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Mol Immunol. 2014 Apr;58(2):187-93. doi: 10.1016/j.molimm.2013.11.022. Epub 2013 Dec 22.

Plasma-derived mannose-binding lectin shows a direct interaction with C1-inhibitor.

Author information

1
Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, AMC, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: m.keizer@sanquin.nl.
2
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, AMC, University of Amsterdam, Amsterdam, The Netherlands.
3
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, AMC, University of Amsterdam, Amsterdam, The Netherlands.
4
Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
5
Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands; Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, AMC, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

MBL-deficiency has been associated with an increased frequency and severity of infection, in particular in children and under immunocompromized conditions. In an open uncontrolled safety and pharmacokinetic MBL-substitution study using plasma-derived MBL (pdMBL) in MBL-deficient pediatric oncology patients, we found that despite MBL trough levels above 1.0μg/ml MBL functionality was not efficiently restored upon ex vivo testing. PdMBL showed C4-converting activity by itself, indicating the presence of MASPs. Upon incubation of pdMBL with MBL-deficient sera this C4-converting activity was significantly reduced. Depletion of the MASPs from pdMBL, paradoxically, restored the C4-converting activity. Subsequent depletion or inhibition of C1-inh, the major inhibitor of the lectin pathway, in the recipient serum restored the C4-converting activity as well. Complexes between MBL/MASPs and C1-inh (MMC-complexes) were detected after ex vivo substitution of MBL-deficient serum with pdMBL. These MMC-complexes could also be detected in the sera of the patients included in the MBL-substitution study shortly after pdMBL infusion. Altogether, we concluded that active MBL-MASP complexes in pdMBL directly interact with C1-inh in the recipient, leading to the formation of a multimolecular complex between C1-inh and MBL/MASPs, in contrast to the classical pathway where C1r and C1s are dissociated from C1q by C1-inh. Because of the presence of activated MASPs in the current pdMBL products efficient MBL-mediated host protection cannot be expected because of the neutralizing capacity by C1-inh.

KEYWORDS:

AP; C1-inh; C1-inhibitor; CP; Functionality; HPE; LP; MASPs; MBL; MBL associated serine proteases; MBL-substitution; MBL/MASP/C1-inh; MMC; Mass-Spec; Plasma-derived MBL; Pre-activated MASPs; TMB; TP; alternative pathway; classical pathway; high performance ELISA buffer; lectin pathway; mannan binding lectin; mass-spectrometry; pAb; pdMBL; plasma-derived MBL; polyHRP; polyclonal antibodies; polymerized Horseradish peroxidase; recombinant human MASP-2; recombinant human MBL; rhMASP-2; rhMBL; terminal pathway; tetramethylbenzidine

PMID:
24368318
DOI:
10.1016/j.molimm.2013.11.022
[Indexed for MEDLINE]

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