Abstract
Mannan-binding lectin (MBL) and ficolins distinguish between self, non-self and altered-self by recognizing patterns of ligands on the surface of microorganisms or aberrant cells. When this happens MBL-associated serine protease-2 (MASP-2) is activated and cleaves complement factors to start inflammatory actions. We examined human populations for MASP-2 levels, MASP-2 function and for the presence of mutations in coding exons of MASP2. The MASP-2 levels were lowest in Africans from Zambia (median, 196 ng/ml) followed by Hong Kong Chinese (262 ng/ml), Brazilian Amerindians (290 ng/ml) and Danish Caucasians (416 ng/ml). In the Chinese population, we uncovered a novel four amino-acid tandem duplication (p.156_159dupCHNH) associated with low levels of MASP-2. The frequency of this mutation as well as the SNPs p.R99C, p.R118C, p.D120G, p.P126L and p.V377A were analyzed. The p.156_159dupCHNH was only found in Chinese (gene frequency 0.26%) and p.D120G was found only in Caucasians and Inuits from West-Greenland. The p.P126L and p.R99Q were present in Africans and Amerindians only, except for p.R99Q in one Caucasian. The MASP-2 levels were reduced in individuals with p.V377A present. The MASP-2 present in individuals homozygous for p.377A or p.99Q had a normal enzyme activity whereas MASP-2 in individuals homozygous for p.126L was non-functional.
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Abbreviations
- MBL:
-
mannan-binding lectin
- SNP:
-
single nucleotide polymorphism
- MASP-2:
-
MBL-associated serine protease-2
- g:
-
genomic
- p:
-
protein
- c:
-
cDNA
References
Hargreaves DC, Medzhitov R . Innate sensors of microbial infection. J Clin Immunol 2005; 25: 503–510.
Staros EB . Innate immunitynew approaches to understanding its clinical significance. Am J Clin Pathol 2005; 123: 305–312.
Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA . Phylogenetic perspectives in innate immunity. Science 1999; 284: 1313–1318.
Holmskov U, Thiel S, Jensenius JC . Collectins and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol 2003; 21: 547–578.
Matsushita M, Fujita T . Ficolins and the lectin complement pathway. Immunol Rev 2001; 180: 78–85.
Weis WI, Drickamer K, Hendrickson WA . Structure of a C-type mannose-binding protein complexed with an oligosaccharide. Nature 1992; 360: 127–134.
Matsushita M, Endo Y, Taira S, Sato Y, Fujita T, Ichikawa N et al. A novel human serum lectin with collagen- and fibrinogenlike domains that functions as an opsonin. J Biol Chem 1996; 271: 2448–2454.
Le Y, Lee SH, Kon OL, Lu J . Human L-ficolin: plasma levels, sugar specificity, and assignment of its lectin activity to the fibrinogen-like (FBG) domain. FEBS Lett 1998; 425: 367–370.
Krarup A, Thiel S, Hansen A, Fujita T, Jensenius JC . L-ficolin is a pattern recognition molecule specific for acetyl groups. J Biol Chem 2004; 279: 47513–47519.
Matsushita M, Fujita T . Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J Exp Med 1992; 176: 1497–1502.
Thiel S, Vorup-Jensen T, Stover CM, Schwaeble W, Laursen SB, Poulsen K et al. A second serine protease associated with mannan-binding lectin that activates complement. Nature 1997; 386: 506–510.
Dahl MR, Thiel S, Matsushita M, Fujita T, Willis AW, Christensen T et al. MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. Immunity 2001; 15: 127–135.
Sorensen R, Thiel S, Jensenius JC . Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. Springer Semin Immunopathol 2005; 27: 299–319.
Walport MJ . Complement First of two parts. N Engl J Med 2001; 344: 1058–1066.
Walport MJ . Complement second of two parts. N Engl J Med 2001; 344: 1140–1144.
Garred P, Larsen F, Seyfarth J, Fujita T, Madsen HO . Mannose-binding lectin and its genetic variants. Genes Immun 2006; 7: 85–94.
Super M, Thiel S, Lu J, Levinsky RJ, Turner MW . Association of low levels of mannan-binding protein with a common defect of opsonisation. Lancet 1989; 2: 1236–1239.
Worthley DL, Bardy PG, Mullighan CG . Mannose-binding lectin: biology and clinical implications. Intern Med J 2005; 35: 548–555.
Thiel S, Frederiksen PD, Jensenius JC . Clinical manifestations of mannan-binding lectin deficiency. Mol Immunol 2006; 43: 86–96.
Stengaard-Pedersen K, Thiel S, Gadjeva M, Moller-Kristensen M, Sorensen R, Jensen LT et al. Inherited deficiency of mannan-binding lectin-associated serine protease-2. N Engl J Med 2003; 349: 554–560.
Lozano F, Suarez B, Munoz A, Jensenius JC, Mensa J, Vives J et al. Novel MASP2 variants detected among North African and Sub-Saharan individuals. Tissue Antigens 2005; 66: 131–135.
Stover C, Endo Y, Takahashi M, Lynch NJ, Constantinescu C, Vorup-Jensen T et al. The human gene for mannan-binding lectin-associated serine protease-2 (MASP-2), the effector component of the lectin route of complement activation, is part of a tightly linked gene cluster on chromosome 1p362-3. Genes Immun 2001; 2: 119–127.
