (MASP2) of recipients and donors were determined. Recipients receiving a donor liver in the principal cohort with polymorphisms in all three components i.e., MBL2 (XA/O; O/O), FCN2+6359T, and MASP2+371A, had a cumulative risk of an infection of 75% as compared to 18% with wild-type donor livers (P = 0.002), an observation confirmed in the second cohort (P = 0.04). In addition, a genetic (mis)match between donor and recipient conferred a two-fold higher infection risk for each separate gene. Multivariate Cox analysis revealed a stepwise increase in infection risk with the lectin pathway gene profile of the donor (hazard ratio = 4.52; P = 8.1 x 10(-6)) and the donor-recipient (mis)match genotype (hazard ratio = 6.41; P = 1.9 x 10(-7)), independent from the other risk factors sex and antibiotic prophylaxis (hazard ratio > 1.7 and P < 0.02). Moreover, patients with a lectin pathway gene polymorphism and infection had a six-fold higher mortality (P = 0.9 x 10(-8)), of which 80% was infection-related. CONCLUSION: Donor and recipient gene polymorphisms in the lectin complement pathway are major determinants of the risk of clinically significant bacterial infection and mortality after OLT.
Hepatology 09/2010; 52(3):1100-10. · 11.66 Impact Factor
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ABSTRACT: This case report describes a 69-year-old man presenting with an extensive subcutaneous emphysema in his neck and generalized peritonitis caused by a lower gastrointestinal tract perforation. This case emphasizes that subcutaneous emphysema patients with negative thoracic findings should be scrutinized for signs of retroperitoneal hollow viscus perforation.
World Journal of Gastroenterology 07/2008; 14(24):3922-3. · 2.47 Impact Factor
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Dermatologic Surgery 09/2007; 33(8):980-1. · 1.80 Impact Factor
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ABSTRACT: Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL polymorphisms have been described that are associated with MBL serum concentration, impaired function, and diabetic complications. We investigated 86 new-onset juvenile type 1 diabetic patients and compared these with their nondiabetic siblings and healthy unrelated control subjects. Polymorphisms of MBL exon 1 and promoter were determined, and serum concentration and MBL-complex activity were measured. Although the genetic polymorphisms of MBL were not different between patients and control subjects, MBL serum concentration as well as MBL complex activity was significantly higher in new-onset diabetic patients compared with their siblings matched for high-producing MBL genotypes (P = 0.0018 and P = 0.0005, respectively). The increase in MBL complex activity in high-MBL-producing patients could only partially be explained by high MBL production, as demonstrated by an increased MBL complex activity-to-MBL concentration ratio (P = 0.004). We conclude that MBL serum concentration and complex activity are increased in early-onset diabetic patients upon manifestation independently of genetic predisposition to high MBL production, indicating a possible role in the immunopathogenesis of type 1 diabetes, in addition to the adaptive islet autoimmunity.
Diabetes 11/2005; 54(10):3002-6. · 8.29 Impact Factor
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Lee H Bouwman,
Anja Roos,
Onno T Terpstra,
Peter de Knijff,
Bart van Hoek,
Hein W Verspaget,
Stefan P Berger,
Mohamed R Daha,
Marijke Frölich,
Arno R van der Slik,
Ilias I Doxiadis,
Bart O Roep,
Alexander F M Schaapherder
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ABSTRACT: Infection is the primary cause of death after liver transplantation. Mannose binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL variant alleles have been described in the coding region of the MBL gene, which are associated with low MBL serum concentration and impaired MBL structure and function. The aims of our study were to establish the role of the liver in production of serum MBL and to evaluate the effect of MBL variant alleles on the susceptibility to infection after liver transplantation.
We investigated 49 patients undergoing orthotopic liver transplantation. MBL exon 1 and promoter polymorphisms were determined in patients and in liver donors. MBL serum concentration was determined before and during 1 year after transplantation. The incidence of clinically significant infections during this period was assessed.
Transplantation of MBL wildtype recipients with donor livers carrying MBL variant alleles resulted in a rapid and pronounced decrease of serum MBL levels. This serum conversion was associated with the disappearance of high molecular weight MBL. No indication for extrahepatic production of serum MBL could be obtained. The presence of MBL variant alleles in the MBL gene of the donor liver, but not in the recipient, was associated with a strongly increased incidence of clinically significant infections after transplantation.
Serum MBL is produced by the liver under strong genetic control. After liver transplantation, the MBL genotype of the donor liver is a major risk determinant for life-threatening infections.
Gastroenterology 08/2005; 129(2):408-14. · 11.68 Impact Factor
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ABSTRACT: Type 1 diabetes mellitus (T1D) is a T-cell-mediated autoimmune disease characterized by the destruction of beta cells in the pancreas. An attractive novel therapy for type 1 diabetes is pancreatic islet transplantation, provided that recurrent islet autoimmunity and allograft rejection can be prevented. We analyzed the response of peripheral blood mononuclear cells (PBMC) from healthy blood donors to human islet-cell preparations with a composition similar to that of islet grafts used in clinical transplantation trials. It was examined whether the degree of major histocompatibility complex incompatibility between PBMC and donor islet cells is related to the degree of proliferative T-cell responses during coculture of human leukocyte antigen (HLA)-matched and mismatched PBMC with human islet cell-preparations (i.e., mixed islet/lymphocyte reaction). Prominent T-cell responses were observed in the vast majority of cases of double HLA class II mismatches. Intermediate T-cell responsiveness was observed in single HLA class II mismatches, whereas HLA matches did not induce a T-cell response. Our results identify the potential immunogenicity of islet preparations transplanted between HLA-DR incompatible subjects regardless of an autoimmune background of the recipient.
