Ficolins

Abstract

Ficolins are innate immune pattern‐recognition molecules. The name of ficolin was derived from its basic structure, consisting of a collagen‐like domain and a fibrinogen‐like domain (FBG). The FBG preferably recognises acetylated compounds. Humans have three homologous proteins: H‐ficolin (or ficolin‐3), L‐ficolin (or ficolin‐2) and M‐ficolin (or ficolin‐1). Mice have ficolin‐A and ficolin‐B, which are homologous to L‐ficolin and M‐ficolin, respectively, whereas a murine homologue of H‐ficolin is absent. Ficolin genes are germinally present and, therefore, their proteins are expressed at healthy state and are circulating in blood or localised in organs, affording an instant host protection. Ficolins are homologous to collectins structurally and functionally but has a difference in target recognition. Ficolins, like collectins, play important roles in innate immunity as activators of the lectin pathway of the complement system.

Key Concepts:

  • Ficolins are molecules of innate immunity, which is the first line of host defence mechanism and is fully functional throughout the body and life regardless of health.

  • Ficolins are similar to collectins in their structures and biologic functions with a major difference that target recognition is through fibrinogen‐like domain unlike carbohydrate recognition domain of collectins.

  • Ficolins are pattern‐recognition molecules, which are able to identify invading pathogens and abnormal cells and tissues, in addition to normal cells, which are not recognised by collectins.

  • Selected genetic mutations affect functions of ficolins and are associated with reduced host defence mechanisms.

  • Some ficolins may be a disease modifier as deficiency itself may cause no problem, whereas it may have adverse effect depending on types of disease, infection or injury.

  • Ficolins have structural and functional homology to collectins and may share and substitute functions in host defence.

Keywords: ficolin; pattern‐recognition; innate immunity; complement; inflammation

Figure 1.

Gene and protein structure of human ficolins. The exon organisation of ficolins is shown in relation to the domain structure of a single functional subunit, a trimer of ficolins. The size and distance of the exons and genes do not reflect actual sequence length.

Figure 2.

Molecular organisation of ficolins. Schematic oligomers are depicted. Detailed FBG of M‐ficolin has been analysed, although the entire molecular organisation is not yet available.

Figure 3.

Gene polymorphisms in ficolin genes. SNPs in gene sequence numbers and amino acid substitution polymorphisms in protein sequence numbers are indicated. SNPs in black, blue and red indicate no change, reduction and increase of blood levels, respectively. Fs and sp indicate flame shift and stop, respectively. Sizes of promoter, exon and intron do not reflect actual distance.

Figure 4.

Activation of complement by ficolin–MASP complex. Ficolin, which can be MBL, is loaded with MASP‐1, MASP‐2, MASP‐3, MAp44 and sMAP. It is not known that how many MASPs and MAps are associated with the ficolin. It is illustrated that MASP‐2 is able to cleave the complement factors, C2 and C4, and it may be that MASP‐1 and MASP‐3 can cleave the complement factors, B and D, leading to activation of the alternative pathway of the complement system.

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References

Ali YM, Lynch NJ, Haleem KS et al. (2012) The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection. PLoS Pathogens 8(7): e1002793.

Cedzynski M, Nuytinck L, Atkinson AP et al. (2007) Extremes of L‐ficolin concentration in children with recurrent infections are associated with single nucleotide polymorphisms in the FCN2 gene. Clinical and Experimental Immunology 150(1): 99–104.

Degn SE, Hansen AG, Steffensen R et al. (2009) MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation. Journal of Immunology 183(11): 7371–7378.

Endo Y, Matsushita M and Fujita T (2011) The role of ficolins in the lectin pathway of innate immunity. International Journal of Biochemistry and Cell Biology 43(5): 705–712.

Fujita T, Matsushita M and Endo Y (2004) The lectin‐complement pathway – its role in innate immunity and evolution. Immunological Reviews 198: 185–202.

Garlatti V, Martin L, Lacroix M et al. (2009) Structural insights into the recognition properties of human ficolins. Journal of Innate Immunity 2(1): 17–23.

Gout E, Garlatti V, Smith DF et al. (2010) Carbohydrate recognition properties of human ficolins: glycan array screening reveals the sialic acid binding specificity of M‐ficolin. Journal of Biological Chemistry 285(9): 6612–6622.

Gout E, Moriscot C, Doni A et al. (2011) M‐ficolin interacts with the long pentraxin PTX3: a novel case of cross‐talk between soluble pattern‐recognition molecules. Journal of Immunology 186(10): 5815–5822.

Gulla KC, Gupta K, Krarup A et al. (2010) Activation of mannan‐binding lectin‐associated serine proteases leads to generation of a fibrin clot. Immunology 129(4): 482–495.

Haerynck F, Van Steen K, Cattaert T et al. (2012) Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients. Human Immunology 72(11): 1175–1183.

Hoffmann JA, Kafatos FC, Janeway CA and Ezekowitz RA (1999) Phylogenetic perspectives in innate immunity. Science 284(5418): 1313–1318.