Moller-Kristensen M, Jensenius JC, Jensen L, Thielens N, Rossi V, Arlaud G et al. Levels of mannan-binding lectin-associated serine protease-2 in healthy individuals. J Immunol Methods 2003; 282: 159–167.
Carlsson M, Sjoholm AG, Eriksson L, Thiel S, Jensenius JC, Segelmark M et al. Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship. Clin Exp Immunol 2005; 139: 306–313.
Stover C, Barrett S, Lynch NJ, Barker JN, Burden D, Trembath R et al. Functional MASP2 single nucleotide polymorphism plays no role in psoriasis. Br J Dermatol 2005; 152: 1313–1315.
Cedzynski M, Szemraj J, Swierzko AS, Bak-Romaniszyn L, Banasik M, Zeman K et al. Mannan-binding lectin insufficiency in children with recurrent infections of the respiratory system. Clin Exp Immunol 2004; 136: 304–311.
Olesen HV, Jensenius JC, Steffensen R, Thiel S, Schiøtz PO . The mannan-binding lectin pathway and lung disease in cystic fibrosis – dysfunction of mannan-binding-lectin-associated serine protease 2 (MASP-2) may be a major modifier. Clin Immunol 2006; 121: 324–331.
García-Laorden MI, García-Saavedra A, Rodríguez de Castro F, Violán JS, Rajas O, Blanquer J et al. Low clinical penetrance of mannose-binding lectin–associated serine protease 2 deficiency. J Allergy Clin Immunol 2006; 118: 1383–1386.
Grunnet N, Steffensen R, Jersild C . Increased frequency of HLA-DRw14b(w6)-associated RFLP in Greenlanders of Eskimo origin. Tissue Antigen 1991; 373: 127–129.
Helgason A, Palsson G, Pedersen HS, Angulalik E, Gunnarsdottir ED, Yngvadottir B et al. mtDNA variation in Inuit populations of Greenland and Canada: migration history and population structure. Am J Phys Anthropol 2006; 130: 123–134.
Ip WK, Chan KH, Law HK, Tso GH, Kong EK, Wong WH et al. Mannose-binding lectin in severe acute respiratory syndrome coronavirus infection. J Infect Dis 2005; 191: 1697–1704.
Garred P, Madsen HO, Marquart H, Hansen TM, Sorensen SF, Petersen J et al. Two edged role of mannose binding lectin in rheumatoid arthritis: a cross sectional study. J Rheumatol 2000; 27: 26–34.
Aggarwal BB . Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003; 3: 745–756.
Wallis R, Dodd RB . Interaction of mannose-binding protein with associated serine proteases: effects of naturally occurring mutations. J Biol Chem 2000; 275: 30962–30969.
Thielens NM, Cseh S, Thiel S, Vorup-Jensen T, Rossi V, Jensenius JC et al. Interaction properties of human mannan-binding lectin (MBL)-associated serine proteases-1 and -2, MBL-associated protein 19, and MBL. J Immunol 2001; 166: 5068–5077.
Stover CM, Thiel S, Thelen M, Lynch NJ, Vorup-Jensen T, Jensenius JC et al. Two constituents of the initiation complex of the mannan-binding lectin activation pathway of complement are encoded by a single structural gene. J Immunol 1999; 162: 3481–3490.
Gregory LA, Thielens NM, Matsushita M, Sorensen R, Arlaud GJ, Fontecilla-Camps JC et al. The X-ray structure of human mannan-binding lectin-associated protein 19 (MAp19) and its interaction site with mannan-binding lectin and L-ficolin. J Biol Chem 2004; 279: 29391–29397.
Gal P, Harmat V, Kocsis A, Bian T, Barna L, Ambrus G et al. A true autoactivating enzyme Structural insight into mannose-binding lectin-associated serine protease-2 activations. J Biol Chem 2005; 280: 33435–33444.
Weg-Remers S, Brenden M, Schwarz E, Witzel K, Schneider PM, Guerra LK et al. Major histocompatibility complex (MHC) class III genetics in two Amerindian tribes from southern Brazil: the Kaingang and the Guarani. Hum Genet 1997; 100: 548–556.
Eiberg H, Nielsen IM . Linkage studies of Cholestasis familiaris Groenlandica/Byler-like disease, with polymorphic protein and blood group markers. Human Heredity 1993; 43: 250–256.
Thiel S, Møller-Kristensen M, Jensen L, Jensenius JC . Assays for the functional activity of the mannan-binding lectin pathway of complement activation. Immunobiology 2002; 205: 446–454.
Acknowledgements
We thank Dr Christine Gaboriaud, Grenoble, France for discussions on the possible structural influences of the polymorphisms. We are grateful for the excellent technical assistance from Hanne Nielsen, Annette Hansen, Louise Jakobsen and Lisbeth Jensen. This study was supported by Danish Research Council and Novo Nordic Foundation.
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ST and JCJ have financial interest in NatImmune A/S, a biotech company exploring the possibilities of therapy with proteins of the innate immune system.
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Thiel, S., Steffensen, R., Christensen, I. et al. Deficiency of mannan-binding lectin associated serine protease-2 due to missense polymorphisms. Genes Immun 8, 154–163 (2007). https://doi.org/10.1038/sj.gene.6364373
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DOI: https://doi.org/10.1038/sj.gene.6364373
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