Human Immunology 06/2005; 66(5):494-500. · 2.84 Impact Factor
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Anja Roos,
Peter Garred,
Manon E Wildenberg,
Nicholas J Lynch,
Jeric R Munoz,
Tahlita C M Zuiverloon, Lee H Bouwman,
Nicole Schlagwein,
Francien C Fallaux van den Houten,
Maria C Faber-Krol,
Hans O Madsen,
Wilhelm J Schwaeble,
Misao Matsushita,
Teizo Fujita,
Mohamed R Daha
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ABSTRACT: Deficiency of mannose-binding lectin (MBL), a recognition molecule of the lectin pathway of complement, is associated with increased susceptibility to infections. The high frequency of MBL deficiency suggests that defective MBL-mediated innate immunity can be compensated by alternative defense strategies. To examine this hypothesis, complement activation by MBL-binding ligands was studied. The results show that the prototypic MBL ligand mannan can induce complement activation via both the lectin pathway and the classical pathway. Furthermore, antibody binding to mannan restored complement activation in MBL-deficient serum in a C1q-dependent manner. Cooperation between the classical pathway and the lectin pathway was also observed for complement activation by protein 60 from Listeria monocytogenes. MBL pathway analysis at the levels of C4 and C5b-9 in the presence of classical pathway inhibition revealed a large variation of MBL pathway activity, depending on mbl2 gene polymorphisms. MBL pathway dysfunction in variant allele carriers is associated with reduced MBL ligand binding and a relative increase of low-molecular-mass MBL. These findings indicate that antibody-mediated classical pathway activation can compensate for impaired target opsonization via the MBL pathway in MBL-deficient individuals, and imply that MBL deficiency may become clinically relevant in absence of a concomitant adaptive immune response.
European Journal of Immunology 10/2004; 34(9):2589-98. · 5.10 Impact Factor
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ABSTRACT: Mannan-binding lectin (MBL) is a major initiator of the lectin pathway (LP) of complement. Polymorphisms in exon 1 of the MBL gene are associated with impaired MBL function and infections. Functional assays to assess the activity of the classical pathway (CP) and the alternative pathway (AP) of complement in serum are broadly used in patient diagnostics. We have now developed a functional LP assay that enables the specific quantification of autologous MBL-dependent complement activation in human serum. Complement activation was assessed by ELISA using coated mannan to assess the LP and coated IgM to assess the CP. Normal human serum (NHS) contains IgG, IgA and IgM antibodies against mannan, as shown by ELISA. These antibodies are likely to induce CP activation. Using C1q-blocking and MBL-blocking mAb, it was confirmed that both the LP and the CP contribute to complement activation by mannan. In order to quantify LP activity without interference of the CP, LP activity was measured in serum in the presence of C1q-blocking Ab. Activation of serum on coated IgM via the CP resulted in a dose-dependent deposition of C1q, C4, C3, and C5b-9. This activation and subsequent complement deposition was completely inhibited by the C1q-blocking mAb 2204 and by polyclonal Fab anti-C1q Ab. Evaluation of the LP in the presence of mAb 2204 showed a strong dose-dependent deposition of C4, C3, and C5b-9 using serum from MBL-wildtype (AA) but not MBL-mutant donors (AB or BB genotype), indicating that complement activation under these conditions is MBL-dependent and C1q-independent. Donors with different MBL genotypes were identified using a newly developed oligonucleotide ligation assay (OLA) for detection of MBL exon 1 polymorphisms. We describe a novel functional assay that enables quantification of autologous complement activation via the LP in full human serum up to the formation of the membrane attack complex. This assay offers novel possibilities for patient diagnostics as well as for the study of disease association with the LP.
Molecular Immunology 02/2003; 39(11):655-68. · 2.90 Impact Factor
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ABSTRACT: Mannose-binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL variant alleles have been described in the coding region of the MBL gene, which are associated with low MBL serum concentration and impaired MBL structure and function. Both high and low serum levels of functional MBL have been associated with a variety of diseases and disease complications. Functioning as double-edged sword, low MBL serum levels have been shown to enhance the risk for infections. On the other hand, high MBL serum levels and high MBL activity have been associated with inflammatory diseases, transplant rejection, and diabetic nephropathy. Underscoring the Jekyll-and-Hyde character of MBL, both high and low serum MBL levels are associated with several aspects of autoimmune diseases. This review provides a general outline of the genetic and molecular characteristics of MBL and discusses MBL-disease association and its consequence in infection, transplantation, and autoimmunity.
Human Immunology 67(4-5):247-56. · 2.84 Impact Factor
