Distinct Pathways of Mannan-Binding Lectin (MBL)- and C1-Complex Autoactivation Revealed by Reconstitution of MBL with Recombinant MBL-Associated Serine Protease-2

Vorup-Jensen, Thomas; Petersen, Steen V.; Hansen, Annette G.; Poulsen, Knud; Schwaeble, Wilhelm; Sim, Robert B.; Davis, Simon J.; Thiel, Steffen; Jensenius, Jens C.

doi:10.4049/jimmunol.165.4.2093

Cited by 187 publications

(131 citation statements)

References 44 publications

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“…MASP-1 and MASP-2 were found to co-elute largely with the highmolecular-mass MBL (750 kDa) on Superose 6 gel filtration [46]. Further, it was reported that MBL/MASP-2 complex, which was reconstituted between MBL and recombinant MASP-2, was eluted on gel filtration chromatography at the position corresponding to the largermolecular form of MBL [47]. Consequently, we extrapolate that MASP-2 should also be eluted in the peak 1 together with MBL/MASP-1/3 complex on gel filtration chromatography.…”

Section: Discussionmentioning

confidence: 97%

Relationship between gene polymorphisms of mannose‐binding lectin (MBL) and two molecular forms of MBL

et al. 2003

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Mannose-binding lectin (MBL) activates complement through MBL-associated serine proteases (MASP). A deficiency in MBL due to mutations at exon 1 of the human MBL gene is reported to cause vulnerability to infection. We examined sera of known MBL genotype by gel filtration and assessed their elution patterns using an ELISA for MBL and identified two MBL forms, a high-molecular-mass form and a lower-molecular-mass form. By the identification of either or both forms in individual sera, three types of patterns emerged: type 1 consisted of a high-molecular form; type 2, of a low-molecular form; and type 3, of both forms. Types 1, 2 and 3 corresponded, respectively, to a wild type (A/A), a homozygous mutation at codon 54 (B/B) and their heterozygote (A/B). One exception was a heterozygous LXPA/LYPB phenotype that exhibited the type-2 pattern. Binding to mannan and MASP-1/3 occurred exclusively with the high-molecular form. An apparent MBL deficiency does not in fact represent a deficiency in MBL molecules but rather the presence of circulating oligomeric mutant MBL with impaired function.

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Section: Discussionmentioning

confidence: 97%

Relationship between gene polymorphisms of mannose‐binding lectin (MBL) and two molecular forms of MBL

et al. 2003

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“…The MBL or any of the ficolins binds to carbohydrate structures presented by a wide range of pathogens and mediate complement activation via activation of MASP-2. MASP-2 cleaves and activates complement proteins C2 and C4, thereby generating the C3 convertase C4b2a (Vorup-Jensen et al, 2000). From this point, the complement cascade is identical to that of the classical pathway (Fig.…”

Section: Introductionmentioning

confidence: 97%

Complement genetics, deficiencies, and disease associations

Mayilyan

2012

Protein Cell

149

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The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

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“…Binding of MBL⅐MASP complexes to sugar residues present on the cell surfaces of microorganisms results in a conformational change of MBL (15,16), which activates MASP-2. Activated MASP-2 cleaves C4 and C2 resulting in the formation of C3/C5 convertases (C4b,C2a) (17)(18)(19).…”

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confidence: 99%

“…Although activation of the lectin pathway generates C3/C5 convertases similar to those generated via the classical pathway (17), C5 activation via the lectin pathway has not been examined. The classical pathway C3/C5 convertase (C4b,C2a) is bimolecular in nature and is made up of C4b as the noncatalytic subunit and C2a as the catalytic subunit.…”

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confidence: 99%

Activation of Complement Component C5

Rawal

Rajagopalan

Salvi

2008

Journal of Biological Chemistry

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Although the initiating complex of lectin pathway (called M1 in this study) generates C3/C5 convertases similar to those assembled by the initiating complex (C1) of the classical pathway, activation of complement component C5 via the lectin pathway has not been examined. In the present study kinetic analysis of lectin pathway C3/C5 convertases assembled on two surfaces (zymosan and sheep erythrocytes coated with mannan (E Man )) revealed that the convertases (ZymM1,C4b,C2a and E Man M1,C4b,C2a) exhibited a similar but weak affinity for the substrate, C5 indicated by a high K m (2.73-6.88 M). Very high affinity C5 convertases were generated when the low affinity C3/C5 convertases were allowed to deposit C3b by cleaving native C3. These C3b-containing convertases exhibited K m (0.0086 -0.0075 M) well below the normal concentration of C5 in blood (0.37 M). Although kinetic parameters, K m and k cat , of the lectin pathway C3/C5 convertases were similar to those reported for classical pathway C3/C5 convertases, studies on the ability of C4b to bind C2 indicated that every C4b deposited on zymosan or E Man was capable of forming a convertase. These findings differ from those reported for the classical pathway C3/C5 convertase, where only one of four C4b molecules deposited formed a convertase. The potential for four times more amplification via the lectin pathway than the classical pathway in the generation of C3/C5 convertases and production of pro-inflammatory products, such as C3a, C4a, and C5a, implies that activation of complement via the lectin pathway might be a more prominent contributor to the pathology of inflammatory reactions.The lectin pathway (1), a more recent discovery of complement, is activated when mannan-binding lectin (MBL), 2 a pattern-recognition molecule, binds to sugars present on the cell surface of microorganisms (2-8). In plasma, MBL circulates in complex with serine proteases called MBL-associated serine proteases (MASPs) (9 -11). We will refer to this complex as M1 in keeping with the complement nomenclature. Three types of MASPs are associated in the proenzyme form with MBL: MASP-1, MASP-2, and MASP-3. The exact function of MASP-1 and MASP-3 has yet to be determined, although MASP-1 has been shown to cleave C3 weakly (12, 13). MASP-2 has been shown to cleave C2 and C4 (12-14). Binding of MBL⅐MASP complexes to sugar residues present on the cell surfaces of microorganisms results in a conformational change of MBL (15, 16), which activates MASP-2. Activated MASP-2 cleaves C4 and C2 resulting in the formation of C3/C5 convertases (C4b,C2a) (17-19).C3/C5 convertases are enzymes that cleave C3 and C5. Products generated upon the cleavage of C3 and C5 (C3a, C3b, C5a, and C5b) have important biological activities (20). C3b, the larger cleavage product of C3, opsonizes bacteria, whereas C3a, the smaller product, is an anaphylatoxin with important functions such as chemotaxis of mast cells and contraction of smooth muscle cells (21-24). C5b, the larger cleavage product of C5, initiates formation ...

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Distinct Pathways of Mannan-Binding Lectin (MBL)- and C1-Complex Autoactivation Revealed by Reconstitution of MBL with Recombinant MBL-Associated Serine Protease-2

Cited by 187 publications

References 44 publications

Relationship between gene polymorphisms of mannose‐binding lectin (MBL) and two molecular forms of MBL

Relationship between gene polymorphisms of mannose‐binding lectin (MBL) and two molecular forms of MBL

Complement genetics, deficiencies, and disease associations

Activation of Complement Component C5

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