Honore C, Rorvig S, Hummelshoj T et al. (2010) Tethering of Ficolin‐1 to cell surfaces through recognition of sialic acid by the fibrinogen‐like domain. Journal of Leukocyte Biology 88(1): 145–158.

Kilpatrick DC, Chalmers JD, MacDonald SL et al. (2009) Stable bronchiectasis is associated with low serum L‐ficolin concentrations. Clinical Respiratory Journal 3(1): 29–33.

Kjaer TR, Hansen AG, Sorensen UB et al. (2011) Investigations on the pattern recognition molecule M‐ficolin: quantitative aspects of bacterial binding and leukocyte association. Journal of leukocyte biology 90(3): 425–437.

Kjaer TR, Hansen AG, Sorensen UB et al. (2012) M‐ficolin binds selectively to the capsular polysaccharides of Streptococcus pneumoniae serotypes 19B and 19C and of a S. mitis strain. Infection and immunity, in press.

Krarup A, Thiel S, Hansen A, Fujita T and Jensenius JC (2004) L‐ficolin is a pattern recognition molecule specific for acetyl groups. Journal of Biological Chemistry 279(46): 47513–47519.

Liu Y, Endo Y, Iwaki D et al. (2005) Human M‐ficolin is a secretory protein that activates the lectin complement pathway. Journal of Immunology 175(5): 3150–3156.

Ma YJ, Doni A, Hummelshoj T et al. (2009) Synergy between ficolin‐2 and pentraxin 3 boosts innate immune recognition and complement deposition. Journal of Biological Chemistry 284(41): 28263–28275.

Munthe‐Fog L, Hummelshoj T, Honore C et al. (2009) Immunodeficiency associated with FCN3 mutation and ficolin‐3 deficiency. New England Journal of Medicine 360(25): 2637–2644.

Pan Q, Chen H, Wang F et al. (2012) L‐ficolin binds to the glycoproteins hemagglutinin and neuraminidase and inhibits influenza A virus infection both in vitro and in vivo. Journal of Innate Immunity 4(3): 312–324.

Schlapbach LJ, Thiel S, Kessler U et al. (2011) Congenital H‐ficolin deficiency in premature infants with severe necrotising enterocolitis. Gut 60(10): 1438–1439.

Skjoedt MO, Hummelshoj T, Palarasah Y et al. (2010a) A novel mannose‐binding lectin/ficolin‐associated protein is highly expressed in heart and skeletal muscle tissues and inhibits complement activation. Journal of Biological Chemistry 285(11): 8234–8243.

Skjoedt MO, Palarasah Y, Munthe‐Fog L et al. (2010b) MBL‐associated serine protease‐3 circulates in high serum concentrations predominantly in complex with Ficolin‐3 and regulates Ficolin‐3 mediated complement activation. Immunobiology 215(11): 921–931.

Thiel S (2007) Complement activating soluble pattern recognition molecules with collagen‐like regions, mannan‐binding lectin, ficolins and associated proteins. Molecular Immunology 44(16): 3875–3888.

Verma A, White M, Vathipadiekal V et al. (2012) Human H‐ficolin inhibits replication of seasonal and pandemic influenza A viruses. Journal of Immunology 189(5): 2478–2487.

Wang CC, Yim KW, Poon TC et al. (2007) Innate immune response by ficolin binding in apoptotic placenta is associated with the clinical syndrome of preeclampsia. Clinical Chemistry 53(1): 42–52.

Wittenborn T, Thiel S, Jensen L et al. (2010) Characteristics and biological variations of M‐ficolin, a pattern recognition molecule, in plasma. Journal of Innate Immunity 2(2): 167–180.

Yang L, Zhang J, Ho B et al. (2011) Histidine‐mediated pH‐sensitive regulation of M‐ficolin: GlcNAc binding activity in innate immunity examined by molecular dynamics simulations. PLoS One 6(5): e19647.

Zhang J, Yang L, Anand GS et al. (2011) Pathophysiological condition changes the conformation of a flexible FBG‐related protein, switching it from pathogen‐recognition to host‐interaction. Biochimie 93(10): 1710–1719.

Zhang J, Yang L, Ang Z et al. (2010) Secreted M‐ficolin anchors onto monocyte transmembrane G protein‐coupled receptor 43 and cross talks with plasma C‐reactive protein to mediate immune signaling and regulate host defense. Journal of Immunology 185(11): 6899–6910.

Further Reading

Garred P, Honore C, Ma YJ et al. (2009) The genetics of ficolins. Journal of Innate Immunity 2(1): 3–16.

Hummelshoj T, Nissen J, Munthe‐Fog L et al. (2011) Allelic lineages of the ficolin genes (FCNs) are passed from ancestral to descendant primates. PLoS One 6(12): e28187.

Kilpatrick DC and Chalmers JD (2012) Human L‐ficolin (ficolin‐2) and its clinical significance. Journal of Biomedicine and Biotechnology 2012: 138797.

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How to Cite close
Takahashi, Kazue, and Thiel, Steffen(Jan 2013) Ficolins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021209.pub2]