Restoration of MBL-deficiency: Redefining the safety, efficacy and viability of MBL-substitution therapy

Keizer, Mischa P.; Wouters, Diana; Schlapbach, Luregn J.; Kuijpers, Taco W.

doi:10.1016/j.molimm.2014.06.005

Cited by 37 publications

(34 citation statements)

References 137 publications

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“…Two genes encode all five naturally-occurring MASP isoforms in mammals (17): three proenzymes (i.e., MASP-1, -2, and -3) and the two non-proteolytic proteins sMAP (MAp19) and MAP-1. The proteolytic MASPs consist of a heavy chain—comprised of two CUB domains separated by an epidermal growth factor (EGF) domain, and two complement control protein/short consensus repeats (CCP/SCR) modules—and a light chain composed of the serine protease domain.…”

Section: Introductionmentioning

confidence: 99%

Chimeric Proteins Containing MAP-1 and Functional Domains of C4b-Binding Protein Reveal Strong Complement Inhibitory Capacities

et al. 2018

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The complement system is a tightly regulated network of proteins involved in defense against pathogens, inflammatory processes, and coordination of the innate and adaptive immune responses. Dysregulation of the complement cascade is associated with many inflammatory disorders. Thus, inhibition of the complement system has emerged as an option for treatment of a range of different inflammatory diseases. MAP-1 is a pattern recognition molecule (PRM)-associated inhibitor of the lectin pathway of the complement system, whereas C4b-binding protein (C4BP) regulates both the classical and lectin pathways. In this study we generated chimeric proteins consisting of MAP-1 and the first five domains of human C4BP (C4BP1−5) in order to develop a targeted inhibitor acting at different levels of the complement cascade. Two different constructs were designed and expressed in CHO cells where MAP-1 was fused with C4BP1−5 in either the C- or N-terminus. The functionality of the chimeric proteins was assessed using different in vitro complement activation assays. Both chimeric proteins displayed the characteristic Ca2+-dependent dimerization and binding to PRMs of native MAP-1, as well as the co-factor activity of native C4BP. In ELISA-based complement activation assays they could effectively inhibit the lectin and classical pathways. Notably, MAP-1:C4BP1−5 was five times more effective than rMAP-1 and rC4BP1−5 applied at the same time, emphasizing the advantage of a single inhibitor containing both functional domains. The MAP-1/C4BP chimeras exert unique complement inhibitory properties and represent a novel therapeutic approach targeting both upstream and central complement activation.

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Section: Introductionmentioning

confidence: 99%

Chimeric Proteins Containing MAP-1 and Functional Domains of C4b-Binding Protein Reveal Strong Complement Inhibitory Capacities

et al. 2018

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“…What is important for this report, both neoepitope–IgM complexes and DAMPs, which are exposed or released at the initial phase of mobilization, are recognized by circulating MBL, which, in cooperation with MASP, triggers activation of both the ComC and the CoaC. 15 …”

mentioning

confidence: 96%

Novel evidence that the mannan-binding lectin pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades

et al. 2016

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“…An extraordinary redundancy of most of the system components may mask a deficiency or malfunctioning of an individual component. Moreover, several components display context specific properties, where they can act as dual function surveillance molecules, suppressing or enhancing inflammation, as, e.g., shown for the lung collectins (27,28). Therefore, we also corrected for the other lectin pathway proteins for which the concentrations upon PICU admission had been measured (17).…”

Section: Discussionmentioning

confidence: 99%

“…To evaluate the association of CL-L1 serum concentrations upon PICU admission with risk of infection, independent of known risk factors, multivariable logistic regression analysis was performed. The classical baseline characteristics and risk factors (age, gender, BMI, randomization, CRP, history of malignancy, cardiac surgery, modified pediatric risk of mortality (PRISM) score) were considered, and in view of the potential context-specificity of disturbances in this system, (27,28), also, the upon-admission concentrations of the other lectin pathway proteins (measured in ref. (17)) were added.…”

Section: Statistical Analysesmentioning

confidence: 99%

The pattern recognition molecule collectin-L1 in critically ill children

Ingels¹,

Vanhorebeek²,

Derese³

et al. 2016

Pediatr Res

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Restoration of MBL-deficiency: Redefining the safety, efficacy and viability of MBL-substitution therapy

Cited by 37 publications

References 137 publications

Chimeric Proteins Containing MAP-1 and Functional Domains of C4b-Binding Protein Reveal Strong Complement Inhibitory Capacities

Chimeric Proteins Containing MAP-1 and Functional Domains of C4b-Binding Protein Reveal Strong Complement Inhibitory Capacities

Novel evidence that the mannan-binding lectin pathway of complement activation plays a pivotal role in triggering mobilization of hematopoietic stem/progenitor cells by activation of both the complement and coagulation cascades

The pattern recognition molecule collectin-L1 in critically ill children

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